TAP Vol 6 Issue 12

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

How CancerLinQ™ Can Benefit People Living With CancerBy Jim Omel, MD

As regular readers of The ASCO Post know, ASCO is developing an exciting new health information

learning system called CancerLinQ™, which will expo-nentially enlarge our understanding of cancer therapy far beyond what we’ve achieved with our system of clinical trials. Cancer clinical trials have led the way to countless new therapies; without them, cancer care would never evolve. Unfortunately, clinical trials are a woefully ineffi-cient—and insufficient—source of information.

Everyone is aware of our dismal 3% adult cancer tri-als accrual rate, but it has been that tiny fraction of 3% of patients willing to participate in clinical studies that has allowed us to advance new treatments. What about the other 97% of patients treated for cancer? How can their treatment and outcomes add to our overall cancer wisdom? CancerLinQ promises to unlock the wealth of data stored in individual patient electronic health re-cords and provide us with answers.

Outcome Information Tool

CancerLinQ is not a clinical trial, but rather, an outcome information tool designed to increase our understanding of cancer and its treatment and im-prove patient outcomes.

ASCO Plenary Report

Biosimilars are biologic drugs that are similar to an already established “refer-

ence” or “innovator” biologic drug product and can be manufactured when an original biologic drug product’s patent expires. Refer-ence to the innovator product is an integral component of approval for a biosimilar. The U.S. Food and Drug Administration (FDA) requires licensed biosimilar and interchange-able biologic products to meet the agency’s rigorous standards of safety and efficacy.

Biosimilars: Questions Remain

By Richard J. Boxer, MD, FACS

Oncology Meetings CoverageASCO Annual Meeting ��1, 3–9, 12–14American Society of Gene and Cell Therapy Annual Meeting �� 15–18National Cancer Policy Forum ��21–22

Leonard Saltz, MD, on Value in Cancer Care ��14Direct From ASCO �� 34, 36–37Integrative Medicine �� 40–41Women in Oncology: Clara Bloomfield, MD, FASCO �� 50–51In Memoriam �� 54–55, 74

MORE IN THIS ISSUE

continued on page 48

Health Information Technology

Survivors of Childhood Cancer Living Longer, Largely Due to Treatment ImprovementsBy Caroline Helwick

Survivors of childhood cancers can expect longer lives than their peers of 30 years ago. Improve-

ments in the care of children with cancer have re-duced the long-term mortality rate, according to an analysis of 34,000 participants in the Childhood Cancer Survivor Study.1

Cumulative all-cause late mortality at 15 years dropped from 10.7% in the 1970s to 7.9% in the 1980s and to 5.8% in the 1990s, according to Gregory T. Armstrong, MD, a pediatric oncologist at St. Jude Children’s Re-search Hospital, Memphis,

who shared the good news at the 2015 ASCO Annual Meeting Plenary Session.

“The improvement in the cure rate for childhood cancers is one of the success stories of modern medi-

cine; however, these indi-viduals are still at risk for late effects and mortality. The punch line of this sto-ry is that deaths due to late effects and other health-re-lated causes have dropped,” Dr. Armstrong said at a press briefing during the Annual Meeting.

“Survivors in more recent eras have a significant re-duction in late mortality attributable to fewer deaths from treatment-related causes, including subsequent ma-lignancies and cardiac deaths,” he noted. “The strategy of reducing the intensity of therapy to lower the occurrence of late effects—along with the promotion of early detec-tion and improved treatment of late effects—has now translated to extend the life span of survivors.”

Gregory T. Armstrong, MD

ASCO 2015 News 1, 3–9, 12–14 | Value in Cancer Care 14 | Checkpoint Inhibitors in NSCLC 30, 31 VOLUME 6, ISSUE 12JULY 10, 2015

continued on page 9


CancerLinQ promises to unlock the wealth of data stored in individual patient electronic health records and provide us with answers.

—Jim Omel, MD

Dr. Boxer is Visiting Professor of Urology and Schol-ar in Residence (Business of Science Center) at the David Geffen School of Medicine at UCLA. He is also Professor of Clinical Urology at the University of Wisconsin–Madison.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

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Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

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Lee S. Schwartzberg, MD University of Tennessee Health Science Center

Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center

Samuel Silver, MD, PhD University of Michigan Health System

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William C. Wood, MD Winship Cancer Institute, Emory University

International EditorsClement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

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Nagi El-Saghir, MD American University of Beirut, Lebanon

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk, Poland

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Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

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ASCOPost.com | JULY 10, 2015 PAGE 3

ASCO Annual Meeting

Ado-Trastuzumab Emtansine Fails to Replace Standard of Care in First-Line Metastatic Breast CancerBy Caroline Helwick

R esults are now in for the phase III MARIANNE trial. Although

ado-trastuzumab emtansine (formerly known as T-DM1, Kadcyla) proved noninferior to trastuzumab (Herceptin) plus a taxane in the first-line metastatic breast cancer setting, it performed no better than the standard of care.1

“T-DM1 and T-DM1 plus pertu-zumab demonstrated a noninferior progression-free survival compared to trastuzumab/taxane, but they were not found to be superior to it,” said Paul Ellis, MD, of Guy’s Hospital and Sarah Cannon Research Institute, Lon-don, presenting the results at the 2015

ASCO Annual Meeting.Ado-trastuzumab emtansine was

better tolerated, in some respects, and maintained health-related quality of life longer. Therefore, Dr. Ellis maintained that it is “an alternative treatment option to trastuzumab/taxane in previously un-treated HER2-positive patients.”

MARIANNE RationaleWhen MARIANNE was designed in

2009, trastuzumab in combination with a taxane was “far and away the com-monest standard of care” in patients with untreated HER2-positive meta-static breast cancer, Dr. Ellis noted.

Ado-trastuzumab emtansine had

shown strong activity in phase II studies in treated and untreated disease, with a favorable safety profile. A subsequent randomized phase II study comparing ado-trastuzumab emtansine against trastuzumab in combination with a taxane in untreated patients showed encouraging efficacy and excellent tol-erability.2 Furthermore, the combina-tion of ado-trastuzumab emtansine and pertuzumab (Perjeta) had demonstrat-ed preclinical synergy and activity in a phase Ib/II study.3

These findings led to the interna-tional randomized MARIANNE trial, which enrolled 1,095 previously un-treated patients with locally advanced or metastatic breast cancer. It evaluated three arms: trastuzumab plus docetaxel or paclitaxel (physician’s choice; trastu-zumab/taxane); ado-trastuzumab em-tansine plus placebo; and ado-trastu-zumab emtansine plus pertuzumab.

The primary endpoint was assess-ment of progression-free survival by in-dependent review, with determinations of both noninferiority and superiority. There were independent comparisons

between ado-trastuzumab emtansine vs trastuzumab in combination with a tax-ane and ado-trastuzumab emtansine/pertuzumab vs trastuzumab in combi-nation with a taxane.

Noninferiority DemonstratedMedian progression-free survival

was 13.7 months with trastuzumab in combination with a taxane compared with 14.1 months for ado-trastuzumab emtansine (hazard ratio [HR] = 0.91, P = .31) and 15.2 months for ado-trastuzumab emtansine/pertuzumab (HR = 0.87, P = .14). This outcome met the noninferiority boundary.

By prestratified subgroups, no sig-nificant differential effects were ob-served. However, numerical trends favoring ado-trastuzumab emtansine were observed among patients who had received adjuvant taxanes and HER2-directed therapy (HR = 0.75) or any prior taxane (HR = 0.69).

At this first interim analysis, Dr. Ellis noted that the overall survival curves “essentially overlapped,” and median

T-DM1 and T-DM1 plus pertuzumab demonstrated a noninferior progression-free survival compared to trastuzumab/taxane, but they were not found to be superior to it.

—Paul Ellis, MD

Breast Cancer

EXPERT POINT OF VIEW

Study discussant Shanu Modi, MD, of Memorial Sloan Ketter-

ing Cancer Center, New York, com-mented, “Neither T-DM1 [Kadcyla] nor T-DM1 plus pertuzumab [Perjeta] proved to be superior to the old stan-dard of care, taxane plus trastuzumab [Herceptin]. MARIANNE was a val-iant trial, but THP (taxane, trastu-zumab, and pertuzumab) remains our first-line standard of care, with T-DM1 a preferred second-line option.”

Dr. Modi emphasized that toxicity and health-related quality of life did appear more favorable with the ado-trastuzumab emtansine–containing regimens. In particular, rates of grade 3/4 neutropenia, febrile neutropenia, and diarrhea were lower in these arms, as was the occurrence of alopecia, and patient-reported outcomes remained positive for much longer. “It would be very informative to reassess these tox-icities based on the taxane delivered,” she offered, “knowing that weekly pa-clitaxel has a very low febrile neutro-

penia rate and may be the preferred partner.”

She also questioned why pertu-zumab provided no additional benefit, since in CLEOPATRA, the addition of this drug greatly improved survival, compared with an HT (trastuzumab [Herceptin] and taxane) arm.1 The role of pertuzumab in adjuvant breast cancer is being explored further in the phase III APHINITY trial, she added.

Assessing the future for ado-trastu-zumab emtansine, Dr. Modi suggest-ed, “Given no progression-free sur-

vival advantage for T-DM1 or T-DM1 plus pertuzumab in the first-line meta-

static setting, it is unlikely to show a survival advantage in the early-stage setting (neoadjuvant or adjuvant).” A number of adjuvant trials, however, are currently testing its potential in early-stage patients.

Unanswered QuestionsRegarding the treatment of HER2-

positive advanced breast cancer in general, Dr. Modi said a number of questions remain unanswered: What

is the value of combining therapies? Is there an optimal combination? Does every case warrant multiple targeted agents? Can we avoid chemotherapy for some patients? What is the ideal trial setting for evaluating these treat-ments, and what are the right end-points in these trials?

Based on current evidence, she concluded, “For the time being, tax-ane/trastuzumab/pertuzumab re-mains our preferred first-line therapy for HER2-positive metastatic breast cancer, and our treatment guidelines for 2015 remain unchanged.” n

Disclosure: Dr. Modi reported no potential conflicts of interest.

Reference1. Swain SM, Kim SB, Cortés J, et al:

Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast can-cer (CLEOPATRA study): Overall sur-vival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461-471, 2013.

MARIANNE was a valiant trial, but THP (taxane, trastuzumab, and pertuzumab) remains our first-line standard of care, with T-DM1 a preferred second-line option.

—Shanu Modi, MD

continued on page 4


ASCO Annual Meeting

Anastrozole and Tamoxifen: Both Options for Ductal Carcinoma in SituBy Alice Goodman

Anastrozole was found to be at least as safe and effective as tamoxifen

in preventing breast cancer recur-rence in women with ductal carcino-ma in situ, in the large NSABP B-35/

SWOG-35 study.1 Among all women in the trial, however, the 10-year breast cancer–free interval rates were higher in women taking anastrozole than tamoxifen (93.5% vs 89.2%).

This is the first study to compare an aromatase inhibitor vs tamoxifen in ductal carcinoma in situ, the earli-est form of breast cancer sometimes considered precancer. Breast cancer–related death is uncommon in women

treated with lumpectomy and radia-tion for ductal carcinoma in situ, like the women in this study. Other studies have compared the two drugs in more invasive forms of cancer.

“The good news is tamoxifen and an-astrozole are both very effective, but it seems that women have better chances of staying well with anastrozole. Women will need to discuss the risks and benefits of both drugs with their doctors, because the side-effect profiles differ,” said lead author Richard G. Margolese, MD, Professor of Surgical Oncology, Jewish General Hospital, McGill University, Montreal, Canada.

He emphasized that adverse events are uncommon with these drugs—from 1% to 3% of all women treated. “Depending on the drug, the side effects are different. It is a personal choice that a woman should make with her physician about the relative bene-fits of a reduced chance of recurrence, with respect to the differing safety pro-files,” Dr. Margolese commented at a press conference.

Other experts at the 2015 ASCO Annual Meeting, where these data were presented, were quick to note that this study expands the options for treatment of ductal carcinoma in situ and does not represent one standard of care.

Study DetailsThe study randomized 3,104 post-

menopausal women with hormone receptor–positive ductal carcinoma in situ to treatment with 5 years of daily tamoxifen or anastrozole. Prior to ran-domization, all women had been treat-ed with lumpectomy and radiation and were stratified by age: < 60 years vs ≥ 60 years.

At an average follow-up of 8.6 years,

114 cancers were identified in the tamoxifen group vs 84 in the anastro-zole group. The 10-year breast cancer–free rates by age were similar in older women: 92.2% for anastrozole vs 88.2% for tamoxifen. There was a larger differ-ence among younger women: 94.9% with anastrozole vs 88.2% with tamoxi-fen, but this difference was not explain-able by body mass index, death due to other causes, or compliance. “We are still looking for other reasons [for this difference],” Dr. Margolese said. “It is a stimulus for further research.”

Overall, there was a 45% relative risk reduction for invasive recurrences with anastrozole, he continued. The number of recurrences was 60 in the tamoxifen group vs 30 in the anastrozole group. The numbers of recurrent ipsilateral or contralateral ductal carcinoma in situ cases were relatively small and not sta-tistically significant between the two treatment arms, but the number of con-tralateral invasive cancers was signifi-cantly reduced in the anastrozole arm.

There were eight deaths due to breast cancer in the tamoxifen group and five deaths in the anastrozole group.

overall survival has not been reached in any arm. Events were recorded in 123 patients in the control arm, 115 in the ado-trastuzumab emtansine arm, and 115 in the ado-trastuzumab emtansine/pertuzumab arm.

Objective responses were low-est with ado-trastuzumab emtansine (59.7%), compared with trastuzumab in combination with a taxane (67.9%) and ado-trastuzumab emtansine/pertu-zumab (64.2%). However, patients who responded to ado-trastuzumab emtan-sine (either arm) had a much longer duration of response: 20.7 months with

ado-trastuzumab emtansine and 21.2 months with ado-trastuzumab emtan-sine/pertuzumab, compared with 12.5 months with trastuzumab in combina-tion with a taxane.

Quality-of-Life BenefitsAccording to the Functional Assess-

ment of Cancer Therapy–Breast Trial Outcome Index, health-related quality of life (a secondary endpoint) was also maintained longer in ado-trastuzumab emtansine–containing arms. The me-dian time to a clinically meaningful de-crease from baseline (≥ 5 points) was

just 3.6 months for the control arm, vs 7.7 months with ado-trastuzumab emtansine and 9.0 months with ado-trastuzumab emtansine/pertuzumab.

“This suggests that health-related quality of life was prolonged in patients treated with T-DM1,” Dr. Ellis suggested.

Ado-trastuzumab emtansine was tol-erated as well as—and in some respects better than—the control arm. Grade ≥ 3 adverse events were observed in 54.1% of the trastuzumab in combina-tion with a taxane cohort, 45.4% of the ado-trastuzumab emtansine arm and 46.2% of the ado-trastuzumab emtan-sine/pertuzumab arm. Adverse events leading to discontinuation of any treat-ment component occurred in 29.7%, 18.3%, and 19.1%, respectively.

Grade ≥ 3 neutropenia, febrile neu-tropenia, and diarrhea were much more common with trastuzumab in combi-nation with a taxane than with either ado-trastuzumab emtansine regimen, whereas hypertension, anemia, throm-bocytopenia, and liver enzyme eleva-tions were greater in the ado-trastuzum-ab emtansine arms. Pertuzumab did not

“dramatically” add to these toxicities, but the drug did increase diarrhea. Alo-pecia was rare with ado-trastuzumab emtansine, Dr. Ellis noted. n

Disclosure: Dr. Ellis has received travel, accommodations, and expenses from Roche Pharma AG.

References1. Ellis PA, Barrios CH, Eiermann W, et

al: Phase III, randomized study of trastu-zumab emtansine ± pertuzumab vs trastu-zumab + taxane for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. 2015 ASCO An-nual Meeting. Abstract 507. Presented June 1, 2015.

2. Hurvitz SA, Dirix L, Kocsis J, et al: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetax-el in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31:1157-1163, 2013.

3. Miller KD, Diéras V, Harbeck N, et al: Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-posi-tive, locally advanced, or metastatic breast cancer. J Clin Oncol 32:1437-1444, 2014.

Ado-Trastuzumab Emtansinecontinued from page 3

Ado-Trastuzumab Emtansine in Metastatic Breast Cancer

■ The international phase III MARIANNE trial compared ado-trastuzumab emtansine and ado-trastuzumab emtansine plus pertuzumab with trastuzumab plus a taxane in patients with advanced or metastatic breast cancer.

■ The trial proved noninferiority for the ado-trastuzumab emtansine arms, but they were not superior to the standard of care.

■ Toxicity and health-related quality of life were overall better in the ado-trastuzumab emtansine arms than in the control arm.

It [tamoxifen or anastrozole] is a personal choice that a woman should make with her physician about the relative benefits of a reduced chance of recurrence, with respect to the differing safety profiles.”

—Richard G. Margolese, MD

Breast Cancer

continued on page 5


ASCO Annual Meeting


“This is an important study. We’ve known for some time that the

aromatase inhibitors tend to be better than tamoxifen for postmenopausal women with hormonally sensitive inva-sive breast cancer. The NSABP B-35 trial asked the same question in ductal carci-noma in situ. These data, which now fol-low patients for a mean of 8.6 years, sug-gest that anastrozole may be better than tamoxifen in preinvasive disease when looking at breast cancer–free interval, particularly in younger postmenopausal women,” said Anees B. Chagpar, MD, Director, The Breast Center, Smilow

Cancer Hospital, Yale University School of Medicine, New Haven.

Dr. Chagpar pointed out that the data show that aromatase inhibitors were sim-ilar to tamoxifen across most endpoints,

with the exception of contralateral in-vasive cancers. “This would fit with the concept that perhaps there is a chemo-preventive effect in this setting,” she said.

“The side-effect profiles of the two agents are different, and although the authors were not able to show significant differences for many of the categories of symptoms they evaluated, at least these data provide us with another potential agent in our tool box for patients with hormone receptor–positive ductal carci-noma in situ,” Dr. Chagpar commented.

She said that some “intriguing” ques-tions remain: “Why do younger wom-

en benefit more from anastrozole? It doesn’t seem to be related to body mass index or compliance, according to the authors who struggled with this ques-tion as well,” Dr. Chagpar continued.

She remains unconvinced of the clear superiority of anastrozole over tamoxifen or vice versa. “Particularly with a low event rate, I think it is safe to say that anastrozole is at least equiva-lent to tamoxifen in this setting. It re-ally should be a conversation a woman has with her doctor,” she concluded. n

Disclosure: Dr. Chagpar reported no potential conflicts of interest.

As for expected side effects, there was a slight increase in the cases of uterine cancers with tamoxifen vs anastrozole: 17 cases vs 8 cases. The average annual rate of the number of new osteoporotic fractures per 1,000 women was increased in women re-ceiving anastrozole (69 vs 50 events), but this difference was not statisti-cally significant.

“Severe adverse events were un-common in general and less common with anastrozole. Events of concern with tamoxifen are thromboembolism and uterine cancer,” he said.

Dr. Margolese did not report in de-

tail on quality of life and other side ef-fects in the trial, including arthralgias and myalgias, which are commonly ex-perienced by women taking aromatase inhibitors. He said a separate analysis of these events would be reported in the future.

Additional Comments“In my view, this does not set a

single standard of care for all women with ductal carcinoma in situ,” said ASCO expert Don S. Dizon, MD, Clinical Co-Director of Gynecologic Oncology, Massachusetts General Hospital Cancer Center, Boston. “The main take-away point is that we now have a new breast cancer preven-

tion option for women treated with ductal carcinoma in situ.”

“Until now, the only option for adju-vant medical treatment of ductal carcino-ma in situ was tamoxifen. The availability of both drugs means there are choices, and we can individualize therapy,” Dr. Dizon stated at a press conference.

“Patients will make this choice de-pending on what motivates them. For some women with ductal carcinoma in situ, the main fear is recurrence. For oth-ers, the fear of toxicity is more impor-tant,” Dr. Dizon noted.

The formal discussant of this trial, Joseph Sparano, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, New York, said:

“Anastrozole and probably other aroma-tase inhibitors are a good option for pre-venting ipsilateral recurrence and con-tralateral breast cancers in women with ductal carcinoma in situ. Anastrozole is probably more suitable for younger patients who are postmenopausal and have a history of thromboembolism.” n

Disclosure: The study was funded by the National Institutes of Health. Drs. Margolese and Sparano reported no potential conflicts of interest.

Reference1. Margolese RG, Cecchini RS, Julian

TB, et al: Primary results, NRG Oncol-ogy/NSABP B-35. 2015 ASCO Annual Meeting. Abstract LBA500. Presented May 30, 2015.

Anees B. Chagpar, MD

Anastrozole and Tamoxifencontinued from page 4

Lenvatinib/Everolimus: Robust Combination in Metastatic Renal Cell CarcinomaBy Alice Goodman

The combination of lenvatinib (Len-vima) plus everolimus (Afinitor)

significantly extended progression-free survival compared with everolimus alone

in metastatic renal cell carcinoma, ac-cording to a randomized phase II trial.1 Median progression-free survival for pa-tients who received the combination was 14.6 months, significantly longer than 5.5 months for everolimus alone (P < .001),

which is currently a National Comprehen-sive Cancer Network–recommended sec-ond-line therapy for unresectable or ad-vanced or metastatic renal cell carcinoma.

“The combination of lenvatinib and everolimus was superior to everolimus in previously treated metastatic renal cell carcinoma patients. Progression-free sur-vival was longer—and response rates were higher—with the combination, and study results suggest that the combination will have a survival benefit over everolimus. This speaks to the high level of efficacy for the combination in this study. Further study of the combination of lenvatinib and everolimus is warranted,” said lead author Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

Targeted therapy with a tyrosine ki-nase inhibitor is the current standard of

Robert Motzer, MD

continued on page 6


“This combination [lenva-tinib and everolimus] is a

potential game-changer in metastat-ic renal cell carcinoma. We’ve stud-ied other combinations to no avail; for example, bevacizumab [Avas-tin] plus everolimus had no advan-tage over everolimus alone. Other combinations are too toxic, such as sunitinib plus bevacizumab. These results are potentially exciting. We have no other approved combina-tions in metastatic renal cell carci-noma,” said Sumanta K. Pal, MD, Researcher and Co-Director, Kid-ney Cancer Program, City of Hope, Duarte, California.

“Typically, we expect pro-gression-free survival of around 5 months, and the combination achieved median progression-free survival approaching 15 months. These are encouraging results and

Sumanta K. Pal, MD

continued on page 6


ASCO Annual Meeting

the best margin of improvement we have seen within the confines of a randomized controlled trial in pretreated patients,” he added.

The toxicities need to be bet-ter characterized, he continued, but they are acceptable for mov-ing to a phase III trial. A phase III trial is being considered, but the design is yet undetermined.

Dr. Pal commented that with this combination, as with all new drugs in oncology, it is important to determine the relevant targets and identify biomarkers to estab-lish which groups of patients will preferentially benefit. n

Disclosure: Dr. Pal has received consulting fees from Pfizer, Novartis, and Genentech.

Genitourinary Cancer

care for metastatic renal cell carcinoma. Lenvatinib, a new, powerful tyrosine ki-nase inhibitor, has potent selectivity and a binding mode that differs from that of other tyrosine kinase inhibitors. Len-vatinib simultaneously inhibits vascu-lar endothelial growth factor receptors (VEGFR-1, -2, -3), fibroblast growth factor receptors (FGFR 1-4), RET, KIT, and platelet-derived growth factor recep-tors (PDGFR), and it is the first tyrosine kinase inhibitor to have these properties.

Lenvatinib is currently approved in the United States for the treatment of refractory differentiated thyroid cancer. Currently, no combination therapy has been approved for metastatic renal cell carcinoma anywhere in the world.

Study DetailsBetween March 2012 and July 2013,

the international, prospective, open-label, phase II study randomized 153 patients with metastatic renal cell carcinoma who progressed on one prior VEGF-targeted therapy to receive lenvatinib, everolimus, or the combination of both drugs. Pa-tients were treated until progressive dis-ease or unacceptable toxicity.

All patients had measurable dis-ease and disease progression within 9 months of stopping their prior therapy. No crossover was allowed in the trial.

At the 2015 ASCO Annual Meeting, Dr. Motzer presented an updated overall survival analysis up to December 2014.

“Patients enrolled in the trial were typical metastatic renal cell carcinoma pretreated patients balanced for Memo-

rial Sloan Kettering risk factors. All pa-tients had prior VEGF treatment, most commonly with sunitinib followed by pazopanib [Votrient],” Dr. Motzer said.

Median progression-free survival was 14.6 months with the combina-tion, 7.4 months with lenvatinib alone, and 5.5 months with everolimus alone,

representing a 60% reduction in dis-ease progression favoring the com-bination over everolimus and a 39% reduction in disease progression favor-ing lenvatinib alone over everolimus.

The highest overall response rates were observed with the combination: 43%, fol-lowed by 27% with lenvatinib alone and

6% with everolimus alone. The median duration of response was 13.1 months for the combination therapy arm.

“At the time of data cutoff, a trend was observed favoring the combina-tion for overall survival,” Dr. Motzer said. Median overall survival was 25.5 months for the combination, 18.4

Lenvatinib/Everolimuscontinued from page 5

Sumanta K. Pal, MDcontinued from page 5


ASCO Annual Meeting

months for lenvatinib alone, and 17.5 months for everolimus alone. The updated overall survival analysis in December 2014 showed a significant difference favoring the combination over everolimus alone (P = .024).

All patients had at least one treat-ment-emergent adverse event. Adverse

events were more frequent in the combi-nation therapy arm but were manageable with dose reduction, Dr. Motzer said.

Lenvatinib was associated with more grade 3 diarrhea, fatigue, nau-sea, and vomiting. The most common treatment-related grade 3 or higher adverse events were diarrhea, hyper-

tension, and fatigue. Relatively few grade 4 adverse events were reported with the combination treatment. There were two grade 5 events, one in each of the lenvatinib-containing arms. n

Disclosure: Dr. Motzer is a consultant for Pfizer; has received research funding (institutional) from Bristol-Myers Squibb, Eisai,

Genentech/Roche, GlaxoSmithKline, Novartis, and Pfizer; and travel expenses from Bristol-Myers Squibb and GlaxoSmithKline.

Reference1. Motzer R, et al: 2015 ASCO Annual

Meeting. Abstract 4506. Presented June 1, 2015.

http://www.neulastahcp.com/characteristics/neulasta-delivery-kit/


ASCO Annual Meeting

UAB Study on Lay Navigation Program Shows Trend Toward Cost Savings

Researchers from the University of Alabama (UAB) at Birmingham pre-

sented preliminary findings of an observa-tional study indicating a rapid decline in Medicare costs and patient resource utili-zation during implementation of a lay nav-

igation program. The study was presented at this year’s ASCO Annual Meeting.1

In 2012, the UAB Comprehensive Cancer Center created the Patient Care Connect Program, a lay patient navi-gation initiative with the support of a

$15 million Health Care Innovation Challenge Grant Award from the Cen-ters for Medicare and Medicaid Innova-tion. The Patient Care Connect Program was designed to pair a trained nonclinical lay navigator with a patient with cancer

to help him through his cancer journey. “The goals of the program are to re-

duce unnecessary emergency room visits and inpatient intensive care unit days, en-courage evidence-based clinical pathways, adopt earlier use of hospice care, reduce use of chemotherapy in the last 2 weeks of life, and provide the highest quality of life for people diagnosed with cancer,” said Edward Partridge, MD, Director of the UAB Comprehensive Cancer Center and Principal Investigator of the Study.

“Our trained navigators help address the barriers patients often have with identifying resources for their care and empower them to recognize clinical symptoms, become more knowledge-able about their disease and treatment, and when necessary engage in end-of-life discussion with their providers,” said Gabrielle Rocque, MD, Assistant Pro-fessor in the UAB Division of Hematol-ogy and Oncology and Medical Director of the Patient Care Connect Program.

About the StudyResearchers examined 30,589 Medi-

care patients receiving cancer care across the Network from January 1, 2012 through December 31, 2014. The study evaluated health-care utilization with hospitalizations, emergency department visits, intensive care admissions, and hos-pice admissions for all eligible Medicare patients. In addition, during implementa-tion, the study analyzed the cost to Medi-care for the overall medical care.

The results of the study indicate a dra-matic trend toward a clinically significant reduction in health-care utilization and Medicare costs, with substantial impact during initial phase, survivorship, and the last 6 months of life.

“Certainly this study has its limita-tions in that some of these trends cannot be fully attributed to the Patient Care Connect Program,” Dr. Rocque noted.

Disclaimer: Drs. Partridge and Rocque reported no potential conflicts of interest.

Reference1. Rocque GB, et al: ASCO Annual Meet-

ing. Abstract 6502. Presented May 29, 2015.

Edward Partridge, MD


ASCO Annual Meeting

Study DetailsThe federally funded Childhood Can-

cer Survivor Study evaluated long-term health outcomes in 5-year sur-vivors of child-hood cancer (leukemia, lym-phoma, central nervous system mal ignanc ies ,

Wilms tumor, neuroblastoma, as well as soft-tissue and bone sarcomas). Sub-jects from 31 participating centers were diagnosed between 1970 and 1999 and followed for an average of 21 years after diagnosis. During the study period, 12% of patients died, and 41% of these deaths were from causes other than their cancer, including other health-related conditions as well as late effects of cancer therapy.

Some of the details presented by Dr. Armstrong at the Annual Meeting follow:• Over the 30-year period, all-cause mor-

tality 15 years from diagnosis dropped from 10.7% to 5.8% (P < .001).

• Mortality due to recurrence or progression of the primary cancer dropped from 7.1% to 3.4% (P < .001).

• Late mortality due to specific child-hood cancers significantly decreased.

This included a reduction from 2.8% to 1.9% (P < .001) for acute lympho-blastic leukemia (ALL); from 4.2% to 2.1% for Hodgkin lymphoma (P = .02); and from 2.2% to 0.4% for Wilms tumor (P < .001).

• The cumulative incidence of deaths from health-related causes not related to recurrences (but potentially relat-ed to late effects) dropped from 3.5% to 2.1% (P < .001).

• The incidence of deaths from subse-quent neoplasms dropped from 1.8% to 1.0% (P < .001); cardiac-related deaths dropped from 0.5% to 0.1% (P = .001); and lung-related deaths dropped from 0.5% to 0.1% (P = .4).

Improvements From Treatment Modifications

These results have been driven by treatment refinements in the clinic, es-pecially a reduction in the intensity of treatment for patients with favorable prognoses. Risk stratification, reserving

the most intensive regimens for the high-est risk patients, has included the elimi-nation of cranial radiotherapy in many patients with ALL; response-based therapy—reduced dose or no radiation at all—for many patients with Hodgkin lymphoma; and reduced radiotherapy dose/volume and reduced anthracycline exposure in the treatment of localized Wilms tumor, he noted.

For example, cranial radiotherapy was

delivered to 85% of pediatric patients with ALL in the 1970s, but it is given to 19% or fewer today. In the 1970s, 78% of patients with Wilms tumor received abdominal radiotherapy, compared with 43% today. Similar trends are seen for an-thracycline exposure.

“Additionally, there have been im-provements in screening and early de-tection of late effects, treatment of late effects, and supportive care,” Dr. Arm-strong noted. n

Disclosure: Dr. Armstrong reported no potential conflicts of interest.

Reference1. Armstrong GT, Yasui Y, Chen Y,

et al: Reduction in late mortality among 5-year survivors of childhood cancer: A re-port from the Childhood Cancer Survivor Study. 2015 ASCO Annual Meeting. Ab-stract LBA2. Presented May 31, 2015.

Childhood Cancer Survivorscontinued from page 1

The improvement in the cure rate for childhood cancers is one of the success

stories of modern medicine. —Gregory T. Armstrong, MD


“W e have had remarkable suc-cess in treating patients

with cancer. Millions of survivors are a testament to this success. But the ‘cost of cure’ borne by our patients is sub-stantial in terms of diminished qual-ity and quantity of life,” commented the formal discussant of the study Michael P. Link, MD, Lydia J. Lee Professor in Pediatric Cancer, Stan-ford University School of Medicine.

Dr. Link applauded the investiga-tors of the Childhood Cancer Survi-vor Study for imparting another “im-portant lesson learned from pediatric oncology.” He noted, “There is good news here for children with cancer,

but many of the lessons are applicable to all our patients.”

“ASCO Plenary Sessions usually focus on exciting new therapies that have the prospect of adding incre-mentally to our goal curing cancer. Dr. Armstrong’s presentation allows us to examine another important aspect of cancer care: survivorship,” he said. “It reminds us that cumulative advances have translated into a growing popula-tion of cancer survivors, who are the beneficiaries of our past efforts.”

Consequences of CuresSince 1990, deaths from cancer in

the United States have dropped 22% and patients surviving cancer are liv-ing longer. Children and young adults cured of cancer have a lifetime ahead of them during which to develop the potential health-related side effects of the therapies that cured them and to suffer their consequences.

Nearly two-thirds of long-term childhood cancer survivors have at least one chronic condition, and in more than one-fourth of cases, it is

severe or life-threatening. “We accept this collateral damage, much like we accept that civilian deaths are the re-grettable price of winning a war,” Dr. Link commented.

Launched in 1994, the Childhood Cancer Survivor Study has been instru-mental in identifying these late effects through a retrospective cohort study. More than 250 peer-reviewed manu-scripts and other publications hare “catalogued the price of cure,” he said.

The study has documented that survivors of childhood cancers, com-pared with national age-adjusted co-horts, have 10-fold excess mortality and 6.4-fold excess second cancers. In addition, these survivors are at in-creased risk of cardiac, pulmonary, and endocrine diseases, as well as obe-sity and psychosocial issues.1

Refining TherapiesChallenged with finding ways to

reduce these late effects and improve the quality of life of survivors, pedi-atric oncologists adjusted treatment protocols that would reduce the inten-

sity of treatments for select, good-risk patients. The aim has been to retain the treatment components believed necessary for cure while eliminating those contributing only toxicity.

“The question remained: Did these modifications actually move the nee-dle on the cost of cure? The good news here,” he said, “is there is a statistically and clinically significant decrease over time in all-cause mortality, nonrecur-rence mortality, and mortality related to second malignancies and cardiac and pulmonary disease.”

Dr. Armstrong’s study, he continued, “is a gratifying validation of 3 decades of refining therapies to accomplish cures while lowering the cost of cure.”

Treatment stratification will con-tinue to be refined, based on a grow-ing understanding of host and tumor genetics. Meanwhile, he said, oncolo-gists have an obligation to continue to refine therapies to balance efficacy against toxicity. “Cure,” Dr. Link em-phasized, “is not enough.” n

Disclosure: Dr. Link reported no potential conflicts of interest.

Michael P. Link, MD

Plenary Session

Results of the Childhood Cancer Survivor Study

■ The Childhood Cancer Survivor Study has been evaluating outcomes in 5-year survivors of childhood cancers since 1994.

■ Over the 30-year period, all-cause mortality 15 years from diagnosis dropped from 12.4% to 6.0% (P < .001).

■ Mortality due to recurrence or progression of the primary cancer dropped from 7.1% to 3.4%, and the cumulative incidence of deaths from health-related causes not related to recurrences (but potentially related to late effects) dropped from 3.5% to 2.1% (both P < .001).

■ The improvements largely stem from reductions in radiation and anthracycline exposure.

An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a signifi cant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3

Do residual disease and immune dysfunction form a cycle that complicates our strategies?

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, ~100 MILLION MYELOMA CELLS MAY REMAIN.4

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNESYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14

References:1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick refl ection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-refl ection-on-the-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:3073-3079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print]. 15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE

IN MULTIPLE MYELOMA

© 2015 Celgene Corporation 03/15 US-CELG140284c

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16

C M Y KCosmos Communications 1

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https://www.celgene.com/

An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a signifi cant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3

Do residual disease and immune dysfunction form a cycle that complicates our strategies?

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, ~100 MILLION MYELOMA CELLS MAY REMAIN.4

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNESYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14

References:1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick refl ection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-refl ection-on-the-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:3073-3079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print]. 15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE

IN MULTIPLE MYELOMA

© 2015 Celgene Corporation 03/15 US-CELG140284c

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16


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ASCO Annual Meeting

Pacritinib for Myelofibrosis: Effective in Patients With ThrombocytopeniaBy Caroline Helwick

An emerging JAK inhibitor, pacri-tinib, appears not only effective in

a broad population of patients with my-elofibrosis but also among a subset with very low platelet counts, investigators from the global phase III PERSIST-1 trial reported at the 2015 ASCO An-nual Meeting.1

“There is a huge unmet clinical need for patients with myelofibrosis,” said Ruben A. Mesa, MD, Deputy Direc-tor of the Mayo Clinic Cancer Center, Scottsdale, Arizona. “Symptoms of my-elofibrosis have a substantial negative impact on both patient quality of life and overall survival.”

This need is especially felt among patients with very low platelet counts (< 50,000/µL), who tend to have shorter survival and are at increased risk for leu-kemic transformation. The one Food and Drug Administration (FA)-approved agent, the JAK inhibitor ruxolitinib ( Jakafi), is not considered safe for pa-tients with low platelet counts, Dr. Mesa indicated. “There’s nothing for this popu-lation that is really efficacious,” he noted. “Individuals with counts < 50,000/µL are likely getting it in modest doses that probably impact efficacy.”

Pacritinib inhibits JAK2 and FLT3, whereas ruxolitinib inhibits JAK1 and JAK2. The drugs also have different ef-fects on cytokines and on the spleen, he explained.

“Current treatments have not dem-onstrated the ability to simultaneously improve splenomegaly, symptoms, and cytopenias in myelofibrosis patients,” he pointed out.

“Pacritinib has activity in persons who do not have current treatments available, in particular, those with sig-nificant thrombocytopenia,” he said. “The endpoint with pacritinib was vastly superior in both the intent-to-treat and evaluable treatment arms. There were no responders in the best available treat-ment arm. The efficacy was similar in the broader group with < 100,000/µL.”

PERSIST-1 DetailsThe phase III PERSIST-1 trial

enrolled 327 patients with myelofi-brosis (primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis), randomizing them to pacritinib or “best alternative ther-apy,” which included a range of off-label treatments. These treatments did not include ruxolitinib due to safety concerns in patients with very low platelet counts, who were part of the study population. Patients in the study had not previously received ruxolitinib.

The primary endpoint was the pro-portion of patients achieving at least a 35% spleen volume reduction at week 24 by centrally reviewed magnetic res-

onance imaging or computed tomog-raphy. Secondary endpoints included the proportion achieving at least a 50% reduction in total symptom score at 24 weeks using the Myeloprolifera-tive Neoplasm Symptom Assessment Form.

In this population, 32% of patients had a platelet count < 100,000/µL, and 15% had a platelet count < 50,000/µL; 75% were JAK2 V617F-positive.

The median duration of treatment was 16.2 months in the pacritinib arm and 5.9 months with the best available treatment. In the control arm, 74.5% received active treatment in the control arm (25.5% were watch and wait), including erythropoietin-stimulating agents, immunomodula-tory drugs, hydroxyurea, and others.

Primary Endpoint Met“This study demonstrated that pac-

ritinib was well tolerated and induced significant and sustained spleen volume reduction and symptom control, even in patients with severe thrombocyto-penia,” Dr. Mesa reported. “Pacritinib therapy also resulted in red blood cell transfusion independence in a signifi-cant proportion of patients.”

At 24 weeks, significant spleen shrinkage was observed in 19.1% of the pacritinib arm, compared with only 4.7% of the control arm (P = .0003), in the intent-to-treat analysis, and in 25.0% vs 5.9% (P = .0001) of the evalu-able population (who both had baseline and 24-week assessments).

Additional BenefitsIn other endpoints, additional ben-

efits were observed with pacritinib, as described here for the evaluable patient population:• Among patients with the lowest

platelet counts, spleen shrinkage of at

least 35% was observed in 33.3% vs 0% (P = .0370);

• Among patients dependent on red blood cell transfusions, transfusion independence was achieved by 25.7% vs 0% (P = .04);

• Among all patients, a significant re-duction (at least 50%) in Total Symp-tom Score at 24 weeks was observed in 40.9% vs 9.9% (P < .0001);

• In the very low platelet subset, this reduction in symptoms was observed in 31.8% vs 11.1% (P = .3791).Overall survival data are prema-

ture, but a landmark analysis at week 24 found that spleen shrinkage was as-sociated with improved survival in the pacritinib arm but not in the control arm. “This highlights the importance of splenic reduction in impacting out-comes,” according to Dr. Mesa.

The most common toxicities with pacritinib were diarrhea, nausea, and vomiting, which were generally mild and resolved within 1 week. Few pa-tients discontinued the drug due to side effects.

The ongoing phase III PERSIST-2 trial is exploring pacritinib in patients with low platelet counts due to their disease or therapy. n

Disclosure: The study received funding from CTI BioPharma Corp. Dr. Mesa has received honoraria from and served as a consultant or advisor to Novartis and also has received research funding from Celgene, CTI, Gilead Sciences, and Incyte.

Reference1. Mesa RA, Egyed M, Szoke A, et al:

Results of the PERSIST-1 phase III study of pacritinib versus best available therapy in primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential throm-bocythemia-myelofibrosis. 2015 ASCO Annual Meeting. Abstract LBA7006. Pre-sented May 30, 2015.

Hematology

New JAK Inhibitor for Myelofibrosis

■ The phase III PERSIST-1 trial evaluated the JAK inhibitor pacritinib in patients with myelofibrosis, finding it to be significantly more effective than best alternative therapy.

■ A significant reduction in spleen volume was observed at 24 weeks in 25.0% of the pacritinib arm, vs 5.9% of the control arm (P = .0001) in the evaluable population.

■ Significant splenic shrinkage was observed with pacritinib, with no increase in toxicity, in the subset of patients with very low platelet counts: 33.3% vs 0% (P = .0370), respectively.

■ Pacritinib also reduced the need for transfusions and improved symptoms.


Lloyd Damon, MD, Professor of Medicine at the University

of California, San Francisco, dis-cussed the study and noted that al-though ruxolitinib ( Jakafi) is asso-ciated with a fair amount of anemia and thrombocytopenia, pacritinib did not increase these conditions in PERSIST-1. In fact, treatment was associated with a reduction in the need for transfusions. The lack of such toxicity allows pacritinib to be given to patients with low platelet counts, for whom ruxolitinib is not indicated or is used at a lower and possibly less effective dose.

For these reasons, he said, “Pac-ritinib is a very important agent for patients with advanced disease.”

Disclosure: Dr. Damon reported no potential conflicts of interest.

Lloyd Damon, MD

Ruben A. Mesa, MD


ASCO Annual Meeting

Investigators Update PVS-RIPO Data in GlioblastomaBy Caroline Helwick

At the 2015 ASCO Annual Meet-ing, Annick Desjardins, MD, As-

sociate Professor of Neurology at Duke University Medical Center, presented a brief update on the ongoing study of oncolytic PVS-RIPO in glioblastoma, which now includes 24 patients.1 The median age of enrolled patients is 57, most have a good performance status, all received radiation therapy and te-mozolomide, and 42% also received bevacizumab (Avastin).

As of May 19, 2015, 11 patients had died. Median survival was 12.5 months, the 6-month survival rate was 82.7%, and the 12-month survival rate was 56%, Dr. Desjardins reported.

Of the 24 patients, 9 have been treat-ed at the optimal dose level, and they are anticipated to have longer survival. Only one has reached the 6-month mark, how-ever, so “it’s too early to tell,” she said.

The survival data for all patients at all dose levels are shown in Table 1 (page 14). The study continues to en-roll at “dose level minus 1” (−1).

Adverse EventsMost adverse events have been re-

lated to secondary inflammatory re-sponse and prolonged steroid use, she said. Grade ≥ 3 neurologic adverse events have included hemiparesis in six patients (14.3%) and steroid my-opathy, intracranial hemorrhage upon catheter removal, and seizure in one patient each. Grade ≥ 3 hematologic toxicity has included lymphopenia in six patients. Other toxicities include

hyperglycemia in three patients and hy-pophosphatemia, fatigue, pneumonia, skin infection, and a thromboembolic event in one patient each.

“At dose level −1, we are seeing many fewer inflammation issues (such as sei-zures and weakness) than we saw in other dose cohorts, and efficacy is just

as good,” Dr. Desjardins said. The investigators started bevacizu-

mab in patients who appear to require

At dose level −1, we are seeing many fewer

inflammation issues than we saw in other dose cohorts, and efficacy is just

as good. —Annick Desjardins, MD

Neuro-oncology


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1. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023-1031.

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ASCO Annual Meeting

Cost of Immunotherapy Projected to Top $1 Million per Patient per YearBy Caroline Helwick

If new immunotherapy combinations were administered to the half a million

Americans dying of cancer each year, the nation’s price tag for treating them—for just 1 year—could top $174 billion, according to projections by Leonard Saltz, MD, Chief of Gastrointestinal Oncology and Chair of the Pharmacy and Therapeutics Committee at Memo-rial Sloan Kettering Cancer Center. Dr. Saltz offered his perspective on value in cancer care at the Plenary Session of the 2015 ASCO Annual Meeting.

“We must acknowledge that there must be some upper limit to how much we can, as a society, afford to pay to treat each patient with cancer,” Dr. Saltz said.

Cost-of-Care CrisisMany of the attention-grabbing

studies presented at the 2015 ASCO Annual Meeting pertained to immuno-therapies, which are being evaluated in a growing number of tumor types. Dr. Saltz pointed out how these exciting new drugs are clearly accentuating the cost-of-care crisis.

As one example, Dr. Saltz fo-cused on the CheckMate 067 trial of nivolumab (Opdivo) plus ipilimum-ab (Yervoy) in advanced melanoma, presented at the Plenary Session by Jedd Wolchok, MD, which yielded a median progression-free survival rate of 11.4 months, compared with 6.9 months for nivolumab alone and 2.9 months for ipilimumab alone.1

“A median progression-free survival of 11.4 months is truly remarkable, for a disease that 5 years ago was thought virtually untreatable,” Dr. Saltz said. “As a clinician, I want these drugs and oth-ers like them to be available for my pa-

tients. As one who worries how we will make them available and minimize dis-parities, I have a major problem—and that is that these drugs cost too much.”

He cited the current per-mg costs to be $28.78 for nivolumab and $157.46 for ipilimumab; the other anti–PD-1 (programmed cell death protein 1) agent, pembrolizumab (Keytruda), costs $51.79/mg. “To put that into perspective, that’s approximately 4,000 times the cost of gold,” Dr. Saltz said.

In the clinic, therefore, the cost of

treating an “average-sized” (80 kg) American patient with the combina-tion of nivolumab plus ipilimumab for advanced melanoma would exceed $295,500. Treatment with nivolumab alone would be $103,220, and ipilim-umab alone—to achieve a median re-mission of less than 3 months—would cost $158,252.

Rounding the cost of treatment up to about $300,000 for the individual patient with a 20% copay, the patient’s responsibility would be approximately $60,000, Dr. Saltz pointed out.

Taking this nationally—with 1.6 million cancer cases expected this

year and 589,430 deaths—giving $295,000 worth of drugs to each pa-tient with metastatic disease would cost $173,881,850,000, Dr. Saltz projected. “That’s $174 billion in 1 year for drugs treating patients with metastatic dis-ease—no adjuvant therapy—for 1 year only,” he emphasized.

Dr. Saltz also questioned the need to use pembrolizumab at a dose of 10 mg/kg—far higher than its U.S. Food and Drug Administration (FDA)-indicated dose of 2 mg/kg every 2 weeks. The

monthly cost for the higher-dose regi-men is $83,500, he calculated, and this dose (10 mg/kg every 2 weeks) was evaluated in at least five studies present-ed at the 2015 ASCO Annual Meeting, he noted.

Single-agent treatment, at this dose, for a 75-kg patient who needs 26 doses per year, generates a per-patient price tag of $1,009,944, Dr. Saltz estimated. “This is unsustainable,” he said.

Solving the ProblemPotential solutions to escalating

drug costs have been bandied about for years now, and Dr. Saltz reiterated

them. Two important changes are to al-low the FDA, the “gatekeeper,” to con-sider price in the approval process and to allow the Centers for Medicare and Medicaid Services, as the major pur-chaser of drugs, to negotiate prices with industry, he said.

Dr. Saltz emphasized that there must be an upper limit to how much society will pay to treat cancer; that discussions of value and cost must be encouraged within industry, government, patients, and “amongst ourselves”; and that al-ternative payment strategies that do not incentivize on the cost of drugs must be adopted. “There’s a tipping point that we have to be willing to search for,” he said.

Meanwhile, he urged ASCO mem-bers to discuss patients’ concerns regard-ing cost and finances and understand and explore the limitations of their insur-ance coverage. If the current trend con-tinues, he noted, by 2028, a full 100% of household income will be required to cover the cost of insurance premiums and out-of-pocket costs, he said.

“We can embrace our responsibility to deliver high-value, cost-effective care. That means choosing wisely, and choos-ing not to deliver lower-value, cost-inef-fective care,” he said. n

Disclosure: Dr. Saltz reported no potential conflicts of interest. Dr. Wolchok is a paid consultant and his institution receives research funding from Bristol-Myers Squibb.

Reference1. Wolchok JD, Chiarion-Sileni V, Gonza-

lez R, et al: Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced mela-noma. 2015 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2015.

As a clinician, I want these drugs and others like them to be available for my patients. As one who worries how we will make them available and minimize disparities, I have a major problem—and that is that these drugs cost too much.

—Leonard Saltz, MD

Plenary Session

PVS-RIPO Datacontinued from page 13more than 4 mg/d of dexamethasone to control inflammation. They used 7.5 mg/kg of bevacizumab every 3 weeks, which is much lower than the therapeutic dose. n

Disclosure: Dr. Desjardins is a co-owner of the intellectual property related to the technology discussed, for which a patent is pending.

Reference1. Desjardins A, Sampson JH, Peters

KB, et al: Oncolytic polio/rhinovirus re-combinant (PVSRIPO) against recurrent glioblastoma: Optimal dose determina-tion. 2015 ASCO Annual Meeting. Ab-stract 2068. Presented June 1, 2015.

Table 1: Dose Escalation, Current Survival Status, and Dose-Limiting Toxicities

* Deceased patients in red. TCID50 = median tissue culture infectious dose. Table courtesy of Desjardins A, et al.1

Dose Level (viral load) Number of Patients Survival After PVS-RIPO Infusion* Dose-Limiting Toxicities

1 (1.0 × 10e8 TCID50) 1 (4.2%) 36+ mo 0

2 (3.3 × 10e8 TCID50) 7 (29.2%) 35+, 11+, 8+, 9, 8, 7, 6 mo 0

3 (1.0 × 10e9 TCID50) 1 (4.2%) 6 mo 0

4 (3.3 × 10e9 TCID50) 2 (8.3%) 23+, 20, 15, 12 mo 0

5 (1.0 × 10e10 TCID50) 4 (16.75) 23+, 20, 15, 12 mo 1 (4.2%)

−1 (5.0 × 10e7 TCID50) 9 (37.5%) 7+, 6+, 5+, 4+, 3+, 2+, 1+, 0.4+, 3 mo 0


American Society of Gene and Cell Therapy Annual Meeting

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Poliovirus for Glioblastoma Grabs National AttentionBy Caroline Helwick

R esearchers at The Preston Rob-ert Tisch Brain Tumor Center at

Duke University are being barraged by patients wishing to enroll in their clini-cal trial of an engineered poliovirus for recurrent glioblastoma. This comes as a result of a CBS 60 Minutes inter-view with lead researcher Matthias Gromeier, MD, Associate Professor of Surgery, Molecular Genetics and Mi-crobiology, and Medicine at Duke.

The results he shared engendered hope within the glioblastoma commu-nity, and understandably so. When glio-blastoma recurs, median survival is 6 to 8 months. Using the engineered polio-virus (PVS-RIPO), Dr. Gromeier and his team have extended survival beyond 3 years in some patients.

“What is remarkable is that we get these types of responses with a single administration of virus without further therapy,” said Dr. Gromeier.

Dr. Gromeier recently discussed the approach at the American Society of Gene and Cell Therapy (ASGCT) An-nual Meeting in New Orleans.1 He also spoke with The ASCO Post.

What Is PVS-RIPO?PVS-RIPO is a live attenuated, oral

serotype 1 poliovirus (Sabin) vaccine that contains a heterologous internal ribosomal entry site from human rhi-novirus type 2. The vaccine recognizes nectin-like molecule-5 (CD155), the poliovirus receptor and a confirmed tu-mor antigen that is widely expressed in solid malignancies.

Dr. Gromeier explained the rationale for this therapy, which has been evaluated

so far in 23 patients, with patients con-tinuing to enroll in the phase I trial. He said that researchers are interested in the poliovirus because of its tropism. Simply put, the poliovirus attacks tumor cells, leading to cell lysis (which does not need to be extensive) and then presentation of tumor antigen from these lysed cells.

“Poliovirus induces a form of cell

death that does not resemble any or-chestrated form of demise (such as apoptosis, necrosis, or necroptosis). It’s a highly unusual, highly danger-signal-ing form of death,” he indicated. “At the same time, it elicits antiviral immunity or interferon response, so the combin-ing of the danger signals and pathogen signals helps to recruit cytotoxic T cells to recognize these tumor antigens.… What you need is activation of innate antiviral response plus cell killing.”

In its very fast-paced life cycle, the poliovirus behaves more like a toxin than a virus, ultimately producing viral polypeptides that exert a toxic effect. Events conspire, he believes, “to set up a classic immune effector response against the tumor that we believe is pro-tecting some of our patients durably.”

Details of TreatmentPVS-RIPO is delivered intratumor-

ally via a form of convection-enhanced delivery, which takes advantage of the natural flow of the cerebral spinal fluid and delivers drug by a stereotactically placed catheter directly into the tumor. Once in the brain, the virus triggers the immune response.

“The true objective of [convection-enhanced delivery] is to cover vast areas of the brain, but in this case, it’s not what we necessarily need,” he explained. “We just want to inject the virus in a way that the tumor is exposed to some degree, so we deliver 3 mL of the virus over about 6 hours.”

At the Society for Neuro-Oncology Annual Scientific Meeting in Miami this past November, Dr. Gromeier’s team re-ported phase I dose-finding and safety results on 15 patients.2 Median survival was 15.2 months, and the 12-month sur-vival rate was 70%; 18- and 24-month survival rates were 43.8% and 29.2%, respectively. Serious adverse events in-cluded hemiparesis, intracranial hemor-rhage at catheter removal, lymphopenia, seizure, and hyperglycemia, as well as

lethargy, headache, diarrhea, paresthesia, and hyperbilirubinemia.

Response and SurvivalAt the ASGCT meeting, Dr. Gromeier

elaborated on these outcomes. “We have very good survival and complete radio-graphic responses,” he said, including complete responses in patients whose tumors could not be completely resected.

“The first patient we treated had a very large tumor excised. She got a single PVS-RIPO infusion, and 2 months later the tumor was significantly enlarged. The [magnetic resonance imaging (MRI) scans] looked awful, but the patient was doing fine,” he recalled. “By 6 months, we saw glial scarring. By 11 months, the tumor had significantly shrunk. And by a year or so, the tumor was gone.”

He added, “Three years out, the pa-tient is tumor-free, she’s working, she’s completely fine. She has to take anti-convulsants for the rest of her life, but otherwise you would never know this patient had a brain tumor.”

Another patient’s MRI at 3 years is essentially normal. “He recently de-livered a half-hour talk at a fundraiser. He’s 74 now, and you would not know that this man had a recurrent [glioblas-toma],” he reported.

Lessons Learned“So what can we learn from our trial?

We started out really, really positive, and then things got difficult,” he noted.

At the time of the ASGCT meeting, two patients were alive past 3 years and another past 2 years, all of whom were

Neuro-oncology

What is remarkable is that we get these types of responses with a single administration of virus without further therapy.

—Matthias Gromeier, MD




complete responders to the infusion and not steroid-dependent. On the other hand, patients on high-dose steroids be-fore PVS-RIPO treatment had worse out-comes. This led the researchers to look at the effect of steroids on the treatment.

By observing differences related to prior steroid use and by realizing they created steroid dependency when us-ing the high doses of PVS-RIPO, the researchers concluded that both steroid use and dose of PVS-RIPO were very important to outcomes. They amended their enrollment criteria to exclude pa-tients on high-dose steroids and low-ered the treatment dose.

“We can’t leave out steroids entirely because we use a neurosurgical procedure to administer the virus, and the surgeons must give some steroid for that to protect the brain from swelling,” he explained. “But we try to taper the patient off within a week or so. We believe that high doses of steroids are inappropriate because they are too immunosuppressive.”

The investigators are now treating with “dose level minus 1,” which is 5 × 10e7 (50 million infectious units) and half the initial starting dose. They have been able to successfully taper steroids in eight patients treated with this dose.

Dr. Gromeier emphasized in the interview that it is rare to settle on the lowest dose in a dose-finding study. “In cancer, it’s always ‘more is better.’ But the immune system does not work on dose. The reason the high dose doesn’t work is not just due to toxicity. I believe we get the wrong kind of response.”

On the lower dose, he reported, “pa-tients are doing well on this therapy, so we just keep on watching what’s hap-pening.” He acknowledged that one patient died, “which reminds us this is a terrifying disease.”

Possible MechanismAs a virologist, Dr. Gromeier attri-

butes the therapeutic benefit to eliciting an innate human response to polio, set-ting up a classic effector immune response against the tumor, stemming from a com-plex interplay of activated macrophages, dendritic cells, cytokines, and “superfast” proinflammatory cell killing.

“I think the most damaging proposal in the oncolytic virus field has been that tumors lack innate immune responses. I don’t believe that’s true. Plenty of evi-dence says the opposite. I actually be-lieve the innate response in the tumors themselves plays a very important role in what we’re doing,” he maintained.

Since his interview on 60 Minutes

aired, he said, “We have received thou-sands of calls, and we answer all of them.” All patients are considered; how-ever, given that this is a phase I safety study, the eligibility criteria are quite narrow, he indicated.

While the researchers are very en-couraged by preliminary data, they ac-

knowledge they need to wait at least an-other year and a half “to be confident.” n

Disclosure: Dr. Gromeier reported no potential conflicts of interest.

References1. Gromeier M: Cancer Immunothera-

py: Cutting Edge – Clinical. Scientific Sym-

posium. 2015 American Society of Gene and Cell Therapy Annual Meeting. Present-ed May 14, 2015.

2. Desjardins A, Sampson J, Peters K, et al: Final results of a phase 1 trial of an oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM). 2014 Society for Neuro-Oncology Annual Scientific Meeting. Abstract AT-21.

Poliovirus for Glioblastomacontinued from page 15

We want to change the faceof EGFR-targeted therapy

Inhibition of wild-type and mutant EGFRin non–small cell lung cancer (NSCLC)Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

90% of patients treated with approved EGFR TKIs experience rash7,8

The skin is dependent on wild-type EGFR signalingfor normal growth and differentiation.1,9,10 Drug-induced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Cutaneous toxicities can bedose-limitingThe symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.7,8

The future of EGFR inhibitionStrategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org/ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed February 2, 2015.

Clovis Oncology is leading the fight

Cutaneous toxicities are caused by inhibition of wild-type epidermalgrowth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2015 Clovis Oncology. DARO-101(1) 3/15

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

31698_clovco_fa2_rash_ASCOPOST.indd 1 3/31/15 9:39 AM

http://t790m.com/?source=targetEGFR



Oncolytic Immunotherapy in Melanoma: It’s Not All About PD-1By Caroline Helwick

The benefit from immune-directed therapies in patients with ad-

vanced melanoma is not limited to the exploding field of checkpoint inhibi-

tors. According to Robert Andtbacka, MD, Associate Professor of Surgical Oncology, at the Huntsman Cancer Institute at the University of Utah, Salt

Lake City, intralesional oncolytic ther-apy also provides benefit, which can be profound for some patients.

“Oncolytic immunotherapies rep-

resent a new important strategy in the treatment of cancer,” he said at the American Society of Gene and Cell Therapy, where he described several emerging approaches now in phase II and III clinical trials. Dr. Andtbacka has been directly involved in many of these studies.

Oncolytic immunotherapies work not only through a lytic effect but by ac-tivating the entire immune system, “not just in lesions we treat, but elsewhere in the body.” He noted that intralesional therapies are tailor-made for local and in-transit cutaneous lesions and the ac-cessible lymph nodes of melanoma.

Intralesional oncolytic immunother-apies aim to achieve a local ablative ef-fect as well as a systemic immune effect, the so-called bystander response. They may also help to prevent the develop-ment of visceral metastases, if given ear-ly, he predicted. Durable responses with limited toxicity are additional goals.

Types of Intralesional AgentsA dozen or so types of intralesional

agents are in development: antibodies, cytokines, glycolipids, microspheres, plasmids, small molecules, radiosensi-tizers, vaccines, viruses, xeno-antigen cell lines, and combinations of these agents. Most are early in the pipeline, but data from phase II and III trials have become available for some of them.

In his talk, Dr. Andtbacka focused on talimogene laherparepvec (T-VEC; a modified herpes simplex type 1 vi-rus), plasmid interleukin-12 (IL-12) electroporation, PV-10 (rose bengal), and coxsackievirus A21 (CVA21), but they are just a few of the many agents in the pipeline.

T-VEC: A Promising CompoundIn April 2015, the U.S. Food and

Drug Administration’s (FDA’s) On-cologic Drugs Advisory Committee (ODAC) and Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted to recommend ap-proval of T-VEC for advanced melano-ma. The FDA is expected to make a final decision in October.

When T-VEC is injected into der-mal, subcutaneous, and intralymphatic lesions, the virus is replicated in the tu-mor cell, which is followed by lysis of the cell, exposure of tumor-specific antigen to the immune system, activation of the immune system, and immune activation

Dermatologic Oncology


We want to change the faceof EGFR-targeted therapy

Inhibition of wild-type and mutant EGFRin non–small cell lung cancer (NSCLC)Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

90% of patients treated with approved EGFR TKIs experience rash7,8

The skin is dependent on wild-type EGFR signalingfor normal growth and differentiation.1,9,10 Drug-induced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Cutaneous toxicities can bedose-limitingThe symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.7,8

The future of EGFR inhibitionStrategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org/ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed February 2, 2015.

Clovis Oncology is leading the fight

Cutaneous toxicities are caused by inhibition of wild-type epidermalgrowth factor receptor (EGFR) and can be debilitating1,2

Copyright © 2015 Clovis Oncology. DARO-101(1) 3/15

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

31698_clovco_fa2_rash_ASCOPOST.indd 1 3/31/15 9:39 AM



against melanoma at distant sites.In the phase III OPTiM trial, 436

patients had lesions injected with either T-VEC or granulocyte macrophage col-ony-stimulating factor (GM-CSF). The primary endpoint, durable response (continuous response for ≥ 6 months), was achieved by 16.3% with T-VEC vs 2.1% with the control, a 14.1% differ-ence (P < .0001).1

“This durable response rate is an un-usual endpoint and very stringent,” he noted. “For comparison, if we had used this in trials of BRAF inhibitors, the end-point would not have been achieved.”

Among the injected lesions, 64% re-sponded, of which 47% were complete responses to T-VEC, as did 34% of non-injected (nonvisceral) lesions. Two-thirds had responses lasting at least 1 year. Pa-tients who responded best were those with earlier stage disease (IIIB/C or IV M1a vs IV M1b/c), for whom median overall survival was 41 months with T-VEC vs 21 months with the control (P < .001).

T-VEC also reduced the develop-ment of visceral metastases, boding well for the use of this agent earlier in the dis-ease. Therefore, a phase II neoadjuvant study is evaluating T-VEC in 150 resect-

able stage IIIB/C/IV M1a patients. In this study, patients will be randomized 1:1 to either surgery (the current stan-dard of care) or T-VEC for 3 months fol-lowed by surgery. The primary endpoint is 2-year recurrence-free survival.

A phase Ib study has also evaluated T-VEC in combination with ipilimumab (Yervoy) in previously untreated stage III/IV patients, showing responses in 56% of patients and complete respons-es in 33%.2 Toxicity was not increased

with the combination compared with what is seen with single agents.

“This study shows we can use these agents in combination, which is ultimate-ly what we need to think about,” said Dr. Andtbacka. “There are a number of treat-ments moving forward in combination.”

Other Intralesional Immunotherapies

Intratumoral electroporation is a means of enhancing cell permeabil-ity—via an electrical current delivered into the tumor—which facilitates entry of plasmid IL-12. In a phase II study of 85 lesions, 53% of injected sites re-sponded (with 31% stabilized), as did 59% of uninjected lesions.3 A random-ized clinical trial is underway.

PV-10 is a fluorescent compound that accumulates in the lysosome of cancer cells and leads to acute autophagy, lysis of cells, and exposure of antigenic tumor fragments to antigen-presenting cells. In a phase II study of 80 patients, 51% of target lesions responded, as did 33% of nontar-get lesions. The median progression-free survival was 11.4 months in responders and 4.1 months in nonresponders.4

CVA21 gains access to cells by bind-ing to the intercellular adhesion mol-ecule 1 (ICAM-1) protein expressed by

the cancer cell. Within the cell, the virus replicates, tumor cells are lysed, and the immune system is activated.

In the phase II CALM study,5 in which patients received multiple injec-tions of CVA21 over 48 weeks, more than 38% of patients were progression-free at 6 months, meeting the study’s primary endpoint. Responses were observed in both localized disease and visceral metastases, and there were no grade 3/4 toxicities.

“After multiple injections, cutaneous lesions are flattened out. We see pigmen-tation but no melanoma left in the lesion,” observed Dr. Andtbacka (see Fig. 1).

Patients often develop neutralizing antibodies to the virus, “but even in the presence of this, we saw responses, which indicates these responses are likely immune-mediated and not just working by a direct lytic effect on the tumor,” he added. Based on the biopsies of lesions before and after injection, he believes CVA21 is capable of “reboot-ing” the immune system after patients stop responding to other treatments. n

Disclosure: Dr. Andtbacka reported no potential conflicts of interest.

References1. Andtbacka RH, Kaufman HL, Col-

lichio F, et al: Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. May 26, 2015 (early release online).

2. Puzanov I, Milhem MM, Andtbacka RHI, et al: Primary analysis of the phase

1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec and ipilimumab in previously untreated, un-resected stage IIIB-IV melanoma. 2014 ASCO Annual Meeting. Abstract 9029. Presented June 2, 2014.

3. Daud A, Algazi AP, Ashworth MT, et al: Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. 2014 ASCO Annual Meeting. Abstract 9025. Presented June 2, 2014.

4. Thompson JF, Agarwala SS, Smithers BM, et al: Phase 2 study of intralesional PV-10 in refractory metastatic melanoma. Ann Surg Oncol. October 28, 2014 (early release online).

5. Andtbacka RH, Curti B, Kaufman H, et al: CALM study: A phase II study of a novel oncolytic immunotherapeutic agent, CVA21, delivered intratumorally in pa-tients with advanced malignant melanoma. 2015 Society of Surgical Oncology Annual Cancer Symposium. Abstract 2093535. Presented March 27, 2015.

Immunotherapy in Melanomacontinued from page 17

Oncolytic immunotherapies represent a new important strategy in the treatment of cancer.

—Robert Andtbacka, MD

Fig. 1: CALM Phase II Trial—Local-injected lesion responses in a male with cutaneous melanoma on the chest. Left: Baseline photos; Right: Day 127–histopathologic analysis confirmed complete melanoma regression. Photos courtesy of Andtbacka RH, et al.1

Visit The ASCO Post website at ASCOPost.com

WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGEGAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal LeukoencephalopathyJC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

5.4 Tumor Lysis SyndromeAcute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

5.5 InfectionsSerious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

5.7 ThrombocytopeniaGAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

5.8 ImmunizationThe safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings

and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1)

GAZYVA® (obinutuzumab) Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information.

Injury, poisoning, and procedural complicationsInfusion 69 21 0 0reactions

Blood and lymphatic system disordersb

Neutropenia 41 35 18 16

Thrombocytopenia 15 11 8 4

Anemia 12 5 10 4

Leukopenia 7 5 0 0

General disorders and administration site conditionsPyrexia 10 < 1 7 0

Respiratory, thoracic, and mediastinal disordersCough 10 0 7 < 1

Infections and infestationsUrinary tract 6 2 3 < 1infection

Musculoskeletal and connective tissue disorderBack pain 5 < 1 2 0

Adverse Reactions (MedDRAa) System Organ Class

GAZYVA + Chlorambucil

n = 336

Rituximab + Chlorambucil

n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %


Injury, poisoning and procedural complicationsInfusion 66 20 38 4reactions




Leukopenia 6 4 2 < 1

General disorders and administration site conditionsPyrexia 9 < 1 7 < 1

Gastrointestinal disordersDiarrhea 10 2 8 < 1

Constipation 8 0 5 0

Infections and infestationsNasopharyngitis 6 < 1 3 0

Urinary tract 5 1 2 < 1infection

a MedDRA coded adverse reactions as reported by investigators. b Adverse events reported under “Blood and lymphatic

system disorders” reflect those reported by investigator as clinically significant.



n = 241

Chlorambucil n = 116

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %

02-12478_R01_GAUS_BriefSummary_A_size.indd 1 1/29/15 3:00 PM


Announcements

Five Presidential Appointees Named to National Cancer Advisory Board

P resident Barack Obama recently announced his intent to nominate

the following individuals to the Na-tional Cancer Advisory Board: Peter C. Adamson, MD; Yuan Chang, MD; Timothy J. Ley, MD; Deborah

Watkins Bruner, RN, PhD, FAAN; and Max S. Wicha, MD.

Peter C. Adamson, MDDr. Adamson is Attending Physi-

cian in the Division of Oncology at

the Children’s Hospital of Philadel-phia, a position he has held since 1999. Dr. Adamson has been Chair of the Children’s Oncology Group, sup-ported by the National Cancer Insti-

continued on page 20Peter C. Adamson, MD

WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGEGAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal LeukoencephalopathyJC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

5.4 Tumor Lysis SyndromeAcute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

5.5 InfectionsSerious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

5.7 ThrombocytopeniaGAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

5.8 ImmunizationThe safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings

and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.


GAZYVA® (obinutuzumab) Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information.

Injury, poisoning, and procedural complicationsInfusion 69 21 0 0reactions




Anemia 12 5 10 4

Leukopenia 7 5 0 0

General disorders and administration site conditionsPyrexia 10 < 1 7 0

Respiratory, thoracic, and mediastinal disordersCough 10 0 7 < 1

Infections and infestationsUrinary tract 6 2 3 < 1infection

Musculoskeletal and connective tissue disorderBack pain 5 < 1 2 0



n = 336


n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %


Injury, poisoning and procedural complicationsInfusion 66 20 38 4reactions





General disorders and administration site conditionsPyrexia 9 < 1 7 < 1

Gastrointestinal disordersDiarrhea 10 2 8 < 1

Constipation 8 0 5 0

Infections and infestationsNasopharyngitis 6 < 1 3 0

Urinary tract 5 1 2 < 1infection

a MedDRA coded adverse reactions as reported by investigators. b Adverse events reported under “Blood and lymphatic

system disorders” reflect those reported by investigator as clinically significant.



n = 241


All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %



Announcements

tute, since 2010. He began his pedi-atric career as a resident at Children’s Hospital from 1984 to 1987. Dr. Ad-amson received his MD degree from Cornell University.

Yuan Chang, MDDr. Chang is currently Professor of

Pathology at the University of Pitts-burgh, a position she has held since 2002. Dr. Chang has been a Distin-guished Professor of Pathology since 2012 and is the University of Pittsburgh Cancer Institute Chair of Cancer Virolo-

gy. Dr. Chang received her MD from the University of Utah College of Medicine.

Timothy J. Ley, MDDr. Ley is Director of the Stem

Cell Biology Section in the Division of Oncology at Washington Univer-sity School of Medicine, a position he has held since 2000. Dr. Ley has also served as Associate Director for Cancer Genomics at The Genome Institute at Washington University since 2008. Dr. Ley received his MD from Washington University School of Medicine.

Deborah Watkins Bruner, RN, PhD, FAAN

Dr. Watkins Bruner is the Robert W. Woodruff Professor of Nursing at the Nell Hodgson Woodruff School of Nursing, Professor of Radiation Oncology, and As-sociate Director for Outcomes Research at the Winship Cancer Institute of Emory University, positions she has held since 2011. Dr. Bruner received her PhD from the University of Pennsylvania.

Max S. Wicha, MDDr. Wicha is the Madeline and Sid-

ney Forbes Professor of Oncology at the University of Michigan Compre-hensive Cancer Center, a position he has held since April 2015. Dr. Wicha received his MD from Stanford Univer-sity School of Medicine. n

Timothy J. Ley, MD

Deborah Watkins Bruner, RN, PhD, FAAN

Presidential Appointeescontinued from page 19

Yuan Chang, MD

Max S. Wicha, MD

Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm

(7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion).

The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).

Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.

6.2 ImmunogenicitySerum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial ExperienceWorsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

7 DRUG INTERACTIONSNo formal drug interaction studies have been conducted with GAZYVA.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers.

Animal DataIn a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

8.3 Nursing MothersIt is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of GAZYVA in pediatric patients has not been established.

GAZYVA® [obinutuzumab]

Manufactured by: Genentech, Inc.

A Member of the Roche Group South San Francisco, CA 94080-4990

U.S. License No: 1048

Initial US Approval: 2013

Code Revision Date: December 2014

GAZYVA is a registered trademark of Genentech, Inc.

GAZ/011615/0009 1/15

© 2015 Genentech, Inc.

Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1)


HematologyNeutropenia 78 48 53 27

Lymphopenia 80 40 9 3


ChemistryHypocalcemia 38 3 33 2

Hyperkalemia 33 5 18 3

Hyponatremia 30 8 12 3

AST 29 1 16 0(SGOT increased)

Creatinine 30 < 1 20 2increased

ALT 27 2 16 0 (SGPT increased)

Hypoalbuminemia 23 < 1 15 < 1

Alkaline phosphatase 18 0 11 0increased

Hypokalemia 15 1 5 < 1



Leukopenia 84 35 62 16


Anemia 39 10 37 10

ChemistryHypocalcemia 37 3 32 <1

Hyperkalemia 14 1 10 <1


AST 27 2 21 <1(SGOT increased)


Hypoalbuminemia 23 <1 16 <1

8.5 Geriatric UseOf 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal ImpairmentBased on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic ImpairmentGAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGEThere has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATIONAdvise patients to seek immediate medical attention for any of the following:

• Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for:

• Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)].

• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)].

• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

InvestigationsGAZYVA

+ Chlorambucil n = 241


All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %




n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %



National Cancer Policy Forum

Assessing and Improving Imaging Interpretation in Breast Cancer Screening By Margot J. Fromer

The quality of mammography imag-es has markedly improved over the

past few decades. However, the quality of the interpretation of mammograms remains variable. That said, more than 38 million mammograms are performed annually in the United States.

So said Diana Buist, PhD, Senior Scientific Investigator, Group Health Breast Cancer Surveillance, as she in-troduced a workshop hosted by the National Cancer Policy Forum and the American Cancer Society.

What Could Be ImprovedCongress authorized the Mammog-

raphy Quality Standards Act (MQSA) in 1992, but image quality and inter-pretation remain problematic. Both depend on many factors and are diffi-cult to measure. Inconsistency, how-ever, is a constant. Therefore, in prepa-ration for reauthorization of MQSA, Congress commissioned a study from the Institute of Medicine (IOM) in 2005 to determine what could be done to increase accuracy and whether cur-rent regulations should be modified. IOM also was asked to consider ac-cess to mammography services and to identify what would ensure safe and effective use of other screening and di-agnostic tools.

The Institute made recommenda-tions about medical audits, centers of excellence, continuing medical educa-tion, reader volume, double reading, computer-aided detection, state and federal regulations, inspections and enforcement, data analysis, workforce, and accreditation for nonmammogra-phy breast imaging methods.

Dr. Buist said that since publica-tion of the 2005 IOM report, Improv-ing Breast Imaging Quality Standards,1 there has been a substantial body of re-search on factors that influence inter-pretation, including minimum volume needed for high quality, identification of radiologists who perform below par, and whether live instructors or self-paced methods are better at improving performance.

Part of the push for improvement is the National Mammography Database, a registry established in 2009 that al-lows facilities and physicians to monitor and improve quality using standardized measures consistent with the Breast Im-aging Reporting and Data System (BI-RADS). It currently has 275 registered sites, 162 of which contribute data from more than 9 million exams.

“This provides good representation across the country and across practice types and locations,” said Carl D’Orsi, MD, Director of Breast Imaging Re-search, Emory Healthcare. The Nation-al Mammography Database is automat-ed, and data are sent to it directly. It now collects only mammography data but will expand to include ultrasound and magnetic resonance imaging (MRI) later this year.

Unlike the National Cancer Insti-tute–funded Breast Cancer Surveil-lance Consortium, the National Mam-

mography Database does not have information on missed cancers, limiting its ability to effectively evaluate perfor-mance and safety.

Medical AuditsEtta D. Pisano, MD, Dean Emerita

and Distinguished University Professor, Medical University of South Carolina, noted that the required elements of an MQSA medical audit in 2005 included: • All mammograms interpreted as pos-

itive, or BI-RADS 4 or 5 • Follow-up of all positive mammograms• All biopsy results• Correlation of pathology results with

final assessment• An interpreting physician for each

case• Annual analysis of results and sharing

them with the interpreting physician and the entire facility

In addition, said Dr. D’Orsi, a com-plete audit should include sensitivity (percent of cancers detected by mam-mography among all cancers that were found in the women receiving screen-ing mammograms), specificity (percent of negative cases interpreted on a mam-mogram among all cases when women received screening), recall rate (screens given additional imaging), abnormal interpretation rate (positive exams), accuracy (cancer and negative cases identified from all cases), positive pre-dictive value type 1 (screening exams with a positive interpretation and can-cer within a year), positive predictive value type 2 (positive exams with a bi-opsy recommended and cancer within a year), positive predictive value type 3 (biopsies done with a positive interpre-tation and a known biopsy of cancer in a year), cancer detection rate (number of cancers detected per thousand wom-en), and percent of minimal cancer (less than 1 cm, or ductal carcinoma in situ). When any of these parameters are un-known, surrogate markers may need to be used for the audit.

A positive screening mammogram, he said, has an assessment of BI-RADS 0, 3, 4, or 5, as does a positive ultra-sound. “Since the number of images and parameters for either a screening or diagnostic MRI are the same, the definition of a positive screen and diag-nostic exam is the same. However, if the screening exam includes additional im-ages [eg, a 90-degree lateral on a screen-ing mammogram or orthogonal images of a cyst on a screening ultrasound], this too is positive.”

Dr. Pisano noted that some changes were made in the revised MQSA audit, but most of IOM’s suggestions were not implemented. Despite the 2005 IOM recommendations, the revised MQSA did not mandate collection of patient characteristics and tumor staging, es-tablishment of a statistical center to analyze data and provide feedback to

interpreting physicians and to report ag-gregate data to the public, nor develop-ment of pay-for-performance incentives for participation in audits and meeting performance criteria—although some payers have implemented pay-for-per-formance mammography metrics.

Mammography ChallengesBarbara Monsees, MD, Emerita

Chief, Breast Imaging Section, Washing-ton University School of Medicine, said that it’s not easy to achieve high-quality mammography. She asked, “How do we ensure broad access? What do patients need to understand about new technol-ogies? How does supplemental screen-ing fit in? Finally, how do state laws man-date notification about breast density, and how does this change expectations and outcome tracking?”

Disparities in performance of and access to screening lead to disparities in outcomes, said Tracy Onega, PhD, De-partment of Biomedical Data Science, Geisel School of Medicine at Dart-mouth. For example, 12.6% of white

Breast Cancer

Digital mammography makes centralized interpretation of screening mammograms feasible but at the same time less workable for diagnostic evaluation, where a radiologist should be present.

—Barbara Monsees, MD

Diana Buist, PhD


Breast Imaging Reporting and Data System (BI-RADS)

T he Breast Imaging Reporting and Data System (BI-RADS)

is a standardized system to describe mammogram findings and results. Developed by the American Col-lege of Radiology (ACR), results of mammograms are sorted into cat-egories numbered 0 through 6 with interpretation as follows:Category 0: Additional imaging evaluation and/or comparison to prior mammograms is needed.Category 1: Negative.

Category 2: Benign (noncancer-ous) finding.Category 3: Probably benign find-ing—Follow-up in a short time frame is suggested.Category 4: Suspicious abnormal-ity—Biopsy should be considered.Category 5: Highly suggestive of malignancy—Appropriate action should be taken.Category 6: Known biopsy-proven malignancy—Appropriate action should be taken. n

Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm

(7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion).

The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).

Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.

6.2 ImmunogenicitySerum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial ExperienceWorsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

7 DRUG INTERACTIONSNo formal drug interaction studies have been conducted with GAZYVA.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CRisk SummaryThere are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers.

Animal DataIn a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

8.3 Nursing MothersIt is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of GAZYVA in pediatric patients has not been established.

GAZYVA® [obinutuzumab]

Manufactured by: Genentech, Inc.

A Member of the Roche Group South San Francisco, CA 94080-4990

U.S. License No: 1048

Initial US Approval: 2013

Code Revision Date: December 2014

GAZYVA is a registered trademark of Genentech, Inc.

GAZ/011615/0009 1/15

© 2015 Genentech, Inc.






ChemistryHypocalcemia 38 3 33 2

Hyperkalemia 33 5 18 3


AST 29 1 16 0(SGOT increased)

Creatinine 30 < 1 20 2increased


Hypoalbuminemia 23 < 1 15 < 1

Alkaline phosphatase 18 0 11 0increased

Hypokalemia 15 1 5 < 1



Leukopenia 84 35 62 16


Anemia 39 10 37 10

ChemistryHypocalcemia 37 3 32 <1

Hyperkalemia 14 1 10 <1


AST 27 2 21 <1(SGOT increased)


Hypoalbuminemia 23 <1 16 <1

8.5 Geriatric UseOf 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal ImpairmentBased on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic ImpairmentGAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGEThere has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATIONAdvise patients to seek immediate medical attention for any of the following:

• Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for:

• Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)].

• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)].

• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].




All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %




n = 321

All Grades %

Grades 3–4 %

All Grades %

Grades 3–4 %



National Cancer Policy Forum

women travel more than 30 minutes to the closest mammography center, 6.4% of black women spend that much time, but 39.6% of Native American women do. In urban areas, only 0.5% of women travel more than a half-hour, but in rural areas, that figure is 27.9%.

The percentages of women over age 40 who have had a mammogram within the past 2 years are 75.4% of whites, 78.6% of blacks, and 63.9% of Native Americans. When white women get breast cancer, 7.6% have stage III or IV at diagnosis, whereas in black women it is 11.2%. Breast cancer mortality had a similar ratio: 22.7% for whites and 30.8% for blacks. Morbidity and mor-tality rates were not available for Native Americans.

“Geography does not seem to af-fect access to mammography, but it may limit other breast services,” said Dr. Onega. “Moreover, at facilities that serve vulnerable populations, screening mammography had the same sensitiv-ity as other facilities, but specificity was significantly higher. In diagnostic mam-mograms, the false-positive rates were much higher at facilities that serve vul-nerable women.”

MQSA audit requirements and the way BI-RADS addresses them will have an effect on outcome. For example, what tools should be used, what are appropri-ate audit measures, and how often should data be reviewed? What are reasonable goals for recall rates, detection rates, and tumor size and stage? Are there reason-able tradeoffs for sensitivity and specific-ity, and if so, what are they?

These challenges are complicated by the fact that breast imaging includes both screening and diagnostic mam-mography, ultrasound, MRI, image-guided needle biopsy, and other mo-dalities. “Expectations are high,” said Dr. Monsees, “and medicolegal impli-cations can be an issue. Variability in interpretation is a problem, but double reading is not feasible even though it is often used in other countries. More mo-dalities and procedures can help with patient management, but they are time consuming and expensive.”

Overall, however, mammography has improved. Technologists have learned how to produce better images

with good compression and position-ing. Digital mammography means that technique is less of a factor because of wider recording latitude and elimina-tion of film processors. Quality control is easier and more streamlined, and there are fewer lost exams.

More and more radiologists do only breast imaging, although some general radiologists interpret screening mam-mograms or perform diagnostic work-ups, including breast ultrasound. “Digital mammography makes centralized inter-pretation of screening mammograms fea-sible but at the same time less workable for diagnostic evaluation, where a radiolo-gist should be present,” said Dr. Monsees.

Dr. Onega added that access to mammography is generally good, but the mammography workforce (radiolo-gists and technologists) is not standard-ized, and quality varies with practices.

Dr. Monsees said that use of com-puter-aided detection during screen-ing mammography among Medicare beneficiaries is a good news–bad news story, leading to an increased incidence of ductal carcinoma in situ, diagnosis of invasive breast cancer at earlier stages, and increased diagnostic testing among women without breast cancer.

Teleradiology, now 67% of the tele-medicine market, also is inconsistent, said Dr. Onega. Whereas local access emphasizes machines and technicians, teleradiology separates interpretation from physical location. Mammography readers could increase volume, but it remains to be seen to what extent vol-ume has a relationship with outcome.

She added that mammography misses about 20% of breast cancers, but digital breast tomosynthesis seems to increase detection and reduce recall.

Training, Experience, and Performance

Dr. Buist said that interpretation variability is due to patient factors, practice and facility characteristics, and radiologist training, years of expe-rience, and volume. “Volume require-ments differ greatly across countries, as do quality standards,” she said. “In the United States, we have demonstrated poorer performance for radiologists with low interpretive volume, leading to higher false-positive rates, lower can-cer detection, and lower sensitivity.”

The most important finding in the United States is improved screening and diagnostic interpretive performance for

radiologists who interpret some pro-portion of diagnostic examinations and also for radiologists who interpret some of their own recalled screening exams.

Diana Miglioretti, PhD, Dean’s Professor in Biostatistics, Department of Public Health Sciences, University of California Davis, said that 18% of radiolo-gists fall into the low-performance range in sensitivity, 48% in specificity, 49% in recall rate, and 38% in positive predictive value type 1 (ie, with abnormal findings at screening). She added that most radi-ologists are in the low range for at least one measure of competence, and many interpret few mammograms associated with a cancer diagnosis.

Patricia A. Carney, PhD, Profes-sor of Family Medicine and of Public Health & Preventive Medicine, Or-egon Health & Science University, con-curred. “There is significant variability in the interpretive acumen of practicing radiologists: 75% to 95% for sensitivity and 83% to 98.5% for specificity.”

Dr. Buist suggested that consider-ation should be given to increasing mini-

mum interpretation volumes, including diagnostic exams, which should be a pro-portion of total volume. She also thinks radiologists should be required to per-form a minimum number of diagnostic workups resulting from their own recalls.

Radiology TechnologistsLouise M. Henderson, PhD, As-

sistant Professor, Department of Ra-diology, University of North Carolina, Chapel Hill, said, “Mammograms are interpreted by radiologists but per-formed by technologists who are re-sponsible for image quality.”

The American Registry of Radiolog-ic Technologists (ARRT) tests, certifies, and registers the more than 250,000 technologists and awards the Regis-tered Technologist designation. Even though ARRT provides continuing education and reregisters technologists every year, certification is voluntary and is not the same as state licensure.

“Technologists have a significant impact on mammography perfor-mance, specifically recall rate, sensi-tivity, specificity, [positive predictive value], and cancer detection rate,” said Dr. Henderson. They also can serve as double readers, although this is more common in Europe than in the United States. Where they do serve as such for screening mammograms, cancer detection rates increase without sig-nificantly increasing recall or false-positive rates. n

Disclosure: Drs. Buist, D’Orsi, Pisano, Monsees, Onega, Miglioretti, Carney, and Henderson reported no potential conflicts of interest.

Reference1. Institute of Medicine: Improving

Breast Imaging Quality Standards. May 23, 2005. Available at http://www.iom.edu/Re-ports/2005/Improving-Breast-Imaging-Qual-ity-Standards.aspx. Accessed June 22, 2015.

Breast Cancer Screeningcontinued from page 21

Geography does not seem to affect access to mammography, but it may limit other breast services.

—Tracy Onega, PhD

Patricia A. Carney, PhD


ONCUS15UB00500-01-01 05/15© 2015 Bristol-Myers Squibb

Pediatric Oncology Research – Funding Available!

IntroductionThe Pediatric Oncology community has invested a major effort over many years to collect and analyze long-term data in the pediatric population. Bristol-Myers Squibb seeks to fund research for Pediatric Oncology investigators to further the surveillance of pediatric/adolescent/young adult patients treated with targeted agents and Immunotherapy to assess for short- and long-term adverse events.

Program GoalsIn 2015, the Pediatric Oncology Research Program seeks to:

» Support research to further strengthen the scienceand knowledge of Pediatric Oncology

» Support the development of future clinicalresearchers

Eligibility Criteria» M.D. pediatric oncology fellows or investigators

» Desire to enhance knowledge within the field ofPediatric Oncology

» Faculty member identified to serve as projectmentor at the applicant’s institution

Enrollment and Funding» $50,000 per year will be funded to prioritized

proposals for up to 3 years. No indirect costswill be provided.

Application Process» To submit an application, visit:

www.bms.com/israpplications• Click on Pediatric Oncology Research Funding

• Select Apply

• Set up an ISR login

• Complete application

» To be considered, completed application mustbe submitted through the website by 5 P.M. ESTon July 31st, 2015

» For questions regarding this program, contactMichael Trigg at [email protected]

All support for Fellows Research Training Program Grants is awarded at the sole discretion of Bristol-Myers Squibb based on the above and other criteria that Bristol-Myers Squibb considers applicable to research grants.

THE ASCO POST – AD FOR JUNE 25, 2015 ISSUE14618302_0050001_Ped_Onc_ASCO_Post_Ad_v3_M.indd 1 5/18/15 3:03 PM

http://www.bms.com/pages/default.aspx

http://www.bms.com/clinical_trials/investigator_sponsored_research/Pages/default.aspx


Journal Spotlight

16-Gene Assay Recurrence Score Predicts Recurrence After Surgery for Localized Renal Cell CarcinomaBy Matthew Stenger

In a study reported in The Lancet Oncology, Brian Rini, MD, of the

Cleveland Clinic Taussig Cancer Insti-tute, and colleagues developed a 16-gene assay and recurrence score that predicted postoperative outcome in pa-tients with stage I to III clear cell renal cell carcinoma.1

Development PhaseIn the development phase, exami-

nation of the association between ex-pression of 732 genes measured by re-verse transcription–polymerase chain reaction and clinical outcome in 942 patients with stage I to III clear cell re-nal cell carcinoma who had undergone nephrectomy at the Cleveland Clinic yielded 516 genes that were associated with a recurrence-free interval.

In this population, 63% of patients were male; the median age was 62 years (26% ≥ 70 years); 58% had radical sur-gery; 49% had a tumor size ≤ 4 cm; stage was I in 68%, II in 10%, and III in 22%; necrosis was present in 17%; Fuhrman grade was 1 in 0.4%, 2 in 56%, 3 in 35%, and 4 in 9%; 0.5% had positive nodes; and 23% had recurrence.

Of the 516 genes, 11 were selected by additional statistical analyses and were combined with 5 reference genes, with a recurrence score (0–100) algorithm be-ing developed. The genes included in the assay consisted of those involved in vascu-lar processes (APOLD1, EDNRB, NOS3, PPAP2B), cell growth/division (EIF-4EBP1, TUBB2A, LMNB1), immune response (CEACAM1, CX3CL1, CCL5), and inflammation (IL-6) as well as the reference genes (AAMP, ARF1, ATP5E, GPX1, RPLP1).

Validation PhaseIn the validation phase, the recurrence

score was investigated in a French cohort

of 626 patients. In this population, 71% of patients were male (P = .002 vs devel-opment cohort); the median age was 61 years (29% ≥ 70 years); 64% had radical surgery (P = .01); 46% had a tumor size ≤ 4 cm; stage was I in 64%, II in 9%, and III in 28% (P = .03); necrosis was pres-ent in 33% (P < .0001); Fuhrman grade was 1 in 4%, 2 in 30%, 3 in 46%, and 4 in 20% (P < .0001); 0.6% had positive nodes; and 16% had recurrence.

Risk PredictionOn univariate analysis, the continu-

ous recurrence score (median = 37) was associated with a recurrence-free inter-val, with a hazard ratio (HR) of 3.91 (P < .0001) for each 25-unit increase in the score. Other significant predictors on univariate analysis were tumor size

(HR = 2.63, P = .002, for ≤ 4 vs > 4 cm), Fuhrman grade (HR = 2.84, P < .0001, for 3–4 vs 1–2), and Leibovich score (HRs = 4.31 for high vs low and 3.08 for intermediate vs low, P = .01).

On multivariate analysis, the recur-rence score was a significant predictor of recurrence, with a hazard ratio of 3.37 (P < .0001) for each 25-unit in-crease after stratification by stage and adjustment for tumor size and Fuhrman grade. No significant interaction of re-

currence score with any of the covari-ates for recurrence-free interval was observed (all P > .10).

In multivariate analysis including the Leibovich score, the recurrence score remained a significant predictor of re-currence, with a hazard ratio of 4.20 (P < .0001) per 25-unit increase, and the Leibovich score was no longer a signifi-cant predictor (P = .06). Tumor size re-mained a significant predictor on multi-

variate analysis (HR = 2.09, P = .02). The C statistic for recurrence with recurrence score alone was 0.79; the addition of re-currence score to the Leibovich score improved the C statistic to 0.81 from 0.74 with the Leibovich score alone.

Change in Risk GroupingThe recurrence score identified pa-

tients with stage I disease at high risk and patients with stage II to III disease at low risk. The recurrence score thresh-

olds of 32 and 44 were identified post hoc as distinguishing risk levels, with scores < 32 indicating low risk, scores 32–44 indicating intermediate risk, and scores > 44 indicating high risk.

On this basis, 39% of 398 stage I pa-tients were at low risk, with a mean 5-year recurrence risk of 2%, and 15% were at high risk, with a mean 5-year recurrence risk of 23%. Among patients with stage II to III disease, 19% of 224 were at low risk, with a mean 5-year recurrence risk of 2%, and 44% were at high risk, with a mean 5-year recurrence risk of 39%. The recurrence score risk groupings distin-guished 5-year overall survival and renal cancer–specific survival rates in patients with stage I disease and in those with stage II to III disease.

The investigators concluded: “Our findings validate the recurrence score as a predictor of clinical outcome in pa-tients with stage I to III clear cell renal cell carcinoma, providing a more accu-rate and individualized risk assessment beyond existing clinical and pathologi-cal parameters.” n

Disclosure: The study was funded by Genomic Health Inc and Pfizer Inc. For full disclosures of the study authors, visit www.thelancet.com.

Reference1. Rini B, Goddard A, Knezevic D, et al:

A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: Development and validation studies. Lancet Oncol 16:676-685, 2015.

Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I to III clear cell renal cell carcinoma, providing a more accurate and individualized risk assessment beyond existing clinical and pathological parameters.

—Brian Rini, MD, and colleagues

Genitourinary Oncology

twitter.com/ascopost

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Predicting Recurrence Risk in Renal Cell Carcinoma

■ The 16-gene assay recurrence score was significantly associated with the risk of recurrence in patients with stage I to III clear cell renal cell carcinoma.

■ The recurrence score identified high-risk stage I patients and low-risk stage II to III patients.


Perspective

Predicting Recurrence After Surgery in Renal Cell Carcinoma: 16-Gene Assay Recurrence Score Ushers in New EraBy Derek Raghavan, MD, PhD

In a study reported in The Lancet Oncology and reviewed in this issue

of The ASCO Post, Brian Rini, MD, of the Cleveland Clinic Taussig Can-cer Institute, and colleagues showed that a 16-gene assay recurrence score could predict postoperative outcome in patients with stage I to III clear cell renal cell carcinoma.1 The work re-ported by Dr. Rini and colleagues rep-resents a forecast of the future.

The team at the Taussig Cancer In-stitute was an early adopter of the ser-vices offered from Genomic Health, during my watch as Head of the Insti-tute, and I was delighted at the produc-tive collaboration that emerged. Several hallmark studies have been published on gene expression in colorectal can-cer, prostate cancer, and now renal carcinoma by the Genomic Health and Taussig Cancer Institute teams. In each case, important signatures that allow molecular prediction and prognostica-

tion with a pretty strong degree of reli-ability have been identified.

Algorithm Stands the Test of Time

The Cleveland Clinic genitourinary oncology team, formerly headed by Ron Bukowski, MD, Eric Klein, MD, and Rob Dreicer, MD, took leadership roles in identifying important clinical prog-nosticators for the management of ad-vanced renal cell carcinoma and created an important algorithm that has stood the test of time. Now Rini et al have ex-tended these clinical observations to the molecular level, leveraging the Cleveland Clinic tissue resources, augmented by an international collaboration.

There are two aspects that particular-ly appeal to me about this work. First, this is intelligent, hypothesis-driven transla-tional science, as one would expect from Dr. Rini and his partners—focused on known gene expression, mechanisms of invasion, metastasis, tumor vasculariza-tion, inflammatory response, and tumor growth. This is so much better than the soft science that we constantly encoun-ter focused on molecular fishing expedi-

tions in which “investigators” perform batteries of random gene tests and hope to find “something.”

Second, as I recall it, Genomic Health actually funded these studies, rather than simply charging the system for unproven technology. I have always been puzzled by the tendency of molecular diagnostic groups to provide unproven and some-times unvalidated services to the oncol-ogy community while happily charging somebody (health funds, Medicare, patients) for their services. By contrast, most of the ethical pharmaceutical in-dustry tends to bankroll its early-phase studies, choosing to make profits once

specific efficacy has been identified.Perhaps the most important issue

here is that we are seeing an elegant inter-play of careful clinical investigation with hypothesis-driven molecular science. Ef-forts such as this one will lead to a new era in prediction of outcomes that will refine our approaches to treatment. n

Disclosure: Dr. Raghavan reported no potential conflicts of interest.

Reference1. Rini B, Goddard A, Knezevic D, et

al: A 16-gene assay to predict recurrence after surgery in localised renal cell carci-noma. Lancet Oncol 16:676-685, 2015.

We are seeing an elegant interplay of careful clinical investigation with hypothesis-driven molecular science. Efforts such as this one will lead to a new era in prediction of outcomes that will refine our approaches to treatment.

—Derek Raghavan, MD, PhD

Don’t Miss these iMportant reports in this issue of The ASCO POST

Amir Qaseem, MD, PhD, MHA, FACP, on High-Value Screening see page 66

Robert Andtbacka, MD, on Oncolytic Immunotherapy see page 17

Robin Hardbattle, MS, LAc, on Fitness Programs for Children With Cancer see page 40

Clara D. Bloomfield, MD, FASCO, Reflects on Her Career see page 50

Edward B. Garon, MD, on Pembrolizumab in NSCLC see page 30

Matthias Gromeier, MD, on the Poliovirus in Glioblastoma Treatment see page 15

Patrick Conway, MD, on Medicare and Translating Science Into Government Policy see page 47

Brian Rini, MD, on a 16-Gene Assay Predictive of Recurrence of Localized Renal Cell Carcinoma see page 24

Leonard Saltz, MD, on Costs of Immunotherapy see page 14

Visit The ASCO Post online at ASCOPost.com

Dr. Raghavan is President, Levine Cancer Institute, Carolinas HealthCare System, and Professor, University of North Caro-lina School of Medicine, Chapel Hill.

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0.8

0.6

0.4

0.2

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TIME FROM RANDOMIZATION (MONTHS)

330

335

308

294

267

241

228

180

185

143

148

109

116

81

78

64

60

47

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24

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CYRAMZA + paclitaxelPlacebo+ paclitaxel

Hazard Ratio=0.81(0.68, 0.96); P=0.017

CYRAMZA+ paclitaxelPlacebo+ paclitaxel

9.6MONTHS

CYRAMZA+ paclitaxel

(8.5, 10.8)

7.4MONTHS

Placebo+ paclitaxel(6.3, 8.4)

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1

• Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1

- The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively

• Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

2 FDA APPROVALSFor use both as monotherapy and in combination with paclitaxel

The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

CI=confidence interval. *Intent-to-treat (ITT) population.† ITT population. ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

RAINBOW OS: MEDIAN - MONTHS (95% CI)*1 MAJOR OUTCOME MEASURE

Warnings and PrecautionsHemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage,

including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest,

cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension• An increased incidence of severe hypertension occurred in patients receiving

CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs)• Prior to the institution of premedication recommendations across clinical

trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations• CYRAMZA is an antiangiogenic therapy that can increase the risk of

gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing• Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis• Clinical deterioration, manifested by new onset or worsening encephalopathy,

ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)• RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA.

Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for

the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction• Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity• Based on its mechanism of action, CYRAMZA can cause fetal harm when

administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—Single Agent• The most commonly reported adverse reactions (all grades; grade 3/4) occurring

in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Most Common Adverse Reactions—Combination with Paclitaxel• The most commonly reported adverse reactions (all grades; grade 3/4)

occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).

• The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.

• Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions• No pharmacokinetic interactions were observed between ramucirumab

(CYRAMZA) and paclitaxel.

Use in Specific Populations• Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm.

Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB HCP ISI 24APR2015

References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b.

RB97116 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALINGHemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

CLIENT: Lilly FINISH SIZE: 21.75” wide x 14” high

JOB#: 29889-22 “Tabloid” ARTIST: MC

LOCATION: Mechanicals COLLECT DATE:

R|O|U|T|I|N|G| |S|T|A|G|E M04ED CW AD CPM ACD AE inserv

B:14.25 in

B:22 in

T:14 in

T:21.75 in

S:13 in

S:19 in

http://www.cyramzahcp.com/index.html?srcid=trusem_google_cyramza&WT.srch=1&WT.mc_id=71700000011132710-58700000587672070-43700007565376308

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30% INCREASEIN MEDIAN OS

1.0

0.8

0.6

0.4

0.2

0.0

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330

335

308

294

267

241

228

180

185

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109

116

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60

47

41

30

24

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0

Number at Risk

CYRAMZA + paclitaxelPlacebo+ paclitaxel

Hazard Ratio=0.81(0.68, 0.96); P=0.017

CYRAMZA+ paclitaxelPlacebo+ paclitaxel

9.6MONTHS

CYRAMZA+ paclitaxel

(8.5, 10.8)

7.4MONTHS

Placebo+ paclitaxel(6.3, 8.4)

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1

• Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1

- The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively

• Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

2 FDA APPROVALSFor use both as monotherapy and in combination with paclitaxel

The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

CI=confidence interval. *Intent-to-treat (ITT) population.† ITT population. ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

RAINBOW OS: MEDIAN - MONTHS (95% CI)*1 MAJOR OUTCOME MEASURE

Warnings and PrecautionsHemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage,

including severe and sometimes fatal hemorrhagic events. In study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events (ATEs)• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac arrest,

cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension• An increased incidence of severe hypertension occurred in patients receiving

CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions (IRRs)• Prior to the institution of premedication recommendations across clinical

trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for grade 3 or 4 IRRs.

Gastrointestinal Perforations• CYRAMZA is an antiangiogenic therapy that can increase the risk of

gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing• Impaired wound healing can occur with antibodies inhibiting the VEGF pathway.

CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis• Clinical deterioration, manifested by new onset or worsening encephalopathy,

ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)• RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA.

Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for

the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome.

Thyroid Dysfunction• Monitor thyroid function during treatment with CYRAMZA. Embryofetal Toxicity• Based on its mechanism of action, CYRAMZA can cause fetal harm when

administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions—Single Agent• The most commonly reported adverse reactions (all grades; grade 3/4) occurring

in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• The most common serious adverse events with CYRAMZA in study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Most Common Adverse Reactions—Combination with Paclitaxel• The most commonly reported adverse reactions (all grades; grade 3/4)

occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%).

• The most common serious adverse events with CYRAMZA plus paclitaxel in study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors.

• Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in study 2 were neutropenia (4%) and thrombocytopenia (3%).

• Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions• No pharmacokinetic interactions were observed between ramucirumab

(CYRAMZA) and paclitaxel.

Use in Specific Populations• Pregnancy: Based on its mechanism of action, CYRAMZA can cause fetal harm.

Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page.

RB HCP ISI 24APR2015

References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b.

RB97116 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved.

CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALINGHemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

CLIENT: Lilly FINISH SIZE: 21.75” wide x 14” high

JOB#: 29889-22 “Tabloid” ARTIST: MC

LOCATION: Mechanicals COLLECT DATE:

R|O|U|T|I|N|G| |S|T|A|G|E M04ED CW AD CPM ACD AE inserv

B:14.25 in

B:22 in

T:14 in

T:21.75 in

S:13 in

S:19 in

http://www.cyramzahcp.com/

CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015 CYRAMZA® (ramucirumab) injection RB-G HCP BS 29APR2015

CYRAMZA RB-G HCP BS 29APR2015 9.25 x 13.25 PRINTER VERSION 1 OF 2

CYRAMZA® (ramucirumab) injectionBRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALINGHemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGEGastric CancerCYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSHemorrhageCYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.HypertensionAn increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.Infusion-Related ReactionsPrior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.Gastrointestinal PerforationsCYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.Impaired Wound HealingImpaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.Clinical Deterioration in Patients with Child-Pugh B or C CirrhosisClinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA.

ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1

Adverse Reactions (MedDRA)a

System Organ Class

CYRAMZA (8 mg/kg)N=236

PlaceboN=115

All Grades(Frequency %)

Grade 3-4(Frequency %)



Gastrointestinal Disorders Diarrhea 14 1 9 2

Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1

Nervous System Disorders Headache 9 0 3 0

Vascular Disorders Hypertension 16 8 8 3

aMedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients

Receiving CYRAMZA plus Paclitaxel in Study 2

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA plus Paclitaxel(N=327)

Placebo plus Paclitaxel(N=329)


Grade ≥3(Frequency %)



Blood and Lymphatic System DisordersNeutropenia 54 41 31 19


Gastrointestinal DisordersDiarrhea 32 4 23 2

Gastrointestinal hemorrhage events

10 4 6 2

Stomatitis 20 1 7 1

General Disorders and Administration Site Disorders

Fatigue/Asthenia 57 12 44 6

Peripheral edema 25 2 14 1

Metabolism and Nutrition Disorders

Hypoalbuminemia 11 1 5 1

Renal and Urinary Disorders

Proteinuria 17 1 6 0

Respiratory, Thoracic, and Mediastinal Disorders

Epistaxis 31 0 7 0

Vascular Disorder

Hypertension 25 15 6 3



Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).ImmunogenicityAs with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONSNo pharmacokinetic interactions were observed between ramucirumab and paclitaxel.

USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryBased on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.Animal DataNo animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.LactationRisk SummaryThere is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.Females and Males of Reproductive PotentialContraceptionFemalesBased on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA.InfertilityFemalesAdvise females of reproductive potential that based on animal data CYRAMZA may impair fertility.Pediatric UseThe safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.Geriatric UseOf the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Renal ImpairmentNo dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.Hepatic ImpairmentNo dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

DOSAGE AND ADMINISTRATION

Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and ScheduleThe recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.PremedicationPrior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.Dose ModificationsInfusion-Related Reactions (IRR)• Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs.• Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.Hypertension• Interrupt CYRAMZA for severe hypertension until controlled with medical management.• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with

antihypertensive therapy.Proteinuria• Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose

of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications• Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding• Permanently discontinue CYRAMZA.

For toxicities related to paclitaxel, refer to the current prescribing information.

PATIENT COUNSELING INFORMATION• Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness]. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. • Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment. • Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA

Additional information can be found at www.CYRAMZAHCP.com.

Eli Lilly and Company, Indianapolis, IN 46285, USACopyright © 2015, Eli Lilly and Company. All rights reserved.

RB-G HCP BS 29APR2015



CYRAMZA® (ramucirumab) injectionBRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALINGHemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

INDICATIONS AND USAGEGastric CancerCYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSHemorrhageCYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding.Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.HypertensionAn increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.Infusion-Related ReactionsPrior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.Gastrointestinal PerforationsCYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.Impaired Wound HealingImpaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.Clinical Deterioration in Patients with Child-Pugh B or C CirrhosisClinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients.

Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA.

ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal.CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months.In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1

Adverse Reactions (MedDRA)a

System Organ Class

CYRAMZA (8 mg/kg)N=236

PlaceboN=115





Gastrointestinal Disorders Diarrhea 14 1 9 2

Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1

Nervous System Disorders Headache 9 0 3 0

Vascular Disorders Hypertension 16 8 8 3

aMedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months.In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%).

Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients

Receiving CYRAMZA plus Paclitaxel in Study 2

Adverse Reactions (MedDRA) System Organ Class

CYRAMZA plus Paclitaxel(N=327)

Placebo plus Paclitaxel(N=329)





Blood and Lymphatic System DisordersNeutropenia 54 41 31 19


Gastrointestinal DisordersDiarrhea 32 4 23 2

Gastrointestinal hemorrhage events

10 4 6 2

Stomatitis 20 1 7 1

General Disorders and Administration Site Disorders

Fatigue/Asthenia 57 12 44 6

Peripheral edema 25 2 14 1

Metabolism and Nutrition Disorders

Hypoalbuminemia 11 1 5 1

Renal and Urinary Disorders

Proteinuria 17 1 6 0

Respiratory, Thoracic, and Mediastinal Disorders

Epistaxis 31 0 7 0

Vascular Disorder

Hypertension 25 15 6 3



Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel).ImmunogenicityAs with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONSNo pharmacokinetic interactions were observed between ramucirumab and paclitaxel.

USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryBased on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.Animal DataNo animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.LactationRisk SummaryThere is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.Females and Males of Reproductive PotentialContraceptionFemalesBased on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA.InfertilityFemalesAdvise females of reproductive potential that based on animal data CYRAMZA may impair fertility.Pediatric UseThe safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.Geriatric UseOf the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Renal ImpairmentNo dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis.Hepatic ImpairmentNo dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA.

DOSAGE AND ADMINISTRATION

Do not administer CYRAMZA as an intravenous push or bolus.

Recommended Dose and ScheduleThe recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel.PremedicationPrior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion-related reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.Dose ModificationsInfusion-Related Reactions (IRR)• Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs.• Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs.Hypertension• Interrupt CYRAMZA for severe hypertension until controlled with medical management.• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with

antihypertensive therapy.Proteinuria• Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose

of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications• Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding• Permanently discontinue CYRAMZA.

For toxicities related to paclitaxel, refer to the current prescribing information.

PATIENT COUNSELING INFORMATION• Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness]. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. • Hypertension: Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • Impaired wound healing: Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment. • Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA

Additional information can be found at www.CYRAMZAHCP.com.

Eli Lilly and Company, Indianapolis, IN 46285, USACopyright © 2015, Eli Lilly and Company. All rights reserved.

RB-G HCP BS 29APR2015


Journal Spotlight

PD-1 Inhibitor Pembrolizumab Active in Advanced NSCLC: Outcomes Better With Higher PD-L1 ExpressionBy Matthew Stenger

In the phase I KEYNOTE-001 trial reported in The New England Journal

of Medicine,1 Edward B. Garon, MD, of the David Geffen School of Medicine at the University of California, Los Ange-les, and colleagues found that the pro-grammed cell death protein 1 (PD-1) inhibitor pembrolizumab (Keytruda) produced durable responses in patients with advanced non–small cell lung can-cer (NSCLC). Response rate and pro-gression-free survival were increased in patients with higher levels of PD-1 ligand 1 (PD-L1).

Study DetailsIn the study, 495 patients received

at least one dose of pembrolizumab between May 2012 and February 2014. Patients were assigned to a dose of 2 mg (n = 6) or 10 mg/kg (n = 287) every 3 weeks or 10 mg/kg every 2 weeks (n = 202) in either a training group (n = 182) or a validation group (n = 313).

PD-L1 expression was measured in tumor samples using immunohisto-chemical analysis; a proportion score was generated using the percentage of neoplastic cells with staining for mem-branous PD-L1. Response was assessed by central review every 9 weeks.

Among all patients: median age was 64 years; 53% were male; 82% were white; 35% and 64% had East-ern Cooperative Oncology Group performance status of 0 and 1; EGFR mutation was present in 15%, KRAS mutation in 26%, and ALK alteration in 2%; histology was nonsquamous in 81%; 24%, 21%, and 21% had received two, three, and at least four prior sys-temic therapies; 10% had a history of brain metastases; and 25% were never-smokers.

Outcome in All PatientsAt the time of data cutoff, median

duration of follow-up was 10.9 months (range = 5.2–27.5 months), and 115 pa-tients (23%) continued to receive treat-ment. Among all patients, the objective response rate was 19.4% (95% confi-dence interval [CI] = 16.0%–23.2%), including 18.0% (95% CI = 14.4%–22.2%) in 394 previously treated pa-tients and 24.8% (95% CI = 16.7%–34.3%) in 101 previously untreated patients. Stable disease was observed in 21.8% of patients.

Response rate was similar irrespec-tive of dose, schedule, or histology. Cur-rent or former smokers had a higher re-sponse rate than never-smokers (22.5% vs 10.3%).

At the time of analysis, 84.4% of pa-tients with a response had no disease progression. Median duration of re-sponse was 12.5 months (range = 1.0–23.3 months) in all patients, including 10.4 months (range = 1.0–10.4 months) in previously treated patients and 23.3 months (range = 1.0–23.3 months) in previously untreated patients.

Median progression-free survival was 3.7 months (95% CI = 2.9–4.1 months) among all patients, including 3.0 months (95% CI = 2.2–4.0 months) in previously treated patients and 6.0

months (95% CI = 4.1–8.6 months) in previously untreated patients. Median overall survival was 12.0 months (95% CI = 9.3–14.7 months) among all the patients, including 9.3 months (95% CI = 8.4–12.4 months) in previously treat-ed patients and 16.2 months (95% CI = 16.2 months to not reached) in previ-ously untreated patients.

Patients With High PD-L1 Expression

PD-L1 expression in ≥ 50% of tu-mor cells was selected as the propor-tion score cutoff for high expression in analysis of the training group. Among 824 samples from the total of 1,143 pa-tients screened for the trial, PD-L1 pro-portion scores were ≥ 50% in 23.2%, 1%

to 49% in 37.6%, and < 1% in 39.2%, with proportion scores ≥ 50% in 24.9% of previously untreated patients and 22.7% of previously treated patients.

In the validation group, PD-L1 status could not be assessed in 83 patients. In the remainder, the objective response rate was 45.2% (95% CI = 33.5%–57.3%) in 73 patients with a proportion score ≥ 50%, including rates of 43.9% (95% CI = 30.7%–57.6%) in previously treated patients and 50.0% (95% CI = 24.7%–75.3%) in previously untreated patients. No marked difference in re-sponse rate was observed according to dose, schedule, or smoking status in patients with a proportion score ≥ 50%.

Among 356 evaluable patients in the training and validation groups, PD-L1 expression proportion scores were ≥ 50% in 119, 1% to 49% in 161, and < 1% in 76. Median progression-free

survival among patients with a propor-tion score ≥ 50% was 6.3 months (95% CI = 2.9–12.5 months) among all pa-tients, including 6.1 months (95% CI = 2.1–12.5 months) in 294 previously treated patients and 12.5 months (95% CI = 2.4–12.5 months) in 62 previous-ly untreated patients. Median overall survival among patients with a pro-portion score ≥ 50% was not reached in all patients (95% CI = 13.7 months to not reached), in previously treated patients (95% CI = 9.3 months to not reached), or in previously untreated patients (95% CI = not reached to not reached).

Adverse EventsThe most common treatment-related

adverse events of any grade were fatigue (19%), pruritus (11%), and decreased appetite (11%), with no clear difference according to dose or schedule. Treat-ment-related grade ≥ 3 adverse events occurred in 9.5% of patients, with the most common being dyspnea (3.8%) and pneumonitis (1.8%). Treatment-related inflammatory or immune-medi-ated adverse events occurring in > 2% of patients consisted of infusion-related re-actions (3.0%), hypothyroidism (6.9%), and pneumonitis (3.6%).

Treatment discontinuation due to an infusion-related reaction occurred in one patient. One patient died from treatment-related pneumonitis.

The investigators concluded: “[W]e have shown the efficacy and safety of pem-brolizumab for previously treated and pre-viously untreated patients with non–small-cell lung cancer. Prospective testing of PD-L1 expression is feasible and retrospec-tively identified patients with an enhanced likelihood of having a clinical benefit from treatment with pembrolizumab.” n

Disclosure: The study was funded by Merck. For full disclosures of the study authors, visit www.nejm.org.

Reference1. Garon EB, Rizvi NA, Hui R, et

al: Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

Thoracic Oncology

Prospective testing of PD-L1 expression is feasible and retrospectively identified patients with an enhanced likelihood of having a clinical benefit from treatment with pembrolizumab.

—Edward B. Garon, MD, and colleagues

Pembrolizumab in Advanced NSCLC: The Promise of Immune Checkpoint Inhibitors See discussion by Vamsidhar Velcheti, MD, and Roy Herbst, MD, PhD, on page 31.

Pembrolizumab in Advanced Lung Cancer

■ Objective response was observed in 19% of patients, including 18% of previously treated patients and 25% of previously untreated patients.

■ Response rate, progression-free survival, and overall survival were greater in patients with higher PD-L1 expression.


Perspective

Thoracic Cancer

Pembrolizumab in Advanced NSCLC: The Promise of Immune Checkpoint InhibitorsBy Vamsidhar Velcheti, MD, and Roy Herbst, MD, PhD

D rugs targeting the immune-checkpoint pathways have

shown promising activity in non–small cell lung cancer (NSCLC). In a recent article in The New England Journal of Medicine, Garon and col-leagues reported the results of the KEYNOTE-001 clinical trial evalu-ating single-agent pembrolizumab (Keytruda) in patients with advanced NSCLC1; the study is reviewed in this issue of The ASCO Post.

Pembrolizumab is a humanized monoclonal IgG4 antibody directed against programmed cell death pro-tein 1 (PD-1). PD-1 is a co-inhibitory receptor on activated T cells that can promote T-cell exhaustion on binding to its ligand PD-L1, thus inhibiting the cytotoxic T-cell response.2 PD-L1 expression is a common mechanism of immune evasion in NSCLC.3

A Closer Look at KEYNOTE-001

KEYNOTE-001 is a large inter-national multicenter phase I trial evaluating the safety and efficacy of pembrolizumab in patients with ad-vanced melanoma and NSCLC. The lung cohort of the trial enrolled a total of 495 patients with advanced NSCLC; among these patients, 384 had received prior therapies, and 101 patients were treatment-naive.

The adverse effect profile of pem-brolizumab in the trial was favorable, with less than 10% of patients expe-riencing grade 3 or higher toxicities. The most common immune-related adverse event was hypothyroidism (6.9%, any grade), which was report-ed to be easily managed with thyroid supplementation. Pneumonitis was reported in 18 of the 495 patients (3.6%), and half of them were report-ed to be grade 3 or higher (including one death, 0.2%).

The overall response rate for the study was 19.4% in the total of 495

patients evaluated (18% in 394 pre-viously treated patients and 24.8% in 101 untreated patients). The median duration of response was 12.5 months in the overall population and nearly 2 years in previously untreated patients.

The trial evaluated the role and the optimal cut point of PD-L1 expres-sion in predicting response to pem-brolizumab. Of the 495 patients, 182 patients were enrolled in the training cohort, and 313 patients were en-rolled in the validation cohort. The PD-L1 diagnostic assay employed was Dako EnVision FLEX+/HRP polymer kit, using the antibody clone 22C3 to detect PD-L1.

Using receiver-operating-charac-teristic curve analysis in the training cohort of 182 patients, the PD-L1 cutoff was determined to be membra-nous PD-L1 expression in at least 50% of tumor cells. Using this cut point, nearly one-quarter of the patients evaluated tested positive for PD-L1 expression.

The objective response rate in PD-L1–positive patients was 45.2%, and the median overall survival was not reached. Response rates were 16.5% in patients who had low expression of PD-L1 (1%–49%) and 10.7% in those who were PD-L1–negative (< 1%).

The results of the KEYNOTE-001 trial further our understanding of and enthusiasm for this exciting class of drugs for the treatment of lung cancer. The most consistent finding with these agents is the du-rability of responses. This was again demonstrated in this trial, with the median duration of response being over a year in patients responding to pembrolizumab (84.4% of the re-sponders had no disease progression at the time of the data cutoff for the publication).

Potential Predictive Biomarker

Early clinical studies with PD-1/PD-L1 inhibitors suggested PD-L1 expression by immunohistochem-istry may predict response to these agents.4-7 However, clinical trials have measured tumor PD-L1 expression using immunohistochemistry with different antibodies, including Dako clone 28-8 (nivolumab [Opdivo]), Spring Bioscience clone SP142 (MP-

DL3280A), Spring Bioscience clone SP262 (MEDI4736), and, in the cur-rent study with pembrolizumab, Dako clone 22C3.

In addition, trials reported thus far had variable definitions of positiv-ity for PD-L1; some assays use tumor expression, whereas others use PD-L1 staining in the stromal immune in-filtrates. The percentages of positive cells required to consider the case as positive or negative are also dissimilar.

Moreover, there also appears to be inherent spatial and temporal hetero-geneity of PD-L1 expression as a func-tion of interaction and adaptation to the dynamic tumor immune microen-vironment. Hence, the reproducibil-ity of PD-L1 assays and their potential as a predictive biomarker have been questioned.

The biomarker evaluation in KEYNOTE-001 trial was well planned and had comprehensive vali-dation in an independent cohort. The findings from this trial suggest the predictive value of PD-L1 expression, with nearly 50% response rates in PD-L1–positive (> 50% tumor cells) pa-tients. However, in patients who were defined as PD-L1–low or –negative (< 50% tumor cells), the responses rates were still higher than expected with cytotoxic chemotherapy (15.2% in the validation cohort overall). These results will be further explored in an ongoing prospective random-ized phase III trial of docetaxel vs pembrolizumab (KEYNOTE-10).

Closing CommentsThe KEYNOTE-001 trial provides

valuable information regarding the role of PD-L1 expression and the ef-ficacy of pembrolizumab in both re-fractory and treatment-naive patients with NSCLC. The PD-L1 assay used in the trial appears to enrich for pa-tients who could potentially respond to pembrolizumab. However, the drug also has activity in low–PD-L1 pa-tients and is comparable (and perhaps superior) to cytotoxic chemotherapy in NSCLC, especially in the refractory setting.

Thus, the utility of the PD-L1 assay in NSCLC patients, particularly in the second line and beyond, remains un-certain. However, PD-L1 expression in the future could potentially be used to stratify patients in clinical trials and inform decisions regarding combina-torial strategies with other immuno-therapies, chemotherapy, or radiation therapy. n

Disclosure: Dr. Velcheti reported no potential conflicts of interest. Dr. Herbst has been a consultant for Merck.

References1. Garon EB, Rizvi NA, Hui R, et

al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

2. Schalper KA, Venur VA, Velcheti V: Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: Current insights. J Receptor Ligand Channel Res 8:1-7, 2015.

The results of the KEYNOTE-001 trial further our understanding of and enthusiasm for this exciting class of drugs for the treatment of lung cancer. The most consistent finding with these agents is the durability of responses.

—Vamsidhar Velcheti, MD (top), and Roy Herbst, MD, PhD (bottom)


Dr. Velcheti is Assistant Professor, De-partment of Hematology and Oncology, Cleveland Clinic. Dr. Herbst is Ensign Professor of Medicine, Professor of Phar-macology, Chief of Medical Oncology, Director, Thoracic Oncology Research Program, Associate Director for Trans-lational Research, Yale Comprehensive Cancer Center, Yale School of Medicine.


Perspective

3. Velcheti V, Schalper KA, Carvajal DE, et al: Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 94:107-116, 2014.

4. Taube JM, Klein A, Brahmer JR,

et al: Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064-5074, 2014.

5. Topalian SL, Sznol M, McDermott DF, et al: Survival, durable tumor remis-

sion, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020-1030, 2014.

6. Herbst RS, Gordon MS, Fine GD, et al: A study of MPDL3280A, an engi-neered PD-L1 antibody in patients with locally advanced or metastatic tumors.

2013 ASCO Annual Meeting. Abstract 3000.

7. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.

Pembrolizumab in NSCLCcontinued from page 31

Don't Miss These Important

Reports in this issue of

The ASCO Post

Gregory T. Armstrong, MD, on Survivors of Childhood Cancer Living Longer and Better Lives see page 1

For more on prostate cancer, visit

ASCOPost.com

Richard J. Boxer, MD, FACS, on Biosimilars see page 1

Richard G. Margolese, MD, on Anastrozole and Tamoxifen for Ductal Carcinoma in Situ see page 4

REFERENCE: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119.

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Studies have shown that the MAPK pathway plays an important role in some cancers.1

Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2015 Genentech USA, Inc. All rights reserved. COB/092414/0002(1) Printed in USA.

79235ha_b.indd All Pages 5/19/15 4:31 PM

http://www.ncbi.nlm.nih.gov/pubmed/?term=Schalper KA%5BAuthor%5D&cauthor=true&cauthor_uid=24217091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Carvajal DE%5BAuthor%5D&cauthor=true&cauthor_uid=24217091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Carvajal DE%5BAuthor%5D&cauthor=true&cauthor_uid=24217091

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sznol M%5BAuthor%5D&cauthor=true&cauthor_uid=24590637

http://www.ncbi.nlm.nih.gov/pubmed/?term=McDermott DF%5BAuthor%5D&cauthor=true&cauthor_uid=24590637

http://www.ncbi.nlm.nih.gov/pubmed/?term=McDermott DF%5BAuthor%5D&cauthor=true&cauthor_uid=24590637

http://www.gene.com/


Announcements

Bert Vogelstein, MD, Receives 2015 Dr. Paul Janssen Award for Biomedical Research

Johnson & Johnson named Bert Vogelstein, MD, of Johns Hop-

kins University, Johns Hopkins Kim-mel Cancer Center, and the Howard

Hughes Medical Institute, the winner of the 2015 Dr. Paul Janssen Award for Biomedical Research for his break-throughs in oncology research, which

have spanned more than 2 decades and have formed the basis of modern cancer research.

Dr. Vogelstein was honored June 16

during a reception at the 2015 BIO In-ternational Convention in Philadelphia.

The award is named for Dr. Paul Janssen, one of the 20th century’s most gifted and passionate researchers. He helped save millions of lives through his contribution to the discovery and de-velopment of more than 80 medicines, four of which remain on the World Health Organization’s list of essential medicines.

“Dr. Vogelstein’s work forms the paradigm for understanding how nearly all forms of human tumors arise and progress,” said Paul Stoffels, MD, Chief Scientific Officer and Worldwide Chairman, Pharmaceuticals, Johnson & Johnson. “His discoveries triggered a new wave of innovation in the field, resulting in transformational solutions for patients.”

Discoveries in Genetics and Biomarkers

Beginning in the 1980s, Dr. Vogel-stein and his colleagues designed novel approaches to study the molecular basis of colorectal tumors and found that they result from the sequential accumulation of alterations in oncogenes and tumor suppressor genes. His group went on to discover many of the most important of these genes, such as TP53, the gene encoding the p53 protein, altered more often than any other gene across tumor types. Dr. Vogelstein’s work throughout the past 2 decades has continued to il-luminate cancer genes and the pathways

I set out to determine what molecular changes drive malignancy, in the

hope that this would lead to improved approaches to

diagnosis and therapy. —Bert Vogelstein, MD


REFERENCE: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119.

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Studies have shown that the MAPK pathway plays an important role in some cancers.1

Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

IN ONCOLOGY, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

© 2015 Genentech USA, Inc. All rights reserved. COB/092414/0002(1) Printed in USA.

79235ha_b.indd All Pages 5/19/15 4:31 PM

https://www.mapkpathwayinfo.com/?cid=cob_PR_00005108_1


Direct From ASCO

2015 Breast Cancer Symposium to Encourage Collaboration in Patient Care, Education, and Research

ASCO’s educational symposia have historically provided attendees

with a forum for learning and discussion, demonstrating ASCO’s commitment to promoting a network of global oncol-ogy expertise. The 2015 Breast Cancer Symposium, to be held in San Francisco, California, from Friday, September 25, to Sunday, September 27, will be no ex-ception. It will bring together attendees from all disciplines of oncology practice and research to exchange ideas and learn from each other, with the ultimate goal of improving patient care.

The theme for this year’s Sym-posium—Enhancing Clinical Care Through Collaboration—highlights the importance of cross-disciplinary interaction and cooperation in mak-ing progress against breast cancer. ASCO will cosponsor the Sympo-sium with the American Society of Breast Surgeons, the American Soci-ety of Radiation Oncology, and the Society of Surgical Oncology.

Truly Multidisciplinary The Breast Cancer Symposium is

open to all members of the oncology community interested in the preven-tion, screening, evaluation, and man-agement of breast cancer, resulting in a diverse group of attendees and a vibrant setting for discussion. Medical oncolo-gists, radiation oncologists, surgeons, and other members of the cancer care team will find ample opportunities to make connections with other breast cancer specialists and expand their pro-fessional networks.

With an educational program de-signed to be as multifaceted as its at-tendees, the Symposium will highlight progress in the field of breast cancer management and examine promising directions for future research. Sessions on topics ranging from risk assessment to survivorship care will feature presen-tations from a variety of perspectives, ensuring that all attendees are able to expand their breast cancer knowledge in every session.

Featured SessionsThis year’s Symposium will feature

multidisciplinary sessions to encourage collaboration in patient care, education, and research advancements, as exem-plified in the Featured Sessions here.

The most up-to-date program informa-tion, including session times, speakers, and presentation topics, is available on breastcasym.org.

General Session 1: State-of-the-Art Breast Cancer Care–Past, Present, and Future

In this session, Eric P. Winer, MD, FASCO, of the Dana-Farber Cancer Institute, Eleftherios P. Mamounas, MD, of the UF Health Cancer Center at Orlando Health, and Timothy J. Whelan, BM, BCh, MSc, of Cancer Care Ontario, will discuss where we are and where we are going in medical, surgical, and radiation oncology and correlate science with current clinical issues. The presentations will include lessons learned from past practice and how they apply to outstanding issues in the management of breast cancer. To continue the conversation, this session will be followed by a session on the fu-ture of therapy, including ongoing trials and where the field is headed next.

General Session 5: Health Policy and Drug Approvals

The legislative and regulatory envi-ronment strongly affects the manage-ment of breast cancer, and this session will focus on key issues of the day, in-cluding breast density legislation, how the Affordable Care Act is changing oncology practice, and the process for U.S. Food and Drug Administration drug approvals, including ways of get-ting drugs to patients sooner. Session faculty includes Otis W. Brawley, MD, FASCO, of the American Cancer Soci-ety, Jafi Alyssa Lipson, MD, of Stan-ford University School of Medicine, and Suparna B. Wedam, MD, of the National Cancer Institute at the Na-tional Institutes of Health.

General Session 7: Genomics and Personalized/Precision Medicine

Personalized precision medicine is gaining prevalence in current clinical practice, with multiple omics technolo-gies already in use and in development. In this session, Daniel F. Hayes, MD, FASCO, of the University of Michigan Comprehensive Cancer Center, and Nancy E. Davidson, MD, FASCO, of the University of Pittsburgh Cancer Institute, will discuss omics as they

are applicable in the clinic and how they may be used in clinical trials. The session will cover the use of whole-genome sequencing in the prediction, detection, and management of disease. After the didactic presentations, the speakers will participate in a case dis-cussion, highlighting real-world issues in the context of the session.

Gianni Bonadonna Breast Cancer Award

The ASCO Gianni Bonadonna Breast Cancer Award and Lecture will also be presented at the Symposium. First given in 2007, it recognizes an active clinical and/or translational re-searcher with a distinguished record of accomplishments in advancing the field of breast cancer. The award also provides $50,000 to a fellow in the institution of the award recipient.

This year’s recipient is Matthew Ellis, MD, PhD, Director of the Les-ter and Sue Smith Breast Center and Professor of Medicine and Cellular and Molecular Biology at Baylor College of

Medicine. A renowned clinician scien-tist in the area of genomics and molecu-lar profiling of breast cancer, Dr. Ellis has been instrumental in developing a Genome Atlas and Therapeutic Road Map for estrogen receptor –positive breast cancer. He also pioneered re-search into the clinical relevance of acti-vating mutations in HER2 and in the de-ployment of patient-derived xenografts for the pharmacological annotation of breast cancer genomes. He is co-leader for The Cancer Genome Atlas (TCGA) Breast Project and Co-Principal Investi-gator for the Clinical Proteomic Tumor Analysis Consortium, which endeavors to translate TCGA genomic discover-ies into protein-based biomarkers with clinical utility.

The 2015 Breast Cancer Symposium hotel reservation and early registration deadline is August 19, 2015. For more information and to register, please visit breastcasym.org. n

© 2015. American Society of Clinical On-cology. All rights reserved.

Jafi Alyssa Lipson, MD

Eric P. Winer, MD, FASCO

Otis W. Brawley, MD, FASCO

Daniel F. Hayes, MD, FASCO

Eleftherios P. Mamounas, MD

Nancy E. Davidson, MD, FASCO

Timothy J. Whelan, BM, BCh, MSc

Suparna B. Wedam, MD

Matthew Ellis, MD, PhD


Direct From ASCO

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At Amgen, we pour commitment, passion, and a drivefor perfection into every biologic medicine we make.

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our roots go deepFor reliability and quality,

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Direct From ASCO

ASCO QOPI® Certification Program Benefits Oncology Practices and Patients

Christa Braun-Inglis, MS, NP, has seen her last three practices certi-

fied through ASCO’s Quality Oncology Practice Initiative (QOPI®). Ms. Braun-Inglis, a nurse practitioner with Kaiser Hawaii Region, was not solely respon-sible for the designations, although she helped some of the practices become certified. She does, however, take pride in knowing her current and former practices are committed to delivering the highest form of cancer care.

“When patients come to you, they want to know ‘Why should I come to you for my oncology care?’,” Ms. Braun-Inglis said. “[With QOPI], you can show you’ve actually met this certain standard. It gives patients and third-par-ty payers more faith in you to provide quality care.”

The QOPI Certification Program is a 3-year certification for outpatient hematology-oncology practices that helps medical providers facilitate bet-ter care for patients through a series of

performance measures and standards measured through data submitted by individual practices.

There are 261 QOPI-Certified Practic-es in the United States, ranging from small practices to large practices, such as the Dana-Farber Cancer Institute, the H. Lee Moffitt Cancer Center and Research Insti-

tute, the University of Pittsburgh Medical Center, and Tennessee Oncology. One of the larger institutions participating in the QOPI Certification Program is the Uni-versity of Arkansas for Medical Sciences (UAMS). Issam Makhoul, MD, helped the institution receive its certification, a process, he admitted, that was larger than he initially anticipated.

QOPI Certification did not solely involve the university’s hematology-oncology division, but rather the whole institution, requiring significant buy-in from staff, Dr. Makhoul said. The end result, however, not only improved the patient care at UAMS, but also raised ex-pectations for the smaller practices in Ar-kansas, he said. “As a leading institution, you lead by example. In that sense, in my opinion, you are setting the stage here for other institutions to follow suit.”

W. Charles Penley, MD, FASCO, a partner with QOPI-Certified Tennessee Oncology, said the quality certification allowed his practice to identify areas for improvement and improved communi-cation between physicians and nurses. ASCO understands the specific needs of oncologic practices, he said.

“It is a program designed by oncolo-gists, for oncology practices,” said Dr. Penley, Chair of the Conquer Cancer Foundation of the American Society of Clinical Oncology Board of Direc-tors. “The program exists solely to pro-mote quality, with no hidden agenda. It is not a quality program that has been developed by a third-party payer, which could have inherent bias.”

The QOPI Certification Program provides performance measures and standards applicable to multiple aspects

of a patient’s care. If a patient is pre-scribed oral chemotherapy, for example, certification requires the monitoring of toxicities the patient may be experienc-ing and the monitoring of treatment regimen adherence. These guidelines ensure patient access to the medication, as well as a comprehensive understand-ing of the treatment plan and the overall ramifications of treatment compliance. The outlined scenario also requires input from all team members on the physician treatment plan, including physicians, nurses, financial advisors, pharmacologists, and social workers.

The measures and practices applied as part of QOPI Certification are the true benefit of the program, according to Dr. Makhoul. “It’s not about the cer-tificate,” he said. “It’s about the measures that are geared toward a healthy practice focusing on patient-centered care.”

The next qualifying QOPI round opens in September 2015, and all prac-tices that achieve a threshold quality score can then apply for certification after the round closes in November. Practices can learn more about the ap-plication process at qopi.asco.org. Cer-tification is open to U.S. and U.S.-terri-tory practices. Practices are encouraged to apply as a whole entity, as long as they demonstrate that all of their office sites are functionally integrated. n

Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “ ASCO QOPI® Certification Program Ben-efits Practices, Patients.” https://am.asco.org/asco-qopi%C2%AE-certification-pro-gram-benefits-practices-patients. All rights reserved.

Top 10 most-accessed articles published in 2011 in Journal of Clinical Oncology

Top 5 articles recently published in

Journal of Oncology Practice

What’s Hot in

JOPUse of Adjuvant Cisplatin-Based Versus Carboplatin-Based

Chemotherapy in Non–Small-Cell Lung Cancer: Findings From

the Florida Initiative for Quality Cancer Care

by Tawee Tanvetyanon, et al

Hepatitis B Virus Screening for Patients With Cancer Before

Therapy: American Society of Clinical Oncology Provisional

Clinical Opinion Update

by Jessica P. Hwang, et al

Choosing Treatments on the Basis of Cost: Can Clinicians Opt for

Less Expensive Treatments?

by Prabashni Reddy, et al

Redesigning Advanced Cancer Care Delivery: Three Ways to

Create Higher Value Cancer Care

by Manali I. Patel, et al

Projected Clinical, Resource Use, and Fiscal Impacts of

Implementing Low-Dose Computed Tomography Lung Cancer

Screening in Medicare

by Joshua A. Roth, et al

JOP.ascopubs.org

Volume 7, Issue 3 May 2011

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al

Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al

Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al

Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al

Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

Journal of oncology Practice

www.jop.ascopubs.org

ASCO Recommends Palliative Care as Part of Cancer Treatment

A SCO recommends that doc-tors, patients, and caregivers

talk about palliative care soon af-ter diagnosis for any patient with metastatic cancer and for patients with many and/or severe symp-toms. ASCO has developed a re-source to help patients understand the importance of palliative care from diagnosis through treatment and beyond. Order ASCO Answers Palliative Care booklets for your practice at www.cancer.net/estore,

and help your patients bet-ter understand the goals of treatment and maintain their quality of life. Free shipping, and members save 20%. n

© 2015. American Society of Clinical Oncology. All rights reserved.


Direct From ASCO

ASCO Releases Payment Reform Proposal to Support Higher Quality, More Affordable Cancer Care

ASCO has released a proposal to significantly improve the qual-

ity and affordability of care for can-cer patients. Expanding on a payment model circulated last year, the ASCO proposal would fundamentally re-structure the way oncologists are paid for cancer care in the United States, by providing sufficient payment to support the full range of services that cancer patients need and removing the barriers created by the current payment system to delivering high-quality, affordable care.

ASCO’s Patient-Centered Oncology Payment: Payment Reform to Support Higher Quality, More Affordable Can-cer Care (PCOP) proposal is designed

to simultaneously improve services to patients and reduce spending for Medi-care and other payers.

ASCO’s proposal addresses one of the major problems in today’s fee-for-service system: inadequate payment for the wide range of services critical to supporting patients with cancer and managing a complex illness that often changes from day to day. They include:• Education and support to help pa-

tients make the best choices about their cancer treatment,

• Rapid response for patients experi-encing problems during treatment to help avoid emergency department visits or hospitalizations,

• Care coordination with other health-

care providers, and• Continued support to patients after

active treatment ends.Under PCOP, oncology practices

would commit to delivering evi-dence-based care ensuring patients are receiving the most appropriate tests and treatments, while avoiding unnecessary expenses.

The PCOP proposal was developed by an ASCO volunteer work group of leading medical oncologists from di-verse practice settings, seasoned prac-tice administrators, and experts in phy-sician payment and business analysis.

The PCOP proposal incorporates extensive input that the Society re-ceived on an earlier draft proposal,

Consolidated Payments for Oncol-ogy Care (CPOC), released in May 2014. Over the past year, many ASCO members and other stakeholders have endorsed the need for payment reform in oncology and provided suggestions on ways to improve the CPOC model. That input was used to develop the PCOP proposal.

ASCO is soliciting comments on its payment reform model through July 20. For more information, and the com-plete text version of the ASCO payment reform model, please visit www.asco.org/paymentreform. n

© 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Members, Public Working Together to ‘Take Down’ Cancer

From Wrigley Field to McCormick Place, Chicago residents and visitors

felt the energy surrounding the launch of The Campaign to Conquer Cancer dur-ing the ASCO 2015 Annual Meeting.

The Conquer Cancer Foundation of the American Society of Clinical Oncology (CCF) threw out the cer-emonial first pitch at a Chicago Cubs game on May 29 before the Annual Meeting to help kick off fundraising for The Campaign to Conquer Cancer. Today, CCF is encouraging all ASCO members to lend their support to the Campaign—a multiyear effort to raise $150 million to support the mission of ASCO and CCF—by sharing informa-tion about CCF and the Campaign in

their communities and practices. “The CCF Campaign is addressing

key elements of ASCO’s mission of re-search, patient education, and quality of oncology practice,” said Campaign Co-Chair Robert J. Mayer, MD, FASCO, Faculty Vice President for Academic Af-fairs and Institute Physician at the Dana-Farber Cancer Institute and Stephen B. Kay Family Professor of Medicine at Harvard Medical School. “To achieve those goals and ensure that we can con-tinue to be leaders in the field, fund the best research, and serve the needs of our members, we need to broaden the circle of supporters who have gotten us this far, and invite new donors to be a part of the collective effort to conquer cancer.”

Dr. Mayer is Co-Chairing the Cam-paign with Thomas G. Roberts Jr, MD, Managing Member of Farallon Capital Management, LLC. Desirée Rogers, CEO of Johnson Publishing Company and long-time Chicago civic leader, is the Honorary Co-Chair.

Members’ participation in the Cam-paign through advocacy and building awareness is perhaps even more impor-tant to Dr. Mayer and Dr. Roberts than financial contributions.

“With this campaign we hope to see participation of a sizable percentage of the ASCO membership,” Dr. Mayer said. “It is not how much one gives, but how many people participate in the ef-fort, indicating the broad support that the oncology community has for the Foundation and its work.”

The Campaign to Conquer Cancer provides a meaningful opportunity for pa-tients, families, caregivers, and community members to support cancer research and the cancer community. Since the Cam-

paign officially began in a silent phase in November 2011, donors have contrib-uted more than $95 million in support of ASCO and CCF initiatives, including cancer research, quality of cancer care and CancerLinQ™, physician and patient edu-cation, and global oncology.

The “jewel in the crown” of CCF is its ability to provide funding oppor-tunities for oncology professionals at various stages of their career, Dr. Mayer said. Funding opportunities available through the CCF include Research Pro-fessorships, Merit Awards, Advanced Clinical Research Awards, Career De-velopment Awards, and Young Investi-gator Awards.

ASCO’s achievements—coupled with CCF’s support—have cemented its place among the world’s top cancer organizations. The Campaign to Con-quer Cancer promises to build on this success and accelerate the field of can-cer research and care for all patients.

To find out more about The Cam-paign to Conquer Cancer and lend your support, visit conquer.org. n

Selected portions reprinted from ASCO Daily News. © American Society of Clinical Oncology. “The Campaign to Conquer Cancer Launched at Chicago Cubs Game.” https://am.asco.org/cam-paign-conquer-cancer-launched-chicago-cubs-game. All rights reserved.

Robert J. Mayer, MD, FASCO

While nearly 1 in 2 people will get cancer in their lifetime, 2 in 3 will survive it.* And that’s a profound testament to the progress you’ve helped forge as we work collectively to make it harder for cancer to survive.

Together, we’re taking it down.

Join The Campaign to Conquer Cancer at conquer.org/progress.#ConquerCancer

* CancerProgress.Net. Progress & Timeline. Timeline. Major Milestones Against Cancer. Available at: http://cancerprogress.net/timeline/major-milestones-against-cancer. Accessed April 7, 2015.

http://conquer.org/


Announcements

they control, guiding the current scien-tific revolution in genome-wide studies of tumors.

“Dr. Vogelstein’s groundbreaking research has transformed our under-standing of cancer biology and holds the promise for new treatments based on cancer genetics,” said Craig Mello, PhD, Professor of Molecular Medi-cine at the University of Massachusetts Medical School, Investigator at the Howard Hughes Medical Institute, and Chair of the Dr. Paul Janssen Award In-dependent Selection Committee. “His work, including examining genetic and biochemical events that initiate solid tumors, is widely applicable to the di-agnosis, treatment, and management of cancer and provides broad practical implications for patients with both he-reditary and sporadic forms of cancer.”

Dr. Vogelstein is the Director of the Ludwig Center for Cancer Genetics & Therapeutics at the Johns Hopkins Kimmel Cancer Center, Clayton Pro-

fessor of Oncology and Pathology at Johns Hopkins University, and an In-vestigator of the Howard Hughes Medi-cal Institute.

“For me, this journey began with one of my first patients, a 4 year old with leukemia—a disease we knew very little about at the time. I set out to determine

what molecular changes drive malig-nancy, in the hope that this would lead to improved approaches to diagnosis and therapy,” said Dr. Vogelstein. “I am honored to have my laboratory’s work recognized and to join the list of excep-tional past winners of the Dr. Paul Jans-sen Award for Biomedical Research.”

The winners of the Dr. Paul Janssen Award for Biomedical Research are cho-sen by an independent selection com-mittee of the world’s most renowned scientists. The Award, which includes a $200,000 prize, will be presented to Dr. Vogelstein at ceremonies in the United States and Belgium in September. n

Bert Vogelstein, MDcontinued from page 33

For interviews with experts conducted live at the

ASCO Annual Meeting on this study and others, visit

http://video.ascopost.com/

EDU-NPS-0027 5/2015 ©2015 Boston Biomedical

Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7

Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells from ordinary cancer cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8

Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, may be highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis.4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9

Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/STAT, Wnt/β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

Learn more at www.bostonbiomedical.com

Cancer Stem Cells and Their Role Boston Biomedical is developing the next

generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways.

Clinical trials are underway with the goal of reducing recurrence and metastasis.

in Recurrence and MetastasisCANCER STEM CELLS SIGNALING PATHWAYS REGROWTH APOPTOSIS

References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci. 2015;112(6):1839-1844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568. 6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed. Topics in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracic-surgery/stage-i-non-smallcell-lung-cancer-recurrence-patterns-prognostic-factors-and-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells. PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149-160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

ADVERTORIAL

00699-BBI_R04_Advertorial_ISL.indd 2-3 5/21/15 5:27 PM


Announcements

Roberto Pili, MD, Expert in Prostate, Renal, and Bladder Cancers, Joins Indiana University Simon Cancer Center

Roberto Pili, MD, a nationally rec-ognized expert in prostate, renal,

and bladder cancers, has joined the Indiana University (IU) Melvin and

Bren Simon Cancer Center.Dr. Pili is the Robert Wallace Miller

Professor of Oncology at the Indiana University School of Medicine and

Researcher at the IU Simon Cancer Center. In his new position, Dr. Pili will also be Director of the Genitourinary Research Program at the Cancer Cen-

ter. In addition, Dr. Pili will serve as the Medical Director of the Genitourinary Clinical Program at the IU Health Si-mon Cancer Center. The genitourinary program supports treatment for pros-tate, bladder, kidney, testicular, and pe-nile cancers.

The Genitourinary Research Pro-gram’s scientists will collaborate with researchers at the Purdue University Center for Cancer Research. The de-veloping program will be co-led by Timothy Ratliff, PhD, the Robert Wallace Miller Director of the Purdue Cancer Center.

On the clinical side, Dr. Pili said his goal is to focus on drug resistance in those genitourinary cancers, providing new options for those patients.

Prior AppointmentsMost recently, Dr. Pili was Professor

of Oncology, Chief of the Genitouri-nary Section, and Leader of the Geni-tourinary Program at the Roswell Park Cancer Institute.

Dr. Pili earned his medical de-gree from the Catholic University School of Medicine, in Rome, Italy. He did his residency training in inter-nal medicine at Montefiore Medical Center, completed a clinical research fellowship in medical oncology at Johns Hopkins University, and a sec-ond fellowship at the National Insti-tute on Aging, National Institutes of Health. His laboratory research fo-cuses on the development of novel therapeutic agents, including epigen-etic agents such as histone deacety-lase inhibitors and understanding their immunomodulatory effects. He also conducts phase I/II clinical tri-als of novel agents for the treatment of genitourinary malignancies.

Dr. Pili is a member of ASCO and the American Association for Cancer Research. He serves as a reviewer for study sections of the National Can-cer Institute and the Department of Defense. n

Roberto Pili, MD

EDU-NPS-0027 5/2015 ©2015 Boston Biomedical

Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7

Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells from ordinary cancer cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8

Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, may be highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis.4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9

Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/STAT, Wnt/β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

Learn more at www.bostonbiomedical.com

Cancer Stem Cells and Their Role Boston Biomedical is developing the next

generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways.

Clinical trials are underway with the goal of reducing recurrence and metastasis.

in Recurrence and MetastasisCANCER STEM CELLS SIGNALING PATHWAYS REGROWTH APOPTOSIS

References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci. 2015;112(6):1839-1844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568. 6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed. Topics in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http://www.intechopen.com/books/topics-in-thoracic-surgery/stage-i-non-smallcell-lung-cancer-recurrence-patterns-prognostic-factors-and-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells. PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149-160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

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Integrative Oncology

The Pediatric Fitness Program: A Mind-Body ApproachBy Robin Hardbattle, MS, LAc

The fundamental challenge in treat-ing children with cancer centers

on how to help relieve their suffering while they undergo difficult care. Typi-cally, they do not yet have adult coping skills, and even if they had some ability to cope, many of the issues they face during treatment are overwhelming. During the span of their treatment, pe-diatric patients with cancer face a range of physical and emotional issues, in-cluding pain, nausea, fatigue, and physi-cal weakness, along with the similarly common emotional challenges of anxi-ety, fear, and depression.

Within the unlikely field of mar-tial arts, we have applied a tailored ap-proach to each individual that greatly relieves these common challenges. At a brief glance, using martial arts in a hos-pital setting as an integrative modality may seem incompatible to the restric-tions inherent in treating cancer. On closer examination and with appropri-ate application, however, it becomes evident that it has much to offer.

Although commonly seen as simply a way to fight, the field of martial arts is a rich, multilayered body of knowledge on dealing with physical, psychologi-cal, emotional, and spiritual adversities. With appropriate adaption to the pedi-atric environment and solid understand-ing of pediatric oncology, the martial arts are well suited to soothe the physical and emotional needs of children in pain.

The MSKCC ProgramSince 2012, Memorial Sloan Ket-

tering Cancer Center (MSKCC) has provided a martial arts program

that serves all pediatric patients with cancer. Combining the mind-body practices of physical fitness, breath awareness, guided imagery, and meditation, this program introduces a range of appropriate coping mech-anisms that improve mood, reduce anxiety, and alleviate pain.

Each session is tailored to the in-dividual needs of the patients, work-ing in small groups or individually in the Pediatric Day Hospital or at the bedside. Sessions are provided also for patients in isolation for extended periods, such as those undergoing

hematopoietic stem cell transplan-tation. Throughout the duration of their treatment, from the first visit to the end of care, the program pro-vides support in close collaboration with nurses, physical therapists, oc-cupational therapists, social workers, and child life specialists.

The program aims to help pa-tients at the time and place of their choosing and when a mind-body intervention would be most effec-tive. This often requires accompa-nying patients while they undergo painful or frightening procedures. Reinforcing the exercises taught earlier while providing emotional support significantly improves the patients’ experience. Ideally, as children integrate the coping skills taught from the outset, they be-come more confident and self-suf-ficient, to the point that the thera-pist is no longer needed.

Benefits of Physical ExerciseWith more than 200 studies demon-

strating the benefits of physical fitness in patients with cancer, physical activity is increasingly acknowledged as a legiti-mate medical therapy.1 Data increasing-ly show that physical activity increases survival.2,3 Evidence also indicates that activity can decrease both physical and emotional symptoms during treatment, with improvement in muscle strength,

aerobic capacity, quality of life, fatigue, and overall emotional status.4,5

Adaptability of Martial Arts Practices

Fitness activities are adapted from a variety of martial arts styles. A suitable activity can be introduced regardless of one’s physical limitations and given a willingness to participate. Specific appropriate techniques can be adapt-ed and applied to each circumstance, whether the children are standing, sit-ting, or supine.

In addition to developing strength, balance, and coordination, these tech-niques can help to reduce anxiety and pain, improve sleep, and serve as an emotional release. The activity offers a healthy physical outlet for the children’s fear when they need it most. Such a re-lease can help with behavioral and com-pliance issues, particularly in younger patients who have few established cop-ing mechanisms in place.

These activities also empower pe-diatric patients, providing a sense of strength when they are physically weak and struggling with fear. That sense of physical strength can translate to a sense of determination to persevere. Within the context of martial arts, the child’s situation is reframed from that of a victim of circumstance to a fighter in the battle against disease.

By working with physical and occu-

GUEST EDITOR

Integrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integra-

tive Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memo-rial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.

mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offer health-care professional and patient versions, and entries are regularly up-dated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Cen-ter’s very first mobile application, can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices.

Barrie R. Cassileth, MS, PhD

Robin Hardbattle, MS, LAc, engages a pediatric patient in martial arts as an integrative modality suited to soothe the physical and emotional needs of children in pain. Photo by Rick DeWitt. Courtesy of Memorial Sloan Kettering Cancer Center.


Integrative Oncologypational therapy, the children’s specific needs can be addressed from multiple angles that they may perceive as fun. They follow the appropriate path to re-habilitation without knowing it. Enthu-siasm for these activities often inspires children to maintain physical activity throughout their treatment. This often continues following discharge and be-

comes a regular pursuit. The most com-mon question parents ask at that point is “My kid wants to do martial arts at home. What do you recommend?”

The foundation of meditative prac-tice is integral to many martial arts ac-tivities. Therefore, physical training and practice are used as a bridge to mind-body activities. Introducing simple breathing exercises in the context of learning correct punching, for example, is an ideal way to introduce the concept of mindful breathing to children.

Mind-Body PracticeThere is now ample evidence indicat-

ing the value of breathing, mindfulness, and meditative practices as effective treatments for a wide range of symp-toms, including pain, anxiety, depres-sion, fatigue, and sleep disturbance.6-8

Research pertaining specifically to

martial arts is more scant. The most notable studies to date address Tai Chi and Qigong, practices that include both physical and meditative components. Early results indicate clear benefits, both physical and cognitive.9-11

Breath regulation and focus, both adapted from the martial arts, are central to mind-body practices. By becoming

mindful of their breathing, patients take the first step in controlling their bod-ies. This activates the parasympathetic nervous system and subsequently their reaction to stress. Moreover, this exer-cise becomes the foundation for more sophisticated visualization practices.

Guided imagery is an ideal way to introduce children to the practice of meditation. A successful guided medi-tation is possible with patients as young as 3 years of age. Even in the busy en-vironment of a pediatric hospital, pe-diatric and adult patients can achieve a deep state of physical and emotional relaxation. Long-term patients, trapped in an environment with little privacy or comfort, often struggle with anxiety and depression. Through the practice of meditation, and especially guided imag-ery, children can reclaim a sense of con-trol in an environment where they have

little if any control. They can close their eyes and “go home.”

In the short term, these skills help with the immediate issues of anxiety, fear, and pain by promoting self-con-trol, inner peace, and tranquility. In the long term, these skills become tools throughout life.

Challenges in PediatricsAn especially difficult challenge in

pediatric oncology is administration of a painful therapy or procedure to an un-cooperative child. From delaying tactics

to outright rebellion, children struggle to prevent it, but inevitably they must undergo the procedure. By arming chil-dren with appropriate mind-body skills, we can reframe the procedure from a traumatic experience to an unpleasant but necessary event.

An especially difficult treatment at Memorial Sloan Kettering’s Pediatric Day Hospital is the monoclonal anti-body therapy for neuroblastoma. This treatment causes extreme pain for 20 to 30 minutes, and children routinely

Visit the free About Herbs website at www.mskcc.org/aboutherbs

Learn More About

Herbs, Botanicals, & Other Products

With appropriate adaption to the pediatric environment and solid understanding of pediatric oncology, the martial arts are well suited to soothe the physical and emotional needs of children in pain.

—Robin Hardbattle, MS, LAc

The Mind-Body Program in Action

H ere are several real-life examples of the positive effects of the mind-body program, shared by Robin Hardbattle, MS, LAc, and the par-

ents of children who benefited from it.• Breathing Practices and Guided Imagery: Prior to learning breathing prac-

tices and guided meditation, Matt, a 12-year-old boy, was experiencing pain and high levels of anxiety every week when it was necessary to have a line inserted. Later, when applying the breathing practices and guided meditation he had learned, he was able to deal with the procedure with little if any pain and without panic. After I guided him through this several times, he told me that he was okay and didn’t need me there anymore. His sense of control in place, Matt knew that he could confidently get through the procedure without fear.

• Meditation and Guided Imagery: One parent explained how this approach helped her daughter and shared her gratitude. “I’ll never forget how you calmed my fearful daughter by teaching her to focus on her breath—her anchor—and how you transported her…. Your voice lulled her out of our tiny, loud, beeping machine-filled space to a space of tranquility, where the ocean waves gently crashed on the shore and the sun was beaming on her back. Thank you: Her body and spirit were so relaxed. You taught her to use her breath and mind to literally remove the noise of the hospital and distract her from her fears.”

• Breathing Exercises, Guided Imagery, and Music Therapy: Another comment by a parent illustrates the benefit of such approaches. “Robin works with my son during very difficult 3F8 monoclonal antibody treatments. He has taught him how to meditate and focus. Both Robin and my son amaze me.” n


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Integrative OncologyPAGE 46 The ASCO Post | JULY 10, 2015

scream in pain. This is traumatic for the patient and difficult for all participants, including parents and medical staff.

In collaboration with other integra-tive medicine therapists and the pedi-atric staff, we are able to guide children through this treatment in relative com-fort. Using breathing exercises, guided imagery, and music, we place them into a deep meditative state. This can pro-foundly relieve pain and fear and im-proves the overall experience, as early data corroborate.12

The most notable organization to have worked successfully in hospitals is the nonprofit “Kids Kicking Cancer.” It was with the committed martial arts instructors at this organization that we were first introduced to the potential of this modality. To our knowledge, Me-morial Sloan Kettering’s martial arts program may be the first dedicated hos-pital program of its kind.

Closing ThoughtsAs an integrative therapy, mar-

tial arts are in their infancy yet have substantial promise. They have sub-stantial potential as a mind-body mo-dality to help not only children with cancer but also to manage other se-vere medical challenges. It is our hope that, as the benefits of this discipline become increasingly well recognized, additional institutions will look to-ward the combination of martial arts and meditation as an important addi-tion to patient care. For children fac-ing pain and adversity, this modality may very well be of help. n

Disclosure: Mr. Hardbattle reported no potential conflicts of interest.

References1. Steindorf K, Leitzmann M, Frieden-

reich C: Physical activity and primary cancer prevention, in Ulrich CM, Steindorf K, Berger NA (eds): Exercise, Energy Balance, and Can-cer, pp 83-106. New York, Springer, 2013.

2. Meyerhardt JA, Giovannucci EL, Holmes MD, et al: Physical activity and sur-vival after colorectal cancer diagnosis. J Clin

Oncol 24:3527-3534, 2006.3. Meyerhardt JA, Giovannucci EL,

Ogino S, et al: Physical activity and male colorectal cancer survival. Arch Intern Med 169:2102-2108, 2009.

4. Mishra SI, Scherer RW, Geigle PM, et al: Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev 8:CD007566, 2012.

5. Cramer H, Lange S, Klose P, et al: Yoga for breast cancer patients and survivors: A systematic review and meta-analysis. BMC Cancer 12:412, 2012.

6. Deng G, Cassileth BR: Integrative on-cology: Complementary therapies for pain, anxiety, and mood disturbance. CA Cancer J Clin 55:109-116, 2005.

7. Birnie K, Garland SN, Carlson LE: Psychological benefits for cancer patients and their partners participating in mindful-ness-based stress reduction (MBSR). Psy-chooncology 19:1004-1009, 2010.

8. Syrjala KL Jensen MP, Mendoza ME, et al: Psychological and behavioral ap-proaches to cancer pain management. J Clin Oncol 32:1703-1711, 2014.

9. Oh B, Butow P, Mullan B, et al: Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: A randomized controlled trial. Ann Oncol 21:608-614, 2010.

10. Oh B, Butow PN, Mullan BA, et al: Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: A random-ized controlled trial. Support Care Cancer 20:1235-1242, 2012.

11. Chen Z, Meng Z, Milbury K, et al: Qigong improves quality of life in women undergoing radiotherapy for breast cancer: Results of a randomized controlled trial. Cancer 119:1690-1698, 2013.

12. Ahmed M, Modak S, Sequeira S: Acute pain relief after Mantram meditation in children with neuroblastoma undergoing anti-GD2 monoclonal antibody therapy. J Pediatr Hematol Oncol 36:152-155, 2014.

Mr. Hardbattle, a third-degree black belt with more than 25 years of experience in teaching and practicing martial arts, leads the Memorial Sloan Kettering Cancer Cen-ter inpatient program in Pediatric Mind-Body Fitness.

Pediatric Fitness Programcontinued from page 41

The ASCO Post Wants to Hear

From You

We encourage readers to share their opinions and thoughts on issues of

interest to the oncology community.

Write to The ASCO Post at [email protected]



Health-Care Policy

Translating Study Recommendations Into Medicare CoverageA Conversation With Patrick Conway, MDBy Ronald Piana

L ung cancer doggedly remains the leading cause of cancer-related

death in the United States. This grim mortality figure is due, in part, to a lack of early detection methods; more than half of all lung cancers have me-tastasized at the time of diagnosis. For decades, lung cancer advocates lobbied

for low-dose computed tomography (CT) screening programs that would help promote early detection and re-duce mortality. In 2011, the National Lung Screening Trial, sponsored by the National Cancer Institute, demonstrat-ed that screening with low-dose CT re-duces lung cancer mortality.

Based on this large trial, the U.S. Preventive Services Task Force issued a report giving low-dose CT in lung cancer a grade B recommendation, which garnered coverage by the Cen-ters for Medicare & Medicaid Services (CMS). However, translating science into policy is difficult. To shed light on the challenge, The ASCO Post spoke with a principal administrator at CMS, Patrick Conway, MD.

Background and Current RolePlease describe your medical back-

ground and a bit about your position at CMS.

I am currently the acting principal Deputy Administrator of CMS, and I also serve as its Chief Medical Officer. I lead the Center for Clinical Standards and Quality and the Center for Medi-care and Medicaid Innovation.

I am a pediatrician by training and, before joining CMS, served as Director of Hospital Medicine and Associate Pro-fessor at Cincinnati Children’s Hospital. In that role, I was also Assistant Vice President for Outcomes Performance, responsible for leading measurement, including the electronic health record

measures, and facilitating improvement of health outcomes across the health-care system. I attended Baylor College of Medicine and completed my pediatrics residency at Harvard Medical School’s Children’s Hospital Boston.

Age Cutoff for ScreeningPlease talk about the difference in age

cutoffs for low-dose CT screening coverage between the U.S. Preventive Services Task Force (80 years) and CMS (77 years). Certain advocacy groups were critical of the CMS decision.

The age range of 55 to 77 years for Medicare coverage is based on data from the National Lung Screen-ing Trial and is within the age range of the [U.S. Preventive Services Task Force’s] grade B recommendation. The [U.S. Preventive Services Task Force] used modeling with potential-ly unrealistic assumptions to extend the age range. However, we found no empirical data to support screening in adults aged 78 to 80 years, as the [National Lung Screening Trial] did not enroll or have follow-up data on these individuals. Therefore, we have not included these ages.

Other Eligibility CriteriaIs CMS confident that eligibility crite-

ria such as a patient’s smoking history can be assessed with accuracy?

We recognize the importance of ac-curate ascertainment of smoking his-tory and have created a specific shared decision-making visit to allow a careful calculation of pack-years, in addition to an interactive discussion of the poten-tial risks and benefits of screening. If calculated carefully and systematically, we believe smoking history can be as-sessed as well as it was in the [National Lung Screening Trial].

High-Quality Screening Availability

The National Lung Screening Trial was conducted in large facilities with the resources to execute standardized low-dose CT testing and data collection. Is CMS confident that widespread low-dose CT screening can be done in controlled high-quality settings across the nation?

In 2014, the Medicare Evidence De-velopment & Coverage Advisory Com-mittee also expressed concerns about the implementation of this service outside a controlled trial. CMS estab-lished specific evidence-based criteria such as beneficiary eligibility, radiolo-gist training, imaging center require-ments, and data collection to increase the likelihood of obtaining true positive results and to ensure that the benefits of screening outweigh harms for the Medicare population.

Benefits vs HarmsIs CMS comfortable that the harms as-

sociated with true false-positive results will be kept to a minimum, so that they are out-weighed by the benefits of low-dose CT?

CMS established evidence-based coverage criteria, including data col-lection and standardized lung nodule identification, classification and re-porting system to facilitate continu-ous improvement in screening tech-niques, and protocols to help reduce false-positive results. With these cri-teria, we believe the number of false-

positives will be minimized and show recognized benefits over harms of screening.

We also included a shared decision-making visit between the clinician and beneficiary to discuss the potential risks and benefits. Finally, in the future, screening programs will improve as ap-propriate data are collected. n

Screening

Key Challenges to CMS Coverage for Low-Dose

CT Screening

■ Patients must be accurately identified for screening to be successful. Although age is typically straightforward to measure, incongruity between the National Lung Screening Trial (which provided data for patients up to 77 years of age) and screening recommendations may potentially compound implementation problems.

■ A patient’s smoking history—usually self-reported and subject to recall bias—is particularly challenging yet critical to determine, since screening trials in patients with a less-extensive smoking history have not shown improved health outcomes.

■ Lung cancer screening must be performed as part of a cohesive screening program to enhance its likelihood of success. Radiologists should not only properly furnish and interpret the low-dose CT but also reinforce the importance of adherence to evidence-based screening, smoking cessation, and follow-up evaluations.

■ During the course of screening, a patient may encounter physicians from a number of different specialties. Each physician has a unique role and responsibility, but effective communication and coordination will be needed.

CMS established evidence-based coverage criteria, including data collection and standardized lung nodule identification, classification and reporting system to facilitate continuous improvement in screening techniques, and protocols to help reduce false-positive results.

—Patrick Conway, MD



Expert’s Corner

Health Information Technology

CancerLinQ will also provide an indi-vidual oncologist seated in a local exam room access to outcome data from hun-dreds or thousands of patients similar to the one sitting in front of him.

A Brief History of CancerLinQASCO has been discussing and refin-

ing this exciting concept since 2010, and its Board of Directors formally voted to go forward with the project in 2012. A proof-of-concept prototype was completed in 2013, with more than 170,000 de-iden-tified medical records of breast cancer patients from four large cancer centers around the country and one oncology data analysis organization. The prototype showed that a full CancerLinQ system en-compassing all cancers was feasible.

CancerLinQ was first presented to the cancer community in 2013 during a briefing at the National Press Club in Washington, DC, and a demonstration of the full system was presented to both oncologists and patient advocates at this year’s ASCO Annual Meeting. Both ses-sions received an enthusiastic response.

As news continues to spread regard-ing this huge venture, it is important that patients with cancer and the gen-eral public know about the great prom-ise of CancerLinQ. It is also important to understand that CancerLinQ is an ongoing work in progress and to keep expectations in line with reality.

ASCO is now beginning to develop CancerLinQ with 15 vanguard oncol-ogy practices that are expected to con-tribute at least 500,000 patient records for research on treatment outcomes. The practices are diverse in geography, size, governing structure, and electronic health record systems.

While easy to explain, making the tech-nology actually work is daunting. SAP, a global software company, is supporting ASCO staff in this monumental job. Both ASCO and SAP are working to meet the needs of patients at every juncture of care and are focused on protecting the privacy and security of patient information. I am among six patient advocates serving on CancerLinQ’s Patient Advisory Commit-tee to help guide these efforts.

Establishing Patient TrustCancerLinQ is for and about better

care for patients with cancer. Maintain-

ing patients’ trust is vital to the suc-cess of this big data learning system. Without full support from patients and agreement to use their data, Cancer-LinQ (and all technologies that capture patient outcomes) will fail.

Approximately 1.3 million patients will be told they have cancer this year. Consider how our collective knowledge would soar if oncologists could access the aggregated treatment and outcome information contained in CancerLinQ for the benefit of those patients and the 1.3 million new patients who will follow them next year, and each successive year.

Currently, the vast bulk of the clini-cal data contained in electronic health records is known only to the patient, the patient’s physician and hospital

point of care, and the patient’s family. By making these data accessible to clini-cians and researchers everywhere, Can-cerLinQ offers the promise of learning about the benefits and harms of specific treatment, improving quality of care, and quickening the development of new therapies.

Patients think this is all being ac-complished right now, but it isn’t. They think their doctors know how most pa-tients being treated with the treatment regimen they are being offered will fare, but they don’t. Oncologists know the results of randomized clinical trials, which guide and slowly change cancer therapy, but they only have outcome in-formation many years after completion of those trials.

Moreover, oncologists are flooded with a tidal wave of information over-load. If we assume only 1% of that new literature is relevant to an individual oncologist’s practice and that the on-cologist reads two articles every night, that oncologist would still be more than 10 years behind in the current literature.

Indeed, keeping up with the mass amounts of cancer data generated is humanly impossible. CancerLinQ will quantify and populate millions of data points, making the information accessi-

ble to practicing oncologists in an exam room with their patient.

How Patient Diversity Impacts Care

As mentioned earlier, CancerLinQ allows physicians to obtain information not just from the 3% of patients accrued into clinical trials each year, but from other patients as well and might allow researchers to see how patient diversity, including race, health status, and age, may impact patient care and outcome.

For example, 90% of patients en-rolled into National Cancer Institute trials are white, but 23% of the U.S. population is nonwhite; 40% of patients with kidney cancer are not healthy enough to qualify for trials that support

the approval of their treatments; and only 25% of patients enrolled in clini-cal trials are over age 65, whereas 61% of patients with cancer are over age 65.

Comorbidities and preexisting con-ditions exclude many cancer patients from clinical trials, but the reality is that these patients will be prescribed treat-ments tested in just a small percentage of patients. Oncologists need outcome data for their many diverse patients de-serving of the best treatment but who may not be well represented in clinical studies or who are ineligible to receive a specific therapy in clinical trials.

ASCO must manage expectations and be careful not to overpromise or under-deliver the benefits of this technology. As stated earlier, patient advocates have been consulted and are involved in the develop-ment of CancerLinQ. We’ve received as-surance of data safety and privacy and dis-cussed how information will be gathered and used. An easy “opt out” policy will be in place for patients who are treated at clinics and institutions using Cancer-LinQ but who choose not to contribute their data. The outcome data provided by CancerLinQ will help patients better un-derstand their treatment options during conversations with their physicians, and we are hopeful that these conversations will lead to better outcomes.

Patients Helping PatientsA detailed description of Cancer-

LinQ’s vision and how it works can be found at CancerLinQ.org. There you will see examples of case histories and how CancerLinQ can improve patient care.

One example is a rural Wyoming pa-tient with a rare throat cancer. His local physician has very little data to support a treatment plan. By accessing Cancer-LinQ, the physician can find treatment and outcome data on many aggregated de-identified patients with the same rare throat cancer across the United States and consider the best treatment course for his patient. The patient’s in-formation then becomes part of Can-cerLinQ’s database to help inform the care of other patients for years to come.

There are other exciting aspects of CancerLinQ being developed—which confidentiality precludes me from re-vealing at this time—that will directly benefit individual cancer patients. In general terms, they include the prom-ise of genomic matching, clinical trial eligibility and suitability matching, and biomarker identification.

In addition to providing clinicians and researchers with usable, real-world can-cer information, CancerLinQ also allows patients, through their data, to help other patients with the disease. Once patients receive information generated by Cancer-LinQ to guide their own treatment deci-sions, their data will then be added to the database to help those following them. One of the greatest comforts patients treated for cancer can have is the ability to use their ordeal to strike out against their disease and to help other patients. Can-cerLinQ provides that comfort.

Keeping Patients InformedAs the development and rollout of Can-

cerLinQ attract more and more attention, it is important for patient advocates and cancer support group leaders to know its capabilities, so they can pass the informa-tion to patients. Soon, Twitter, Facebook, and other social media outlets will be dis-cussing this new technology, and it is quite probable that patients will be asking their oncologists if they are part of the Cancer-LinQ network or if they intend to be.

Although completion of the full de-velopment of CancerLinQ is several years away, with each progress report, we can take comfort in the promise that this exciting health information technol-ogy platform offers to guide personal-ized cancer treatment decisions, inform research, and improve quality of life for millions of patients with cancer. n

Disclosure: Dr. Omel reported no potential conflicts of interest.

CancerLinQ™ Can Benefitcontinued from page 1

Although completion of the full development of CancerLinQ is several years away, with each progress report, we can take comfort in the promise that this

exciting health information technology platform offers to guide personalized cancer treatment decisions,

inform research, and improve quality of life for millions of patients with cancer.

—Jim Omel, MD

Dr. Omel is a patient advocate, multiple myeloma survivor, and full-time caregiver for his wife, who has multiple sclerosis. He was diagnosed with myeloma in 1997 and retired from active medical practice in 2000.


Announcements

First Winners of Tri-Institutional Breakout Awards Announced

Six young scientists at Memorial Sloan Kettering Cancer Center,

Rockefeller University, and Weill Cor-nell Medical College have been named the inaugural winners of a new prize established to recognize postdoctoral investigators in the life sciences. The Tri-Institutional Breakout Awards for Junior Investigators, which include a $25,000 prize for each recipient, were established by three Tri-Institutional winners of the 2013 Breakthrough Prize in Life Science — one from each of the three institutions — with addi-tional financial support from the insti-tutions themselves.

The seed money for the Breakout Awards came from three investigators—Charles L. Sawyers, MD, of Memorial Sloan Kettering; Cornelia I. Bargmann, PhD, of Rockefeller; and Lewis C. Cantley, PhD, of Weill Cornell—who each received a $3 million award from the 2013 Breakthrough Prize, which was established by a group of well-known Silicon Valley entrepreneurs.

Beginning this year, Breakout Awards will be given annually to be-tween three and six outstanding post-doctoral trainees, with one prize given to an applicant from each of the three founding institutions and additional awards made to the best candidates, re-gardless of affiliation. A committee con-taining faculty members from each of the institutions selects awardees on the basis of their past research accomplish-ments, the impact of their science, and

the likelihood of their future success as independent investigators. The contrib-uting Breakthrough Prize winners were not involved in the selection of the win-ning postdocs.

2015 Breakout Recipients (Oncology-Focused)

Hani Goodarzi, PhD, Rockefeller University Dr. Goodarzi is using an algo-rithm he developed during his doctoral research at Princeton University to scan both the sequence and shape of RNA molecules in breast cancer cells, leading to the discovery of a post-transcription-al network that regulates metastasis.

Julian Lange, PhD, Memo-rial Sloan Kettering Cancer Center Dr. Lange has pioneered novel methods for studying recombination in the cre-ation of egg and sperm cells in mice. In his recent work, he has uncovered how meiotic cells regulate the distribution of DNA damage.

Costas Lyssiotis, PhD, Weill Cor-nell Medical College Dr. Lyssiotis inves-tigates the biochemical pathways and metabolic requirements that enable pancreatic tumor growth, and is trans-lating discoveries into the development of targeted therapies.

The other three recipients are Ziv Shulman, PhD (Rockefeller); Jing Yang, PhD (Rockefeller); and Dilek Colak, PhD (Weill Cornell).

For more information about the Tri-In-stitutional Breakout Awards, visit https://breakthroughprize.org/Prize/2. n

Julian Lange, PhD

Lewis C. Cantley, PhD

Hani Goodarzi, PhD

Cornelia I. Bargmann, PhD

Costas Lyssiotis, PhD

Charles L. Sawyers, MD

Mission The mission of the ASPIRE Awards is to support clinical research of a Pfizer compound in advanced breast cancer through a competitive grants program to advance knowledge in the treatment and disease management of advanced breast cancer.

Awards 2015 ASPIRE Breast Cancer Research Awards program intends to fund three to six clinical studies within scope, for a total of approximately 3 million US dollars. It is open to US investigators. Selection of research proposals will be performed by an independent external review panel of breast cancer experts.

Submissions are due September 8, 2015

Call for Research Proposals

For complete information on the scope of research, please visit ASPIRE website at

www.aspireresearch.org

2015 ASPIRE Breast Cancer Research Awards Program

Pfizer is proud to announce the Advancing Science through Pfizer – Investigator

Research Exchange (ASPIRE) Breast Cancer Research Awards, a competitive, peer-

reviewed grants program sponsored by Pfizer for investigators in the United States

www.aspireresearch.org

https://www.aspireresearch.org/index.aspx

https://www.aspireresearch.org/index.aspx


Women in Oncology

Clara D. Bloomfield, MD, FASCO: Never One to Back Down From a ChallengeBy Ronald Piana

Clara D. Bloomfield, MD, FASCO, always sat in the front row at school.

She grew up during a rigidly paternalist period in American society, and her early feminist leanings were brushed aside as grade-school adventures. The medical school lecture room of the 1960s was a male-dominated culture, and when Dr. Bloomfield sat front-row center, it raised eyebrows. “The dean called me into his office and rather curtly explained that sitting in the front row that way was un-ladylike. I said, ‘When you become a lady you can tell me how to act like one,’ and walked out,” Dr. Bloomfield told The ASCO Post.

Academic ChildhoodDr. Bloomfield was born in New

York, New York, during World War II. Both parents were academics, and the household brimmed with a bookish environment: comic books and even TV, once available, were not allowed. With her trademark frankness, Dr. Bloomfield told The ASCO Post that she was conceived to spare her father from combat in the war. Early on, a man with a dependent was deferred.

Dr. Bloomfield’s father was an expert in labor and industrial relations, which was needed on the War Labor Board, so he uprooted the family and moved to Washington DC. “When the war ended, my father took a position at the University of Illinois in Champaign-Ur-bana. Many of his trainees and visitors were foreign, and we’d often have din-ner guests from South America or sub-Saharan Africa. It was an exciting time, full of possibilities,” said Dr. Bloomfield.

Mother as MentorAlthough her father filled the house-

hold with worldly intellectuals, Dr. Bloomfield regards her mother as her

mentor, the spark that set her career path toward medicine. She had an early interest in science, and one day, when she was in second grade, she told her mother that she wanted to be a nurse when she grew up. “My mother, not one to disparage nursing, said, ‘If you want to go into medicine, why not become a doctor!’ So that’s when I made my de-cision to become a doctor, and I never swayed,” said Dr. Bloomfield.

Her mother, a feminist in her own right, was one of the first women to at-tend the law school at the University of Illinois. Having an independent and self-motivated mother also helped mold Dr. Bloomfield’s mettle and career drive.

“My mother began law school when I was in first grade, and she received her law degree when I graduated high

school,” said Dr. Bloomfield, adding, “When I was 9, my mother announced that she wasn’t spending enough time with the family, so she decided to quit law school. My younger brother and I started crying and screaming that we couldn’t have a mother who wasn’t go-ing to law school,” said Dr. Bloomfield.

She commented that the state had to pass a law allowing her mother to obtain her law degree since her lengthy school-ing had passed the statute of limitations governing the time it takes to complete law school.

Interest in Oncology and Genetics

While attending grade school, Dr. Bloomfield had classmates who developed leukemia. Because of the limited options in the early 1950s, they were sent to the National Cancer Institute for treatment. “Then they’d return with steroid-bloated faces and soon die,” she said.

“I remember thinking to myself, how cool it would be to develop a medicine that could save kids from dying of child-hood leukemia. I’d already decided to be-come a doctor, so seeing the real-life ef-fects of cancer certainly helped shape my early desire to become an oncologist.”

In 1959, after graduating from the

University of Illinois Laboratory High School, Dr. Bloomfield entered the University of Wisconsin and while do-ing her premed, she became very inter-ested in genetics, which would inform much of her later research. She mar-ried a chemist during her junior year who wanted to do his postdoctoral work in a renowned research institute in La Jolla, California, so off they went to the West Coast.

“Since the University of California at San Diego did not exist at the time, I finished my last year of college at San Diego State College and then was faced with the challenge many women in academia face: how to coordinate two academic careers,” said Dr. Bloomfield. Coordinating careers resulted in a long-distance commuter marriage: Her hus-

band accepted a chemistry professor-ship offer at the University of Illinois in Champaign-Urbana, and she decided to go to medical school at the University of Chicago.

In the year prior to entering medical school, Dr. Bloomfield worked in a bio-chemistry lab at the prestigious Scripps Research Institute, which was at the cutting edge of scientific exploration. “At that time, a prominent faculty mem-ber working where my husband was had Hodgkin disease, and he was trav-eling back and forth to Stanford to see renowned Hodgkin specialist Henry Kaplan, MD, a radiotherapist who was largely responsible for the transforma-tion of Hodgkin disease from a hopeless to highly curable disease.”

She continued, “My mindset, from my grade school days seeing classmates die of leukemia, was that cancer was a death sentence—I was amazed by how well my husband’s professor colleague was responding. That experience had a significant effect on my decision to study hematologic malignancies,” said Dr. Bloomfield.

At the University of Chicago, Dr. Bloomfield worked with Henry Rappaport, MD, best known for his “Rappaport Classification” in lympho-

ma. “The structure at the University was geared toward an academic career, which fit in to how I’d been brought up,” said Dr. Bloomfield.

Grand Rounds With Dr. KaplanBetween her junior and senior years,

Dr. Bloomfield did a subinternship at the University of California at San Francisco (UCSF). “After a month or so, I saw a patient with Hodgkin disease who was not being treated with cura-tive intent. I said, this is terrible, you’re not giving this patient modern therapy,” said Dr. Bloomfield. Her attending re-plied, “Well, if you’re so smart, we’ll have you do grand rounds on how to treat Hodgkin disease.”

Not one to back down from a chal-lenge, but also wanting support, Dr. Bloomfield called Stanford and asked the famous Dr. Kaplan for advice. “Henry was really nice; he said he’d be thrilled to come and help me do grand rounds,” said Dr. Bloomfield. To the surprise of the attending at UCSF, Dr. Bloomfield, a medical student, con-ducted grand rounds with her associate from Stanford, Dr. Henry Kaplan.

Confronted Pay DiscriminationIn 1971, Dr. Bloomfield began her

medical oncology fellowship at the University of Minnesota, where she be-came one of the institution’s first female Chief Residents and was awarded an American Cancer Society Junior Clini-cal Faculty Fellowship.

“Throughout my career in academia, I’ve confronted issues of pay discrimi-nation for women,” said Dr. Bloomfield. While at the university, she moved from Assistant Professor to Associate Profes-sor in just 3 years and later became the university’s first female full Professor of Medicine.

Dr. Bloomfield recalled how her promotion unfolded. “My husband also worked at the university. When the head of medicine called me into his office, he said, ‘Congratulations on the promotion, Clara, but because your husband makes such a good sal-ary, we’ve decided not to give you a raise.’ And he said it with a straight face! When I got home, I told my husband. He was a bit of a heavyweight there, so he called his dean who called the Uni-versity president, and my pay issue was immediately solved. That was my first,

Clara D. Bloomfield, MD, FASCO

Don’t be afraid to challenge authority…. Look at what’s in front of you and trust your own analysis.

That’s the way breakthroughs happen. —Clara D. Bloomfield, MD, FASCO


Women in Oncology

but certainly not my last, exposure to the pay bias women face in the academ-ic setting,” Dr. Bloomfield said.

Leukemia ResearchAs a beginning assistant professor,

she created and ran the Medical Oncol-ogy Division’s newly formed Leukemia and Lymphoma Service at the Univer-sity of Minnesota, initially seeing every patient herself. It proved to be an in-valuable career move.

As a fellow, she conducted a seminal study looking at all adult patients with acute leukemia seen at her institution over the past 10 years. “The majority had acute myeloid leukemia (AML). Our longest survivor was 17 years old and lived for 33 months. Given the success we were beginning to see in childhood leukemia, I saw an opportu-nity in adult disease. We stratified the patients by age, and as a result, I found that the older adult patients could do just as well as the younger ones,” said Dr. Bloomfield.

Dr. Bloomfield and coauthor Athanasios Theologides, MD, PhD, published their results in 1973 in JAMA, showing that older adult pa-tients could respond just as well to treat-ment as their younger counterparts. “At the time, all of the major hematologists contended that treating AML patients over 50 years of age was tantamount to malpractice. So you can imagine the stir I caused,” said Dr. Bloomfield.

“It was an important lesson,” she con-tinued, “one that resulted in my telling my fellows, don’t be afraid to challenge authority, even if it’s the biggest name in the field. Look at what’s in front of you

and trust your own analysis. That’s the way breakthroughs happen.”

Dr. Bloomfield’s subsequent re-search further helped reshape the clinical approach to hematologic ma-lignancies. “We conducted one of the first prospective studies on bone mar-row chromosomes and their clinical significance. We learned that leukemia and lymphoma belong to a heteroge-neous group of genetic diseases.” Sub-sequently, she and her team were the first to identify the Philadelphia chro-mosome in acute lymphoblastic leuke-mia as well as the biologic and genetic markers important in the diagnosis and treatment of AML—more contro-versial, groundbreaking work from the young, indomitable researcher.

“Many prominent cytogeneticists did not believe my data on the Phila-delphia chromosome. However, one of them, Dr. Avery Sandberg, while sur-prised by the discovery said, ‘She may be right. Sometimes these youngsters get things that we’ve missed,’” said Dr. Bloomfield.

Dr. Bloomfield left Minnesota in 1989, taking a position at Roswell Park Cancer Institute, serving as Roswell’s Chair of the Department of Medicine. In 1997, a career turn took her to The Ohio State University (OSU), where she served as Director of the Division of Hematology and Oncology and Di-rector of the OSU Comprehensive Can-cer Center – Arthur G. James Cancer Hospital and Solove Research Institute (OSUCCC–James) until 2003. She is currently a Distinguished University Professor, William G. Pace III Professor of Cancer Research and Senior Advisor

at the OSUCCC–James.On the global scale, her work has

also translated into internationally ac-cepted classification systems for blood disorders, including that of the World Health Organization, which incorpo-rated genetics into its classification of AML. “We now cure 40% of adult pa-tients between the ages of 16 and 60 with primary (de novo) acute leuke-mia,” Dr. Bloomfield pointed out.

Baroness BloomfieldAfter Dr. Bloomfield’s first mar-

riage ended, she married Albert de la Chapelle, MD, PhD, a geneticist and Professor in the Department of Mo-lecular Virology, Immunology, and Medical Genetics at Ohio State Univer-sity. “We’ve been married for 31 years,

but as we have different names and are prominent in separate fields, lots of people don’t know we’re a couple,” said Dr. Bloomfield.

Dr. de la Chapelle is of Finnish nobil-ity, a landed baron whose family owns a vast estate by the sea in his homeland. So, among Dr. Bloomfield’s other notable designations, she has added baroness.

Asked what she and her husband do besides work, Dr. Bloomfield said, “That’s about it. Although we have a tandem bicycle that we have enjoyed riding. But last year, my husband was unable to ride in the 180-mile cancer fundraiser at the OSUCCC, so now I ride with one of my fellows on the tan-dem bike. He’s a bull.” n

Disclosure: Dr. Bloomfield reported no potential conflicts of interest.

Clara D. Bloomfield, MD, FASCO, is the Distinguished University Professor & Wil-liam G. Pace III Professor of Cancer Research at The Ohio State University.

Save the DateBest of ASCO® San Francisco

August 7–8, 2015

San Francisco Marriott Marquis

San Francisco, California

Best of ASCO® BostonJuly 31 –August 1, 2015

Renaissance Boston Waterfront Hotel

Boston, Massachusetts

Best of ASCO® Chicago

August 28–29, 2015

Swissotel Chicago

Chicago, Illinois

JOB#: 52420D CLIENT: Medivation DESC: Spread Tabloid Ad FILE NAME: MDV_XTN_Q52420D_JA_D02.indd DATE: 3-25-2015 4:14 PM ROUND: D02PG: GolaG/WangJames AD: E Hannula x4607 PM: B Fu x4416 AE: J Surla x4846 CW: N/A Last Saved: 3-25-2015 4:14 PMTRIM: 21” x 13.5” BLEED: 22.5” x 14.5” SAFETY: 19.5” x 12.5” PROD: M Haight x4245 INK Spec: 4 color process PRINT SCALE: 50%FONTS: Whitney (Semibold, Book, Book Italic, Medium, Light), Whitney Condensed (Book, Medium), Minion Pro (Regular), Myriad Pro (Light)

IMAGES: 52420D_TA_SPR_fn.tif (CMYK; 300 ppi; 100%), AstNoTag_and_MDVNoTag_4C.ai (24.3%), Xtandi_KO-4Crings-prm-40mg.ai (54.2%), Xtandi-RedTag_4C-prm-40mg_footer.ai (56.2%)INKS: Cyan, Magenta, Yellow, BlackDOC PATH: Macintosh HD:Users:golag:Deskt...JA_D02:MDV_XTN_Q52420D_JA_D02.inddNOTES: None

MDV_XTN_Q52420D_JA_D02.indd Galley: 1

S&H PharmaGraphics

Disk

DATE

SIGNOFF

PG QC TC AD CD CW AE/AS ED PROD

*Or after bilateral orchiectomy.1

Signifi cantly improved overall survival†1

• 29% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.71 [95% CI, 0.60-0.84]; P < 0.0001)

• Estimated median overall survival was 32.4 months (95% CI, 30.1-not reached) for XTANDI + GnRH therapy* and 30.2 months (95% CI, 28.0-not reached) for placebo + GnRH therapy*1

Oral, once-daily dosing with no required steroid coadministration1

• Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily

• Steroids were allowed but not required‡

Start XTANDI at disease progression

to metastatic CRPC for your patients

on GnRH therapy*1

Signifi cantly extended radiographic progression-free survival†1

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Estimated median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*1

Signifi cantly delayed time to chemotherapy initiation†1

• Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI +

GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI,

0.30-0.40]; P < 0.0001)

© 2015 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-0800-PM 3/15 XTANDI, Astellas, and the fl ying star logo are trademarks of Astellas Pharma Inc.

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

of insured patient lives are covered for XTANDI§3

To learn more, please visit XtandiHCP.com

94% §As of February 2015. A product’s placement on a plan formulary involves

a variety of factors known only to the plan and is subject to eligibility.


1ej

30308a 03.25.15 133

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• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • E� ect of Other Drugs on XTANDI - Administration of strong

CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• E� ect of XTANDI on Other Drugs - XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

Important Safety InformationContraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and fi ndings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot fl ush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4

neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

• Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

†As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2

‡In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebo-controlled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc.2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433. 3. Data on fi le, Medivation, Inc.

S:19.5”

S:12.5”

T:21”

T:13.5”

B:22.5”

B:14.5”

F:10.5”

FS:9.5”

F:10.5”

FS:9.5”

https://www.xtandihcp.com/?utm_source=google&utm_medium=ppc&utm_term=xtandi&utm_campaign=brand%20-%20homepage_exact&gclid=COC6pLnG2MYCFQMbaQodMrQHwA&gclsrc=aw.ds

JOB#: 52420D CLIENT: Medivation DESC: Spread Tabloid Ad FILE NAME: MDV_XTN_Q52420D_JA_D02.indd DATE: 3-25-2015 4:14 PM ROUND: D02PG: GolaG/WangJames AD: E Hannula x4607 PM: B Fu x4416 AE: J Surla x4846 CW: N/A Last Saved: 3-25-2015 4:14 PMTRIM: 21” x 13.5” BLEED: 22.5” x 14.5” SAFETY: 19.5” x 12.5” PROD: M Haight x4245 INK Spec: 4 color process PRINT SCALE: 50%FONTS: Whitney (Semibold, Book, Book Italic, Medium, Light), Whitney Condensed (Book, Medium), Minion Pro (Regular), Myriad Pro (Light)

IMAGES: 52420D_TA_SPR_fn.tif (CMYK; 300 ppi; 100%), AstNoTag_and_MDVNoTag_4C.ai (24.3%), Xtandi_KO-4Crings-prm-40mg.ai (54.2%), Xtandi-RedTag_4C-prm-40mg_footer.ai (56.2%)INKS: Cyan, Magenta, Yellow, BlackDOC PATH: Macintosh HD:Users:golag:Deskt...JA_D02:MDV_XTN_Q52420D_JA_D02.inddNOTES: None

MDV_XTN_Q52420D_JA_D02.indd Galley: 1

S&H PharmaGraphics

Disk

DATE

SIGNOFF

PG QC TC AD CD CW AE/AS ED PROD

*Or after bilateral orchiectomy.1

Signifi cantly improved overall survival†1

• 29% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.71 [95% CI, 0.60-0.84]; P < 0.0001)

• Estimated median overall survival was 32.4 months (95% CI, 30.1-not reached) for XTANDI + GnRH therapy* and 30.2 months (95% CI, 28.0-not reached) for placebo + GnRH therapy*1

Oral, once-daily dosing with no required steroid coadministration1

• Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily

• Steroids were allowed but not required‡

Start XTANDI at disease progression

to metastatic CRPC for your patients

on GnRH therapy*1

Signifi cantly extended radiographic progression-free survival†1

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Estimated median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*1

Signifi cantly delayed time to chemotherapy initiation†1

• Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI +

GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI,

0.30-0.40]; P < 0.0001)

© 2015 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-0800-PM 3/15 XTANDI, Astellas, and the fl ying star logo are trademarks of Astellas Pharma Inc.

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

of insured patient lives are covered for XTANDI§3

To learn more, please visit XtandiHCP.com

94% §As of February 2015. A product’s placement on a plan formulary involves

a variety of factors known only to the plan and is subject to eligibility.


1ej

30308a 03.25.15 133

Q1 Q2

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas.

• Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • E� ect of Other Drugs on XTANDI - Administration of strong

CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• E� ect of XTANDI on Other Drugs - XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

Important Safety InformationContraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and fi ndings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot fl ush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4

neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

• Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

†As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2

‡In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebo-controlled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc.2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433. 3. Data on fi le, Medivation, Inc.

S:19.5”

S:12.5”

T:21”

T:13.5”

B:22.5”

B:14.5”

F:10.5”

FS:9.5”

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FS:9.5”




In Memoriam

Noted Pediatric Oncologist, Robert J. Arceci, MD, PhD, DiesBy Ronald Piana

Over the past 50 years, great strides have been made in diagnosis,

treatment, and survival of childhood cancer. In the 1960s, the probability

of survival for a child with cancer was less than 25%, whereas today it may exceed 80%. This incredible cancer success story has been made possible

by the work of researcher-physicians such as Robert J. Arceci, MD, PhD, who co-directed the Ronald A. Matri-caria Institute of Molecular Medicine

at Phoenix Children’s Hospital, in Ari-zona. Dr. Arceci was killed in a motor-cycle accident on June 8, 2015. He was 65 years old.

XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012BRIEF SUMMARY OF PRESCRIBING INFORMATIONThe following is a brief summary. Please see the package insert for full prescribing information.INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).CONTRAINDICATIONSPregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].WARNINGS AND PRECAUTIONSSeizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure.Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.ADVERSE REACTIONSClinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

Table 1. Adverse Reactions in Study 1 Respiratory Disorders

Epistaxis 3.3 0.1 1.3 0.3a CTCAE v4b Includes asthenia and fatigue.c Includes dizziness and vertigo.d Includes amnesia, memory impairment, cognitive disorder, and

disturbance in attention.e Includes nasopharyngitis, upper respiratory tract infection, sinusitis,

rhinitis, pharyngitis, and laryngitis.f Includes pneumonia, lower respiratory tract infection, bronchitis, and

lung infection.

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 2. Adverse Reactions in Study 2

XTANDIN = 871

PlaceboN = 844

Grade 1-4a

(%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)

General DisordersAsthenic Conditionsb 46.9 3.4 33.0 2.8

Peripheral Edema 11.5 0.2 8.2 0.4

Musculoskeletal And Connective Tissue Disorders

Back Pain 28.6 2.5 22.4 3.0

Arthralgia 21.4 1.6 16.1 1.1

Gastrointestinal Disorders

Constipation 23.2 0.7 17.3 0.4

Diarrhea 16.8 0.3 14.3 0.4

Vascular Disorders

Hot Flush 18.0 0.1 7.8 0.0

Hypertension 14.2 7.2 4.1 2.3

Nervous System Disorders

Dizzinessc 11.3 0.3 7.1 0.0

Headache 11.0 0.2 7.0 0.4

Dysgeusia 7.6 0.1 3.7 0.0

Mental Impairment Disordersd

5.7 0.0 1.3 0.1

Restless Legs Syndrome 2.1 0.1 0.4 0.0

Respiratory Disorders

Dyspneae 11.0 0.6 8.5 0.6

Infections And InfestationsUpper Respiratory Tract Infectionf

16.4 0.0 10.5 0.0

Lower Respiratory Tract And Lung Infectiong

7.9 1.5 4.7 1.1

Psychiatric DisordersInsomnia 8.2 0.1 5.7 0.0

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.Table 1. Adverse Reactions in Study 1

XTANDIN = 800

PlaceboN = 399

Grade 1-4a

(%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)




Back Pain 26.4 5.3 24.3 4.0

Arthralgia 20.5 2.5 17.3 1.8Musculoskeletal Pain 15.0 1.3 11.5 0.3

Muscular Weakness 9.8 1.5 6.8 1.8

Musculoskeletal Stiffness 2.6 0.3 0.3 0.0


Diarrhea 21.8 1.1 17.5 0.3

Vascular Disorders

Hot Flush 20.3 0.0 10.3 0.0



Headache 12.1 0.9 5.5 0.0

Dizzinessc 9.5 0.5 7.5 0.5Spinal Cord Compression and Cauda Equina Syndrome

7.4 6.6 4.5 3.8

Paresthesia 6.6 0.0 4.5 0.0Mental Impairment Disordersd

4.3 0.3 1.8 0.0

Hypoesthesia 4.0 0.3 1.8 0.0

Infections And InfestationsUpper Respiratory Tract Infectione

10.9 0.0 6.5 0.3

Lower Respiratory Tract And Lung Infectionf

8.5 2.4 4.8 1.3

Psychiatric Disorders

Insomnia 8.8 0.0 6.0 0.5

Anxiety 6.5 0.3 4.0 0.0

Renal And Urinary Disorders

Hematuria 6.9 1.8 4.5 1.0

Pollakiuria 4.8 0.0 2.5 0.0

Injury, Poisoning And Procedural Complications

Fall 4.6 0.3 1.3 0.0Non-pathologic Fractures 4.0 1.4 0.8 0.3

Skin And Subcutaneous Tissue Disorders

Pruritus 3.8 0.0 1.3 0.0

Dry Skin 3.5 0.0 1.3 0.0

(cont.)

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Hematuria 8.8 1.3 5.8 1.3


Fall 12.7 1.6 5.3 0.7

Non-Pathological Fracture

8.8 2.1 3.0 1.1

Metabolism and Nutrition DisordersDecreased Appetite 18.9 0.3 16.4 0.7

Investigations

Weight Decreased 12.4 0.8 8.5 0.2

Reproductive System and Breast Disorders

Gynecomastia 3.4 0.0 1.4 0.0a CTCAE v4b Includes asthenia and fatigue. c Includes dizziness and vertigo.d Includes amnesia, memory impairment, cognitive disorder, and

disturbance in attention.e Includes dyspnea, exertional dyspnea, and dyspnea at rest.f Includes nasopharyngitis, upper respiratory tract infection, sinusitis,

rhinitis, pharyngitis, and laryngitis.g Includes pneumonia, lower respiratory tract infection, bronchitis, and

lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.DRUG INTERACTIONSDrugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)].Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].USE IN SPECIFIC POPULATIONSPregnancy - Pregnancy Category X [see Contraindications (4)].Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062Medivation, Inc., San Francisco, CA 94105Revised: September 201414B006-XTA-BRFSRx Only© 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0472-PM

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In Memoriam

Dr. Arceci completed his under-graduate studies at Trinity College, Hartford, and received his PhD and MD degrees from the University of Rochester. He then completed his residency in pediatrics and fellow-ship in pediatric hematology/oncol-ogy at The Children’s Hospital, Bos-

ton, and at Harvard Medical School. Following faculty appointments at

Harvard Medical School, the Dana-Farber Cancer Institute, and Boston Children’s Hospital, Dr. Arceci became Director of Pediatric Hematology/On-cology at Children’s Hospital Medical Center in Cincinnati.

In 2000, Dr. Arceci became Di-rector and King Fahd Professor of Pediatric Oncology and Professor of Oncology and Pediatrics at the Johns Hopkins University School of Medi-cine. In 2012, Dr. Arceci was teach-ing at the Johns Hopkins University School of Medicine when he moved

to Arizona, after being recruited to be part of Phoenix Children’s Hospital’s Institute of Molecular Medicine.

An International AuthorityHe was considered an international

authority in many challenging areas of clinical pediatric oncology, including the diagnosis and treatment of leuke-mia and Langerhans cell histiocytosis. He has served on a variety of commit-tees in the Pediatric Oncology Group; the Children’s Cancer Group; and the Children’s Oncology Group, including Chairperson for the Myeloid Leuke-mia Committee and Vice-Chair of the Biology and Therapeutics Translational Committee.

As an avid motorcyclist, Dr. Arceci married two of his passions by explor-ing the desert landscape of Arizona and participating in charitable motorcycle rides to benefit pediatric medicine. “I love motorcycles because really, every-thing else is just transportation,” he was fond of saying.

About his life’s work in pediatric cancers, Dr. Arceci said, “Children are going to be the people who help the adults. They are going to save us. I think it is truly phenomenal.”

Dr. Arceci is survived by his wife and two children. n

In Memoriam

Robert J. Arceci, MD, PhD

1950 – 2015

Robert J. Arceci, MD, PhD

XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012BRIEF SUMMARY OF PRESCRIBING INFORMATIONThe following is a brief summary. Please see the package insert for full prescribing information.INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).CONTRAINDICATIONSPregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].WARNINGS AND PRECAUTIONSSeizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure.Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.ADVERSE REACTIONSClinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

Table 1. Adverse Reactions in Study 1 Respiratory Disorders

Epistaxis 3.3 0.1 1.3 0.3a CTCAE v4b Includes asthenia and fatigue.c Includes dizziness and vertigo.d Includes amnesia, memory impairment, cognitive disorder, and

disturbance in attention.e Includes nasopharyngitis, upper respiratory tract infection, sinusitis,

rhinitis, pharyngitis, and laryngitis.f Includes pneumonia, lower respiratory tract infection, bronchitis, and

lung infection.

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.


XTANDIN = 871

PlaceboN = 844

Grade 1-4a

(%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)




Back Pain 28.6 2.5 22.4 3.0

Arthralgia 21.4 1.6 16.1 1.1


Constipation 23.2 0.7 17.3 0.4

Diarrhea 16.8 0.3 14.3 0.4

Vascular Disorders

Hot Flush 18.0 0.1 7.8 0.0



Dizzinessc 11.3 0.3 7.1 0.0

Headache 11.0 0.2 7.0 0.4

Dysgeusia 7.6 0.1 3.7 0.0

Mental Impairment Disordersd

5.7 0.0 1.3 0.1

Restless Legs Syndrome 2.1 0.1 0.4 0.0

Respiratory Disorders

Dyspneae 11.0 0.6 8.5 0.6

Infections And InfestationsUpper Respiratory Tract Infectionf

16.4 0.0 10.5 0.0

Lower Respiratory Tract And Lung Infectiong

7.9 1.5 4.7 1.1

Psychiatric DisordersInsomnia 8.2 0.1 5.7 0.0

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.Table 1. Adverse Reactions in Study 1

XTANDIN = 800

PlaceboN = 399

Grade 1-4a

(%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)




Back Pain 26.4 5.3 24.3 4.0

Arthralgia 20.5 2.5 17.3 1.8Musculoskeletal Pain 15.0 1.3 11.5 0.3

Muscular Weakness 9.8 1.5 6.8 1.8

Musculoskeletal Stiffness 2.6 0.3 0.3 0.0


Diarrhea 21.8 1.1 17.5 0.3

Vascular Disorders

Hot Flush 20.3 0.0 10.3 0.0



Headache 12.1 0.9 5.5 0.0

Dizzinessc 9.5 0.5 7.5 0.5Spinal Cord Compression and Cauda Equina Syndrome

7.4 6.6 4.5 3.8

Paresthesia 6.6 0.0 4.5 0.0Mental Impairment Disordersd

4.3 0.3 1.8 0.0

Hypoesthesia 4.0 0.3 1.8 0.0

Infections And InfestationsUpper Respiratory Tract Infectione

10.9 0.0 6.5 0.3

Lower Respiratory Tract And Lung Infectionf

8.5 2.4 4.8 1.3

Psychiatric Disorders

Insomnia 8.8 0.0 6.0 0.5

Anxiety 6.5 0.3 4.0 0.0


Hematuria 6.9 1.8 4.5 1.0

Pollakiuria 4.8 0.0 2.5 0.0


Fall 4.6 0.3 1.3 0.0Non-pathologic Fractures 4.0 1.4 0.8 0.3

Skin And Subcutaneous Tissue Disorders

Pruritus 3.8 0.0 1.3 0.0

Dry Skin 3.5 0.0 1.3 0.0

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Hematuria 8.8 1.3 5.8 1.3


Fall 12.7 1.6 5.3 0.7

Non-Pathological Fracture

8.8 2.1 3.0 1.1

Metabolism and Nutrition DisordersDecreased Appetite 18.9 0.3 16.4 0.7

Investigations

Weight Decreased 12.4 0.8 8.5 0.2

Reproductive System and Breast Disorders

Gynecomastia 3.4 0.0 1.4 0.0a CTCAE v4b Includes asthenia and fatigue. c Includes dizziness and vertigo.d Includes amnesia, memory impairment, cognitive disorder, and

disturbance in attention.e Includes dyspnea, exertional dyspnea, and dyspnea at rest.f Includes nasopharyngitis, upper respiratory tract infection, sinusitis,

rhinitis, pharyngitis, and laryngitis.g Includes pneumonia, lower respiratory tract infection, bronchitis, and

lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.DRUG INTERACTIONSDrugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)].Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl

enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)].The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)].Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)].USE IN SPECIFIC POPULATIONSPregnancy - Pregnancy Category X [see Contraindications (4)].Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062Medivation, Inc., San Francisco, CA 94105Revised: September 201414B006-XTA-BRFSRx Only© 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0472-PM

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2015 Oncology Meetings 2015 JuneASCO Review 2015June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/courses/2015/ASCO15/default.asp

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July7th World Congress on Gastrointestinal CancerJuly 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/WGIC2015/index.asp

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AugustAdvances in Cancer ImmunotherapyTM

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Best of ASCO - San FranciscoAugust 7-8 • San Francisco, California For more information: http://www.keck.usc.edu/events/6th-annual-pain-management-symposium-from-evidence-to-clinical-practice/

6th Annual Pain Management Symposium: From Evidence to Clinical PracticeAugust 20-21 • Pasadena, California For more information: http://boa.asco.org/

World Congress on Cancer and Prevention MethodsAugust 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/oncology-2015/

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International Palliative Care WorkshopSeptember 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/international-palliative-care-workshops

25th World Congress of the International Association of Surgeons, Gastroenterologists, and OncologistsSeptember 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

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29th Annual Canadian Association of Radiation Oncology (CARO) Annual Scientific MeetingSeptember 9-12 • Kelowna, Canada For more information: www.caro-acro.ca

American Society of Head and Neck Radiology (ASHNR) Annual MeetingSeptember 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

18th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO)September 16-20 • Xiamen, China For more information: www.csco.ac.cn

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2nd International Symposium of the Cancer Research Center of Lyon (CRCL)September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr


New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST.Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.

Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.

Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

The fi rst and only FDA-approved combination therapy

Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST.

Important Safety Information for TAFINLAR and MEKINIST when used in combination

To learn more, visit TAFINLARMEKINISTHCP.com

DEMONSTRATED DURABLE RESPONSE RATEDEMONSTRATED DURABLE RESPONSE RATEIN A PHASE II STUDY 1-3

Novartis recently acquired these products from GSK. To ensure a seamless transition, GSK is continuing to provide support for these products and related programs on behalf of Novartis at this time.

Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

AGENTS. THERAPY.2 1AGENTS. THERAPY.2 1

overallresponse

rate1,2

overallresponse

rate1,2

median durationof response1,2

median durationof response1,2

months(95% CI: 7, 15)

months(95% CI: 5, 7)

(95% CI: 62, 87)

(95% CI: 40, 67)

10.510.510.510.55.65.65.65.6

76%76%76%76%

54%54%as a single agent

Investigator-assessed analysis

TAFINLAR150 mg twice daily


MEKINIST2 mg once daily

in combination

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Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1,2

• 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1,2

– Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39%

• Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1,2

TAFINLAR + MEKINIST demonstrateda 76% overall response rate1,2

TAFINLAR + MEKINIST achieved a medianduration of response of 10.5 months1,2



MEKINIST and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR.Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent.

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1,2

0

10

20

30

40

50

60

70

80

TAFINLAR as a single agent150 mg twice daily

(N=54)R

espo

nse

Rat

es

4%

CompleteResponse

PartialResponse

50%

CompleteResponse

9%

PartialResponse

67%

Overall Response

54%(95% CI: 40, 67)

Overall Response

76%(95% CI: 62, 87)

+ MEKINIST2 mg once daily


(N=54)

Major effi cacy outcome: Investigator-assessed overall response rate1,2

Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent.In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

TAFINLAR 150 mg twice daily

+ MEKINIST 2 mg once daily

(N=54)

TAFINLAR as a single agent 5.6 months(95% CI: 5, 7)

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(N=54)150 mg twice daily

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Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1,2

• 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1,2

– Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39%

• Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1,2

TAFINLAR + MEKINIST demonstrateda 76% overall response rate1,2

TAFINLAR + MEKINIST achieved a medianduration of response of 10.5 months1,2



MEKINIST and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR.Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent.

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1,2

0

10

20

30

40

50

60

70

80

TAFINLAR as a single agent150 mg twice daily

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Overall Response

54%(95% CI: 40, 67)

Overall Response

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+ MEKINIST2 mg once daily


(N=54)

Major effi cacy outcome: Investigator-assessed overall response rate1,2

Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent.In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

TAFINLAR 150 mg twice daily

+ MEKINIST 2 mg once daily

(N=54)

TAFINLAR as a single agent 5.6 months(95% CI: 5, 7)

10.5 months(95% CI: 7, 15)

Months

(N=54)150 mg twice daily

Effi cacy outcome: Investigator-assessed median duration of response1,2


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Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 © 2015 Novartis 4/15 MAF-1111266


respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).Drug InteractionsEffects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST.Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent,

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. MEKINIST [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 3. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703.


Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

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respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).Drug InteractionsEffects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST.Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent,

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. MEKINIST [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 3. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703.


Please see additional Important Safety Information for TAFINLAR and MEKINIST, when used in combination, on the following pages.Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) BRIEF SUMMARYTAFINLAR® (dabrafenib) capsules, for oral useMEKINIST® (trametinib) tablets, for oral useThe following is a brief summary only; see Full Prescribing Information for each product to view the complete product information

1 INDICATIONS AND USAGETAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST.Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS5.1 New Primary MalignanciesNew primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST.Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type MelanomaIn vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 HemorrhageHemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST.Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous ThromboembolismVenous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST.In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST.Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 CardiomyopathyCardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular ToxicitiesRetinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST.

5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR.

5.7 Serious Febrile ReactionsThe incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

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Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5.8 Serious Skin ToxicitySerious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 HyperglycemiaHyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase DeficiencyTAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal ToxicityTAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions

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Grades 3 and 4

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

General disorders and administrative site conditionsPyrexia 71 5 69 9 26 0Chills 58 2 50 2 17 0Fatigue 53 4 57 2 40 6Edema peripheralb 31 0 28 0 17 0

Skin and subcutaneous tissue disordersRashc 45 0 43 2 53 0Night Sweats 24 0 15 0 6 0Dry skin 18 0 9 0 6 0Dermatitis acneiform 16 0 11 0 4 0Actinic keratosis 15 0 7 0 9 0Erythema 15 0 6 0 2 0Pruritus 11 0 11 0 13 0

Gastrointestinal disordersNausea 44 2 46 6 21 0Vomiting 40 2 43 4 15 0Diarrhea 36 2 26 0 28 0Abdominal paind 33 2 24 2 21 2Constipation 22 0 17 2 11 0Dry mouth 11 0 11 0 6 0

Nervous system disordersHeadache 29 0 37 2 28 0Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disordersCough 29 0 11 0 21 0Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disordersArthralgia 27 0 44 0 34 0Myalgia 22 2 24 0 23 2Back pain 18 5 11 0 11 2Muscle spasms 16 0 2 0 4 0Pain in extremity 16 0 11 2 19 0

Metabolism and nutritional disordersDecreased appetite 22 0 30 0 19 0Dehydration 11 0 6 2 2 0

Psychiatric DisordersInsomnia 18 0 11 0 8 2

Vascular disordersHemorrhagee 16 5 11 0 2 0

Infections and infestationsUrinary tract infection 13 2 6 0 9 2

Renal and urinary disordersRenal failuref 7 7 2 0 0 0

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.bIncludes the following terms: peripheral edema, edema, and lymphedema.c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.

d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.

fIncludes the following terms: renal failure and renal failure acute.Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were:Eye Disorders: Vision blurred, transient blindness.Gastrointestinal Disorders: Stomatitis, pancreatitis.General Disorders and Administration Site Conditions: Asthenia.Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Tests


N = 55


N = 54TAFINLAR

N = 53

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

HematologyLeukopenia 62 5 46 4 21 0Lymphopenia 55 22 59 19 40 6Neutropenia 55 13 37 2 9 2Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0

Liver Function TestsIncreased AST 60 5 54 0 15 0Increased alkaline phosphatase 60 2 67 6 26 2

Increased ALT 42 4 35 4 11 0Hyperbilirubinemia 15 0 7 4 0 0

ChemistryHyperglycemia 58 5 67 6 49 2Increased GGT 56 11 54 17 38 2Hyponatremia 55 11 48 15 36 2Hypoalbuminemia 53 0 43 2 23 0Hypophosphatemia 47 5 41 11 40 0Hypokalemia 29 2 15 2 23 6Increased creatinine 24 5 20 2 9 0Hypomagnesemia 18 2 2 0 6 0Hyperkalemia 18 0 22 0 15 4Hypercalcemia 15 0 19 2 4 0Hypocalcemia 13 0 20 0 9 0

aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS7.1 Effects of Other Drugs on DabrafenibDabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other DrugsDabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 TrametinibCoadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTAFINLARPregnancy Category DRisk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINISTPregnancy Category DRisk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing MothersIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric UseOne hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive PotentialTAFINLARContraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

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Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST.

5.8 Serious Skin ToxicitySerious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST.Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 HyperglycemiaHyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST.In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase DeficiencyTAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal ToxicityTAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST.

6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST.BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Adverse Reactions


N = 55


N = 54TAFINLAR

N = 53

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

All Gradesa

Grades 3 and 4

General disorders and administrative site conditionsPyrexia 71 5 69 9 26 0Chills 58 2 50 2 17 0Fatigue 53 4 57 2 40 6Edema peripheralb 31 0 28 0 17 0

Skin and subcutaneous tissue disordersRashc 45 0 43 2 53 0Night Sweats 24 0 15 0 6 0Dry skin 18 0 9 0 6 0Dermatitis acneiform 16 0 11 0 4 0Actinic keratosis 15 0 7 0 9 0Erythema 15 0 6 0 2 0Pruritus 11 0 11 0 13 0

Gastrointestinal disordersNausea 44 2 46 6 21 0Vomiting 40 2 43 4 15 0Diarrhea 36 2 26 0 28 0Abdominal paind 33 2 24 2 21 2Constipation 22 0 17 2 11 0Dry mouth 11 0 11 0 6 0

Nervous system disordersHeadache 29 0 37 2 28 0Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disordersCough 29 0 11 0 21 0Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disordersArthralgia 27 0 44 0 34 0Myalgia 22 2 24 0 23 2Back pain 18 5 11 0 11 2Muscle spasms 16 0 2 0 4 0Pain in extremity 16 0 11 2 19 0

Metabolism and nutritional disordersDecreased appetite 22 0 30 0 19 0Dehydration 11 0 6 2 2 0

Psychiatric DisordersInsomnia 18 0 11 0 8 2

Vascular disordersHemorrhagee 16 5 11 0 2 0

Infections and infestationsUrinary tract infection 13 2 6 0 9 2

Renal and urinary disordersRenal failuref 7 7 2 0 0 0

aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.bIncludes the following terms: peripheral edema, edema, and lymphedema.c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.

d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.

fIncludes the following terms: renal failure and renal failure acute.Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were:Eye Disorders: Vision blurred, transient blindness.Gastrointestinal Disorders: Stomatitis, pancreatitis.General Disorders and Administration Site Conditions: Asthenia.Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2

Tests


N = 55


N = 54TAFINLAR

N = 53

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4

All Grades

Grades 3 and 4a

HematologyLeukopenia 62 5 46 4 21 0Lymphopenia 55 22 59 19 40 6Neutropenia 55 13 37 2 9 2Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0

Liver Function TestsIncreased AST 60 5 54 0 15 0Increased alkaline phosphatase 60 2 67 6 26 2

Increased ALT 42 4 35 4 11 0Hyperbilirubinemia 15 0 7 4 0 0

ChemistryHyperglycemia 58 5 67 6 49 2Increased GGT 56 11 54 17 38 2Hyponatremia 55 11 48 15 36 2Hypoalbuminemia 53 0 43 2 23 0Hypophosphatemia 47 5 41 11 40 0Hypokalemia 29 2 15 2 23 6Increased creatinine 24 5 20 2 9 0Hypomagnesemia 18 2 2 0 6 0Hyperkalemia 18 0 22 0 15 4Hypercalcemia 15 0 19 2 4 0Hypocalcemia 13 0 20 0 9 0

aNo Grade 4 events were reported in patients receiving TAFINLAR as a single agent.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS7.1 Effects of Other Drugs on DabrafenibDabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other DrugsDabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 TrametinibCoadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTAFINLARPregnancy Category DRisk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINISTPregnancy Category DRisk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing MothersIt is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseThe safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

8.5 Geriatric UseOne hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive PotentialTAFINLARContraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

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ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.


GlaxoSmithKlineResearch Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR: 4BRS

B:14

.25

inB:10.75 in

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inT:10.5 in

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2015 Oncology Meetings 2015 4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015)September 25-26 • Seattle, WA For more information: www.seattlechildrens.org/research/childhood-cancer/CIPO-2015/

2015 Breast Cancer SymposiumSeptember 25-27 • San Francisco, CA For more information: http://breastcasym.org

European Cancer Congress (ECC 2015)September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/European-Cancer-Congress-2015

17th Annual International Meeting of the Institute of Human VirologySeptember 27-30 • Baltimore, MD For more information: http://medschool.umaryland.edu/ihvmeeting/default.html

5th World Congress on Cancer TherapySeptember 28-30 • Atlanta, Georgia For more information: http://cancer.global-summit.com/america/

OctoberAdvances in Cancer ImmunotherapyTM

October 2 • Nashville, Tennessee For more information: www.sitcancer.org/sitc-meetings/aci2015/tn

5th International Breast Cancer Prevention SymposiumOctober 2-3 • Le Gosier, Guadeloupe, French West Indies For more information: www.purdue.edu/breastcancer/

CAP ’15-The Pathologists’ MeetingTM (College of American Pathologists)October 4-7 • Nashville, Tennessee For more information: www.thepathologistsmeeting.org

American College of Surgeons Clinical CongressOctober 4-8 • Chicago, Illinois For more information: www.facs.org/meetings_events/future_congress/future

30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology”October 5-8 • Boston, Massachusetts For more information: http://steele.mgh.harvard.edu/tumorcourse

20th World Congress on Advances in Oncology and 18th International Symposium on Molecular MedicineOctober 8-10 • Athens, Greece For more information: www.spandidos-publications.com/pages/conference

Congress of the International Society of Pediatric OncologyOctober 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com

Palliative Care in Oncology SymposiumOctober 9-10 • Boston, Massachusetts For more information: http://pallonc.org

National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/meetings/hematological/default.aspx

ASTRO’s 57th Annual MeetingOctober 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-and-Events/2015-Annual-Meeting/Index.aspx

2015 International Cancer Education ConferenceOctober 21-23 • Tucson, Arizona For more information: http://2015.attendicec.org

ACCC 32nd National Oncology ConferenceOctober 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/calendar.asp

53rd Annual Meeting of the Japan Society of Clinical Oncology (JSCO)October 24-26 • Kyoto, Japan For more information: www.jsco.or.jp/english/index/page/id/73

ESGO 2015-International Meeting of the European Society of Gynaecological OncologyOctober 24-27 • Nice, France For more information: http://esgo2015.esgo.org

Lynn Sage Breast Cancer SymposiumOctober 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

NovemberNRCI Cancer ConferenceNovember 1-4 • Liverpool, UK For more information: http://conference.ncri.org.uk

Chemotherapy Foundation SymposiumNovember 4-6 • New York, New York For more information: www.chemo-therapyfoundationsymposium.org

Society for Immunotherapy of Cancer 30th Anniversary Annual MeetingNovember 4-8 • National Harbor, MD For more information: www.ncer.org/sitc-meetings/sitc2015

Advanced Breast Cancer Third International Consensus ConferenceNovember 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org

14th International Kidney Cancer SymposiumNovember 6-7 • Miami, Florida For more information: http://registeruo.niu.edu/iebms/wbe/wbe_p1_main.aspx?oc=40&cc=WBE4014167

ESMO Summit Americas 2015–Oncology Updates: From Evidence to PracticeNovember 6-8 • Miami, Florida For more information: www.esmo.org/Conferences/ESMO-Summit-Americas-2015

Best of ASTRO November 13-14 • San Diego, California For more information: www.astro.org/Meetings-and-Events/2015-Best-of-ASTRO/Index.aspx

Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www.integrativeonc.org/conference

12th International Conference of the Society for Integrative OncologyNovember 15-16 • Boston, MA For more information: www.integrativeonc.org/index.php/events

Advances in Cancer ImmunotherapyTM

November 18 • San Francisco, CA For more information: www.sitcancer.org/sitc-meetings/aci2015/casf

20th Annual Scientific Meeting of the Society for Neuro-OncologyNovember 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org

ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/Immuno-Oncology-2015

continued from page 56

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINISTContraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR.

8.7 Hepatic ImpairmentTAFINLARNo formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].MEKINISTNo formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal ImpairmentNo formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].10 OVERDOSAGEThere is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.

17 PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Medication Guide) for TAFINLAR.See FDA-approved patient labeling (Patient Information) for MEKINIST.Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.MEKINIST is a registered trademark of GlaxoSmithKline.


GlaxoSmithKlineResearch Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR: 4BRS

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In the News

Agreement on High-Value Screening for Five Common CancersBy Charlotte Bath

F inding agreement on high-value cancer screening among organiza-

tions publishing screening guidelines, the American College of Physicians (ACP) issued advice listing the least-in-tensive screening strategies that all the organizations recommend—as well as strategies not recommended—for five common cancers: breast, colorectal, ovarian, cervical, and prostate. Publish-ing the advice in the Annals of Internal Medicine, the ACP High Value Care Task Force stressed that the advice ap-plied to asymptomatic adults at average risk for the five cancers.1

The report has received national media attention, including CBS News, the Los Angeles Times, AP, and Reuters, and generated interest among its target audience of clinicians. “It has only re-cently been published, but generally we have received very positive feedback,” one of the paper’s lead authors, Amir Qaseem, MD, PhD, MHA, FACP, told The ASCO Post. “All these recom-mendations that we have summarized in this paper are evidence-based clini-cal recommendations from reputable guideline groups. So it is not a surprise that everyone is in agreement,” added Dr. Qaseem, Director of Clinical Policy of the ACP and President Emeritus of Guidelines International Network.

“There is no doubt that screening is one of the strategies to reduce cancer deaths. No one is arguing that. The is-sue that people have started to come to

realize is that more intensive screening does not result in any additional reduc-tion in cancer deaths but increases the harm. As intensity increases beyond a certain level, the increase in benefits is not really there, but the harms keep on going up, and, hence, the value of any kind of screening test starts going

down,” Dr. Qaseem stated. “We wanted to focus on appropriate screening, to do the high-value screening and avoid the low-value screening. That is what we tried to clarify in this paper.”

Review of Guidelines and Evidence

The ACP High Value Care Task Force based its advice on a review of clinical guidelines and evidence syn-thesis from the ACP, U.S. Preventive Services Task Force, American Cancer Society, American Academy of Family Physicians, American Congress of Ob-stetricians and Gynecologists, Ameri-

can Urological Association, and Ameri-can Gastroenterological Association.

Strictly defined, a guideline is “a systematic review of evidence,” Dr. Qaseem noted. The ACP Task Force did not review primary literature or evidence because that had already been done by those organizations.

“What we tried to do was essentially look at the guidelines that are already out there and identify areas of agree-ment, and there are plenty of areas of agreement, across most of these orga-nizations,” Dr. Qaseem said.

Areas of Common Agreement Breast Cancer: The review of guide-

lines from all the organizations cited previously found that “all groups rec-ommend mammography screening, or discussions about screening, at least every 2 years for women aged 40 to 74 years,” the ACP Task Force noted. “No group recommends regular systematic

magnetic resonance imaging (MRI) or tomosynthesis screening for average-risk women.”

Colorectal Cancer: “All organiza-tions recommend screening persons aged 50 to 75 years with one of four strategies,” the ACP Task Force noted. These strategies are high-sensitivity fecal occult blood test or fecal immu-nochemical test every year, sigmoidos-copy every 5 years; combined high-sen-sitivity fecal occult blood test or fecal immunochemical test every 3 years plus sigmoidoscopy every 5 years; or optical colonoscopy every 10 years.

Ovarian Cancer: “All organizations recommend against pelvic examina-tions, cancer antigen 125 blood tests, and transvaginal ultrasonography for ovarian cancer screening.”

Cervical Cancer: “All organizations recommend starting screening with cytology without human papilloma-virus (HPV) tests every 3 years at age 21 years, regardless of sexual history. At age 30 years, women have the choice of continuing cytology screening ev-ery 3 years or cotesting with cytology plus HPV testing every 5 years. Do not screen in women who had a hysterec-tomy and the cervix was removed.”

Prostate Cancer: “No organization recommends prostate-specific anti-gen (PSA) testing for prostate cancer screening without a discussion of the benefits and harms and a patient’s ex-pressed, clear preference for screening.”

Screening

Yes, cancer screening is one of the strategies that has saved lives, but maybe the pendulum swung too far on the other end, where we start realizing that there are harms of each and every one of these tests.

—Amir Qaseem, MD, PhD, MHA, FACP

Expect and Encourage Questions About the Benefits and Harms of Cancer Screening

Issuing advice for high-value care in screening for five common

cancers, the High Value Care Task Force of the American College of Physicians (ACP) stated: “The target audience for this paper is all clinicians. The target patient popu-lation is average-risk, asymptomatic patients.”

“What we tried to do is simplify the message, not only just for phy-sicians and clinicians, but also for patients. So if any patient picks up this document, they will be able to see that as well,” ACP task force member Amir Qaseem, MD, PhD, MHA, FACP, said in an interview with The ASCO Post. Dr. Qaseem is

Director of Clinical Policy, ACP, and President Emeritus, Guidelines In-ternational Network. The screening advice was published in the Annals of Internal Medicine. The article and a summary for patients are available at acponline.org.

Team-Based Approach“It is a team-based approach. We

have to work together,” Dr. Qaseem said. “As a patient, I need to know what is happening. But as a physi-cian, I am also responsible to edu-cate the patient: Here are the ben-efits, but here are the harms. Every test is associated with false posi-tives. Some tests may have more or

less, but every test has some harms.”The screening advice is based on

guidelines from “reputable guideline groups” for breast, colorectal, ovarian, cervical, and prostate cancers, Dr. Qa-seem noted, but “these are guidelines only. They are population-based, and, of course, physicians have to use their own judgment.”

“It is important for patients to be-come educated consumers as well. Pa-tients should be empowered anyway,” he added, and encouraged to ask questions.

What if the Patient Persists?What if a patient acknowledges

screening may not be high value, but still wants it, to feel safer or not

to break well-established routine, or for whatever reason?

“That really comes down to a physi-cian’s responsibility to do no harm,” Dr. Qaseem said. “You need to sit down and talk to your patients, to hear them out and find out why they feel like that. There might be some reason. Maybe they have a family history” not previ-ously disclosed. “Maybe they have heard something from their neighbor, who might have been getting screened. In that case, you would need to explain that maybe the neighbor had a family history or some other risk factor. Most patients are reasonable.” n

Disclosure: Dr. Qaseem reported no potential conflicts of interest.


In the News

It’s Not Just About the MoneyAs defined by ACP, “value is deter-

mined by an intervention’s health ben-efits vs its harms and costs,” the Task Force wrote. “High-value strategies re-turn large health benefits for the harms and costs incurred; low-value strategies return disproportionately small benefits for the harms and costs. Although high-intensity strategies aim to maximize cancer detection, value is optimized by finding the level of intensity that best balances benefits with harms and costs.”

The authors searched databases, models of screening effectiveness, and national studies for information on costs, but that was just one factor and not a major focus in formulating the screening advice. “We need to differ-entiate between this value and costs,” Dr. Qaseem said, so that the screening advice is not misinterpreted merely as a means to save money. “A cheap test can actually still be a low-value test. And an expensive test actually can still be of high value.”

‘A Classic Example’“Screening average-risk adults aged

50 to 75 for colorectal cancer with a high-sensitivity fecal occult blood test every year is an example of high-value care. Screening women without a cervix for cervical cancer is an example of low-value care,” according to an ACP press release announcing the publication of the screening advice.2 And according to the published article, “Nearly 70% of women without a cervix received a Pap test for cervical cancer screening in 2002.”3

Really? “Yes, it still happens. Dr. Qa-seem confirmed. “The Pap test is one of those tests that is being overused for sure. It’s a classic example. Just a simple Pap test is actually a low-cost test. But it still is of low value if you are going to do it on an annual basis.”

Screening Is Popular“Regardless of value, cancer screen-

ing is popular among the U.S. public and is done more frequently than in other countries,” the article pointed out. Among adults receiving colonoscopies, 60% had them more frequently than guidelines recommend, “and screening often occurs in adults with life expec-tancies of 5 years or less,” the authors reported. “Most persons having PSA testing received annual cancer screen-ing, and one-half of men aged 75 to 79 years had recent screening,” the authors added. Overall, more than 50% of men and women older than 75 years report that their physicians continue to recom-mend screening, according to the article.

The ACP Task Force found “20% of women aged 30 to 39 years received a physician recommendation for mam-mography, and 23% to 35% in this age group had mammography. Most women having mammography receive it annually. One-third of surveyed pri-mary care physicians screen with ul-

trasonography and MRI, in addition to mammography, in women not at increased risk for breast cancer.” Not only is cervical cancer screening “com-monly done earlier and more frequent-ly than recommended,” but it contin-ues to be done in 38% of women aged 80 years or older.”

‘Perfect Storm of Overuse’In a companion article4 outlining a

framework for thinking about the value of varying intensities of cancer screen-ing, the ACP Task Force noted: “Phy-sicians and patients are under great pressure from many sources to use the


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In the News

‘maximal cancer detection’ framework rather than the value framework.”

Factors that could contribute to this pressure include a lack of knowledge or understanding of the harms of screen-ing, fear of cancer, belief that earlier de-tection is always better, media messages about screening, stories of survivors, belief that action is better than inaction, and intolerance of uncertainty. “The relative importance of these factors in stimulating the use of overly intensive low-value screening strategies is un-derinvestigated and largely unknown,” the authors acknowledged. “However, many factors seem to encourage this practice, creating what has been de-scribed as a ‘perfect storm’ of overuse.”

‘Cascade of Events’“Screening is a cascade of events

rather than a single test,” the ACP Task Force members noted in the compan-ion article.

“Absolutely,” Dr. Qaseem resolutely concurred. “Because once you do the test and you find something, it always leads to the next test. You never just leave it at that. It just does not happen. Once you find something, it is going to

lead to more tests, more biopsies. Once you are in that cycle, it gets very difficult to get out.”

Freeing Up Time and MoneyReducing the intensity of screening

would not only reduce the harms asso-ciated with it, but “the other benefit is that you are going to spend time talking about other services that might provide higher value,” Dr. Qaseem said. “So in the 10 to 15 minutes you have to sit down and to talk to patients, rather than talking about something that might not provide much benefit, you can spend time discussing things that actually might have much added value. It could be about exercise. It could be about their cholesterol. It could be about their hypertension.”

Moving to the value approach to screening could redirect funds to in-crease screening among disadvantaged groups, people for whom screening is not popular because they haven’t been able to afford health care. If funds were so redirected, Dr. Qaseem said that he hoped it would be for screening based on the ACP advice and not past practices.

“Hopefully, funds will be directed to the right place, where we need the money, to the uninsured, or the folks who may

not have enough, the underserved popu-lation.” He cited the example of colorectal cancer, for which high-value screening is available, but it currently is not being used in many average-risk, asymptom-atic adults. “We are not even screening the people who should be screened, and on the other hand, we are actually over-screening people who are already in the system,” Dr. Qaseem said.

Understanding of Concepts Increasing

At the conclusion of the value frame-work article, the authors noted, “There is reason to believe that understanding of these concepts is increasing.” They credit campaigns to increase profes-sional and public awareness of overly intensive low-value screening, as well as articles and books about screening harms and costs.

In addition to publishing and publi-cizing the high-value screening advice, ACP is sponsoring education programs in several formats for physicians. A summary of the screening advice for pa-tients also is available at acponline.org.

“Slowly, definitely, things are chang-ing,” Dr. Qaseem said. “It comes back to how the message is being conveyed. Yes, cancer screening is one of the strat-

egies that has saved lives, but maybe the pendulum swung too far on the other end, where we start realizing that there are harms of each and every one of these tests.” n

Disclosure: Dr. Qaseem reported no potential conflicts of interest.

References1. Wilt TJ, Harris RP, Qaseem A, for the

High Value Care Task Force of the Ameri-can College of Physicians: Screening for cancer: Advice for high-value care from the American College of Physicians. Ann Intern Med 162:718-725, 2015.

2. American College of Physicians: American College of Physicians releases high value care screening advice for five common cancers. May 18, 2015. Available at http://www.eurekalert.org/pub_releas-es/2015-05/acop-arh051215.php. Accessed June 11, 2015.

3. Sirovich BE, Welch HG: Cervical cancer screening among women without a cervix. JAMA 291:2990-2993, 2004.

4. Harris RP, Wilt TJ, Qaseem A, for the High Value Care Task Force of the Ameri-can College of Physicians: A value frame-work for cancer screening: Advice for high-value care from the American College of Physicians. Ann Intern Med 162:712-717, 2015.

Cancer Screeningcontinued from page 66

Visit ASCOPost.com for Interviews Filmed During the 2015 ASCO Annual Meeting

The ASCO Post presents these and other important discussions:

Visit The ASCO Post online at ASCOPost.com

■ Whole-Brain Radiation and Radiosurgery in Patients With Brain Metastases

■ Issues of Value in Melanoma Treatment ■ PALOMA3 Study on Hormone Receptor–Positive,

HER2-Negative Metastatic Breast Cancer ■ Global Oncology: Cancer Care in Resource-Challenged Areas ■ Ibrutinib, Bendamustine, and Rituximab in Previously Treated

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma


Patient’s Corner

Building and Adjusting to My Life After CancerBy Jennifer Titche, as told to Jo Cavallo

I had been watching a lump in my left breast for signs of cancer for 10 years,

from around the time I was 21. Screen-ing tests had failed to find any tissue abnormality, and my doctor said I was too young to have cancer, so I wasn’t overly concerned. But when I noticed the lump getting bigger in 2010, I went back to my doctor, and she performed a biopsy of the tumor, which showed that I had invasive ductal carcinoma. At just 31, I thought I still had time to meet someone, get married, and start a fam-ily, but now I was facing treatment that would irrevocably alter those plans.

My oncologist was recommending trastuzumab (Herceptin) to shrink the tumor, then a lumpectomy, then adju-vant radiation, followed by 5 years—which has since changed to 10 years—of tamoxifen. Because I was still hoping to have a family one day, before my treat-ment began, I met with a fertility special-ist who counseled me on harvesting my eggs, then fertilizing the eggs through a sperm donor, and cryopreserving them until after my cancer treatment was over and I was once again cancer-free.

We were successful at harvesting eight eggs, but four failed to become fer-tilized, so four eggs are cryopreserved for possible future use, but the idea of going through this process again after I’m finished with tamoxifen, when I’m in my 40s, is daunting, and it’s difficult for me to plan that far into the future.

Financial and Physical BurdensThe fertility treatment and insurance

copays for my cancer treatment have left me $28,000 in debt, which will take

me a long time to repay. But even more difficult to cope with than the financial burden cancer has left in its wake is its physical destruction. Because a substan-

tial amount of tissue had to be removed to capture all the cancer cells, I opted to have breast reconstruction surgery, but

Once you are through with cancer and its treatment, it is impossible to reconstruct the

exact life you had prior to your diagnosis. So, my challenge

now is building a life with new goals that will make me happy

and fulfilled. —Jennifer Titche


@ APPLY TODAY www.asco.org/leadership

& OURS

Join ASCO’s Leadership Development Program

SHAPE YOUR FUTURE

The ASCO Leadership Development Program strives

to teach its participants how to build a team and then lead

that team to greatness. As participants in this program, we have been challenged to define a strategic issue and work together to reach a desired outcome. I see

this program as a springboard for future leadership opportunities in

my clinic and oncology.

— Melissa Dillmon, MD, FACP,HARBIN CLINIC

• Participate in a diverse class of oncologists from different practice settings

• Enhance your leadership skills through interactive sessions

• Network and receive mentorship from ASCO leadership

• Gain exposure to ASCO committees

• Receive first-hand advocacy experience on Capitol Hill

• Be assigned an ASCO strategic issue to research and deliver recommendations to the Board of Directors

Participants in this year-long leadership program will learn valuable leadership skills as well as gain extensive exposure to the mission of ASCO. This program requires a time commitment for travel and training.

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Patient’s Corner

the result was not good, and I’m self-conscious about how I look. In addition to the scars on my chest and my back from the muscle flap and skin graft used to rebuild my breast, tamoxifen has left me 60 pounds heavier and in full-blown

menopause, so the thought of meeting someone and becoming intimate is un-imaginable to me right now.

The Patient/Doctor PartnershipAfter my breast cancer diagnosis,

I was plagued by the thought of a re-currence. I still worry the cancer will

come back, but the possibility doesn’t consume me, and I’m getting on with my life. I see my oncologist every 6 months for checkups, and he has been a lifeline for me. From the beginning, he made sure I was his partner in all our treatment discussions. He would give me his opinion and educate me

about my options and never pressured me into a decision I wasn’t comfort-able with. Most of all, he is a compas-sionate person and a good listener, and I can’t imagine going through this ex-perience without him.

Facing the FutureCancer has taught me that it is a

family disease. Although there is no history of cancer in our family, the fact that I’ve had breast cancer at such a young age means that my sister and her daughter will have to be extra vigilant about performing breast self-exams and getting cancer screenings, and I regret that they now have that burden.

I’m still sorting through all that has happened over the past 5 years and adjusting to a life I never expected to have. Once you are through with can-cer and its treatment, it is impossible to reconstruct the exact life you had prior to your diagnosis. So, my chal-lenge now is building a life with new goals that will make me happy and ful-filled. The pace has been slow, but I’m finding my way. n

Jennifer Titche lives in Lafayette, Indiana.

Life After Cancercontinued from page 69


From YouWe encourage readers to share

their opinions and thoughts on issues of interest to the

oncology community.

Write to The ASCO Post at [email protected]

Harborside PressPhone: 631.692.0800

Fax: 631.692.0805 www.ASCOPost.com

Register at NCCN.org/hem

NCCN 10th Annual Congress:

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• Management of Myelodysplastic Syndromes

• Optimizing Small Molecular Inhibitor Therapy for Chronic Lymphocytic Leukemia

• PET-Guided Treatment Approach for Advanced Stage Classical Hodgkin Lymphoma

• Survivorship Issues: Late Effects of Curative Therapy in Lymphoma Survivors

• Targeted Therapies for Relapsed or Refractory Classical Hodgkin Lymphoma

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In the Literature

Emerging Clinical Data on Cancer Management

HEALTH-CARE DISPARITIES

Significant Differences in Age at Diagnosis Between Blacks and Whites for Six Types of Cancer

Although blacks were diagnosed at a younger age than whites for nearly every cancer type, after adjustments for popu-lation structure shifted the comparisons toward older ages among blacks, only six statistically significant differences of 3 or more years remained, according to a study in the Journal of the National Cancer Insti-tute. Blacks were 10.2 years younger than whites at diagnosis for Kaposi sarcoma, 5.6 years younger for male soft-tissue cancer, 5.5 years younger for male anal cancer, and 3.7 years younger for non-Hodgkin lym-phoma. Blacks were 4.7 years older than whites at diagnosis for cervical cancer and 3.3 years older for female thyroid cancer.

“Smaller differences (< 3 years) were present for female breast, female colon, lung, pancreas, prostate, and uterine corpus cancers (all P ≤ .001),” reported researchers from the National Cancer Institute and Johns Hopkins Bloomberg School of Public Health.

Using Surveillance, Epidemiology, and End Results (SEER) data for non-Hispan-ic blacks and whites from 18 regions for the year 2010, the investigators “calculated crude mean ages at diagnosis among cases of 29 cancer types for whites and blacks. Separately, we calculated adjusted means that corrected for differences in popula-tion structure, which we obtained by fit-ting linear regression models to the ages at diagnosis with statistical weights specific to age and sex,” the authors explained.

The population distribution in the

SEER data was older for whites than blacks. “Individuals older than age 50 years made up 23.2% and 34.7% of the population for blacks and whites, respec-tively, and individuals older than age 70 years made up 4.2% and 8.1%, respec-tively. The mean age among blacks was 33 years, compared with 39 years for whites,” the authors reported.

Among 29 cancer types included in the analysis, “a statistically significant (P < .10) interaction between gender and race was present for esophageal, colon, anal, soft-tissue, and thyroid cancers,” the research-ers stated, and analyses for these cancers were stratified by gender. This resulted in 34 comparisons, and in 32 of them, the crude mean age at cancer diagnosis was younger in blacks than in whites, with dif-ferences ranging from 13.3 years younger for blacks diagnosed with Kaposi sarcoma to 1.3 years older for cervical cancer.

“After adjusting for differences in population structure between blacks and whites, the apparently younger mean age for blacks was greatly diminished for most cancers, and for a few cancers, adjust-ment for population structure revealed older ages in blacks that were previously masked,” the researchers stated. Adjusted mean differences ranged from 10.2 years younger for blacks with Kaposi sarcoma to 4.7 years older for cervical cancer.

“Most differences between blacks and whites in the age at cancer diagnosis are small,” the investigators concluded. “Large differences for a few cancer types may be driven by etiologic and subtype heteroge-neity as well as disparities in access to care.”

Robbins HA, et al: J Natl Cancer Inst 107:dju489, 2015.

LUNG CANCER

Date of Last Chemotherapy Is Not a Proxy for Deciding When to Stop Treating Metastatic NSCLC

“Patients, their families, and oncolo-gists recognize the administration of che-motherapy near death as aggressive and poor-quality care,” William F. Pirl, MD, MPH, and colleagues from Massachu-setts General Hospital, Boston, wrote in the Journal of Oncology Practice. “How-ever, rates have been slowly rising over the last decade, and 5% to 22% of all patients with advanced cancer receive chemother-apy within 2 weeks of death.”

To identify the processes leading to dis-continuation of chemotherapy for patients with metastatic non–small cell lung cancer (NSCLC) at the end of life, the research-ers reviewed health records of a prospec-tive cohort of 151 patients with newly diagnosed metastatic NSCLC from a trial of early palliative care. The mean age of pa-tients was 64, and the median number of lines of chemotherapy was 2 to 2.5.

Of 144 patients who died, 81 had re-ceived intravenous chemotherapy and 48 had received oral chemotherapies as their final regimen, but 40 of those 48 patients (83.3%) switched from intravenous to oral delivery as their final regimen, the investigators noted. The median time be-tween transitioning from intravenous to oral chemotherapy was 134.5 days. Nine patients did not receive chemotherapy, and six were excluded due to transfer of care or lack of end-of-life data.

The median time between the last in-travenous chemotherapy infusion and death was 55 days. “However, almost one-quarter of patients in the sample had no documented decision to discontinue [in-travenous] chemotherapy altogether,” the researchers wrote. For patients with docu-mented final decisions, the median time from the decision to the patient’s death was only 20 days.

Five ProcessesThe authors identified five processes

for stopping intravenous chemotherapy: definitive decisions (19.7%), deferred de-cisions or breaks (22.2%), disruptions for radiation therapy (22.2%), disruptions re-sulting from hospitalization (27.2%), and no decisions (8.6%). Notes for patients in the no-decision category “suggest that they were unexpected, with some oncolo-gists indicating that patients died a “sud-den death.” Nonetheless, several notes

raise the possibility that oncologists may not have recognized that patients were close to death,” the authors wrote.

“The five processes occurred at signifi-cantly different times before death and, except for definitive decisions, ultimate decisions for no further chemotherapy and referral to hospice were often made months later,” the researchers reported. The processes “seemed to vary based on how confident the oncologist might be in his or her assessment of the time course of a patient’s disease,” the authors added. “Oncologists have been shown to overes-timate the survival of their terminally ill patients, which could lead to overconfi-dence in administering chemotherapy to a patient close to death.”

Study ImplicationsThe “study demonstrates that the date

of last chemotherapy treatment is not a proxy for when a decision to stop cancer treatment is made,” the investigators ob-served. “In this sample of patients with metastatic NSCLC, < 20% had evidence of a definitive decision to stop chemotherapy at the time their chemotherapy was discon-tinued. For the majority of patients, a sub-stantial amount of time followed the last [intravenous] chemotherapy treatment be-fore a final decision to stop chemotherapy was made.”

Although ASCO “recommends stop-ping chemotherapy when evidence-based therapies show no benefit and the clinical value of further treatment lacks supporting evidence,” in this study “discontinuation of chemotherapy seemed to occur more often in response to failures rather than fu-tility or lack of benefit,” the authors noted.

The authors concluded that “chemo-therapy discontinuation should not just be considered a date before death; it is a process. Differentiating the processes of discontinuing chemotherapy seems to be meaningful, because these process-es occur at significantly different time points before death and may affect sub-sequent end-of-life care, such as hospice referral, days in hospice, and death in the hospital. Understanding these processes has the potential to reduce the adminis-tration of chemotherapy at end of life by identifying not only practices with bet-ter outcomes but also factors that trigger earlier discontinuation.”

Pirl WF, et al: J Oncol Pract 11:e405-e412, 2015.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.©Michael Crawford/The New Yorker Collection/www.cartoonbank.com


Perspective

Laws and DefinitionsAccording to the FDA,1 a biologic

product may be demonstrated to be bi-osimilar if data show that, among other things, the product is “highly similar” to an already-approved biologic product. The biosimilar also must show it has no clinically meaningful differences from the innovator product in terms of safety and effectiveness. Only minor differ-ences in clinically inactive components are allowable in biosimilar products.

The Affordable Care Act amended the Public Health Service Act to create an abbreviated licensure pathway for biologic products that are demonstrated to be “biosimilar to” or “interchangeable with” an FDA-licensed biologic prod-uct. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act.

A phrase used to describe the bio-similar creation—“the process is the product”—illustrates that it is critical to understand the biosimilar development process.2 Biosimilars are derived from many sources, including humans, animals, microorganisms, or yeast. Some, such as blood cells or stem cells, are extracted from living beings. Others are produced using advanced genetic technology. If the host cells, cell culture process, or purifi-cation methods are different, there may be clinically significant alterations in the safety and effectiveness of the drug.

Regulatory GuidanceRecently, the FDA clarified its views

through regulatory guidance. The FDA suggested that manufacturers of bio-

similar drug products would be allowed to extrapolate innovator data to sup-port the approval of all indications the branded product is approved for. While they may reduce the overall resources required in bringing a biosimilar to market, other aspects of the guidance were not as favorable to these stake-holders. The guidance also suggested that the FDA does not believe the cur-rent technology is evolved enough to truly establish the interchangeability of a biosimilar with a branded product.3

The World Health Organization has

stated, “The approach established for generic medicines is not suitable for development, evaluation, and licensing of similar biotherapeutic products since biotherapeutics consist of relatively large and complex proteins that are dif-ficult to characterize.”4

Indeed, biosimilars are not generics. “It is important to note that a biosimilar is not just like a generic drug,” according to Leah Christl, PhD, Associate Di-rector for Therapeutic Biologics in the FDA’s Office of New Drugs. “Because of the differences in complexity of the structure of the biologic and the process used to make a biologic, biosimilars are

not as easy to produce as generics, which are copies of brand-name drugs.”5

Thus, uncertainties about inter-changeability and their implications for biosimilar development remain to be resolved. In the meantime, federal regu-lators are charged to determine whether a biosimilar product is sufficiently simi-lar clinically to an innovator biologic drug to merit the same approval for use.

Cost ConsiderationsQuestions about interchangeability

aside, it is predicted that biosimilars will

save patients money. Biosimilars are ex-pected to save $13 billion over the next 10 years, according to the Congres-sional Budget Office. The initial prom-ise of biosimilars was that they would save patients 30% to 40%. (As a point of reference, generic drugs, which have 85% of the U.S. pharmaceutical market, cost about 80% to 85% less than their corresponding brand-name products, according to the FDA.3)

Unfortunately, bringing biosimilars to market is proving far more complex than anticipated, and therefore, 10% to 20% less than the cost of the branded medication is a more reasonable expec-tation. In Europe, biosimilars have often been associated with only a 10% dis-count from the brand-name product.3

Express Scripts, a pharmacy benefits manager, has stated that biosimilars will provide $250 billion in U.S. health-care savings over the next decade if 11 bio-logics gain biosimilar competition,6 but the RAND Corporation projects much lower savings—about $44 billion—from the introduction of biologics.7

Another class of new biologic drugs is called “biobetter drugs.” A biosimilar drug is a mere structural imitation; a biobetter drug possesses some molecu-lar modification that constitutes an im-

provement over the original innovator drug. Such improvements may range from a longer half-life (allowing for less frequent dosing) to more potency with less toxicity. Biosimilar drugs and biobetter drugs offer the very real pos-sibility of quality alternatives and even enhanced treatments at better prices.

More Key IssuesAnother important question is, will

biosimilar drugs stymie innovation in research and development? Clearly, there must be a return on investment for original biologic medication, and it can take hundreds of millions of dollars to prove a drug’s efficacy and bring it to market. The cost of discovery is stag-gering, but the cost of copying, even though biosimilars are not chemically exact copies, is significantly less.

There must be a balance between encouraging the development of new, lifesaving, or life-improving drugs and their cost. Whether biosimilars will help in achieving such balance remains to be seen. n

Disclosure: Dr. Boxer reported no potential conflicts of interest.

References1. U.S. Food and Drug Administration:

Biosimilars. Available at www.fda.gov. Ac-cessed June 23, 2015.

2. Thelwell C, Longstaff C: Biosimilars: The process is the product. The example of recombinant streptokinase. J Thromb Hae-most 12:1229-1233, 2014.

3. Howell P: How much cheaper will biosimilars be? March 2, 2012. Available at www.fiercepharma.com. Accessed June 23, 2015.

4. Expert Committee on Biological Standardization: Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). Geneva, Switzerland, World Health Orga-nization, 2009. Available at www.who.int. Accessed June 23, 2015.

5. U.S. Food and Drug Administration: Biosimilars: More treatment options are on the way. March 6, 2015. Available at www.fda.gov. Accessed June 23, 2015.

6. Milman J: The cheaper cancer drug that could pave the way for much more af-fordable medicine. The Washington Post. January 5, 2015.

7. RAND Corporation: Biosimilar med-ications could create billions in health care savings. November 3, 2014. Available at rand.org. Accessed June 23, 2015.

Biosimilarscontinued from page 1

There must be a balance between encouraging the development of new, lifesaving, or life-improving drugs, and their cost. Whether biosimilars will help in achieving such balance remains to be seen.

—Richard J. Boxer, MD, FACS

Summer 2015


From You

We encourage readers to share their opinions and thoughts on issues of

interest to the oncology community.

Write to The ASCO Post at [email protected] Beach State Park, Wantagh, New York: A boat docked offshore at Jones Beach on the south

shore of Long Island on the 5th of July. Photo by iStock. Send your image to [email protected]. Please include your name and a caption for the photo.

ASCO Meetings

Gastrointestinal Cancers Symposium

January 21-23, 2016 | San Francisco, California Cosponsored with: American Gastroenterological Association Institute, American Society for Radiation Oncology, and Society of Surgical Oncology

Celebrating Ten Years

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January 7-9, 2016 | San Francisco, California Cosponsored with: American Society for Radiation Oncology and Society of Urologic Oncology

ASCO Quality Care Symposium February 26-27, 2016 | Phoenix, Arizona


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Cancer Survivorship Symposium: Advancing Care and Research

A Primary Care and Oncology Collaboration

January 15-16, 2016 | San Francisco, California Cosponsored with: American Academy of Family Physicians and American College of Physicians, Inc.

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Markers in Cancer Diagnostic Development Tutorial May 2-3, 2016 | Bethesda, Maryland In collaboration with European Organisation for Research and Treatment of Cancer and National Cancer Institute

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Annual Meeting June 3-7, 2016 | Chicago, Illinois

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Best of ASCO® Boston July 31-August 1, 2015 | Boston, Massachusetts

San Francisco August 7-8, 2015 | San Francisco, California

Chicago August 28-29, 2015 | Chicago, Illinois

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Breast Cancer Symposium

September 25-27, 2015 | San Francisco, California Cosponsored with: American Society of Breast Surgeons, American Society for Radiation Oncology, and Society of Surgical Oncology

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and Multinational Association of Supportive Care in Cancer

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In Memoriam

Frederick Pei Li, MD, Pioneer of Cancer Genetics, Dies at 75

Frederick Pei Li, MD, who helped inaugurate the era of cancer ge-

netics by demonstrating that people can inherit a genetic susceptibility to develop certain malignancies, died on June 12 at the age of 75. A Profes-

sor at Dana-Farber Cancer Institute, Harvard Medical School, and Harvard T.H. Chan School of Public Health, Dr. Li laid the groundwork for today’s genetic counseling services for people with an inherited risk of cancer—and for efforts to develop cancer preven-tion strategies for such individuals.

Unprecedented DiscoveriesIn the late 1960s, Dr. Li and his col-

league at the National Cancer Institute (NCI), Joseph Fraumeni, MD, MSc, began tracking patterns of cancer in children. Together, they identified a small number of families in which the same rare cancers had arisen across multiple generations. Their research

led them to describe what is now known as Li-Fraumeni syndrome, a rare but devastating condition in which people are highly prone to de-velop a variety of serious cancers at an early age.

For the next 2 decades, Dr. Li and his colleagues worked to identify the mutated gene or genes responsible for the syndrome. In 1990, they published a paper identifying a mutation in p53, a tumor-suppressor gene, as the culprit. It was one of the first times an inherit-ed abnormal gene was linked to cancer in humans. The finding paved the way for the discovery of other cancer-sus-ceptibility genes such as BRCA1 and BRCA2.

For their breakthrough research, Drs. Li and Fraumeni received the prestigious Charles S. Mott Prize of the General Motors Cancer Research Foundation. Their work led to the development of a genetic test for Li- Fraumeni syndrome, which became a paradigm for the evolving field of ge-netic epidemiology.

“I was attracted to studies of can-cer families, because epidemiological studies show that virtually all can-cers manifest a tendency to aggregate in families,” Dr. Li wrote about his research.

Following his discovery of a con-nection between mutated p53 and Li-Fraumeni Syndrome, Dr. Li helped create a center at Dana-Farber to test people for inherited risks for cancer. That center, the Friends of Dana-Far-

ber Cancer Institute Cancer Risk and Prevention Clinic, became a model for genetic testing and counseling centers across the country.

Dr. Fraumeni, of the Division of

Cancer Epidemiology and Genetics at NCI, said, “Fred had a knack for making important clinical and epi-demiological observations and tak-ing them to the next level. This often meant crossing disciplines, which in my experience is not always easy, but collaborators were drawn not only to the scientific ideas generated by Fred, but also by his friendly, calm, and thoughtful demeanor and his gener-osity of spirit.”

A Multidisciplinary Background

Born in Canton, China, in 1940, Dr. Li was raised in New York City, where his parents operated a Chinese restau-rant. He received a BA in physics from New York University, an MD from the University of Rochester, and an MA in demography from Georgetown Univer-sity. In 1967, he joined the Epidemiol-ogy Branch of the NCI.

He first came to Dana-Farber in the early 1970s as a Medical Officer

in the NCI’s Epidemiology Branch and became an Attending Physician in 1976. He joined the Dana-Farber faculty in 1981 as an Associate Physi-cian, was Head of the Division of Can-

cer Epidemiology and Control from 1991–1998, and served as Vice Chair for Population Sciences in the Depart-ment of Adult (now Medical) Oncol-ogy from 1998–2002.

He was Professor of Clinical Cancer Epidemiology at Harvard T.H. Chan School of Public Health and Profes-sor of Medicine at Harvard Medical School, where he held the position of Harry and Elsa Jiler American Cancer Society Clinical Research Professor. In 1996, Dr. Li was appointed by Presi-dent Bill Clinton to the NCI’s National Cancer Advisory Board.

Dr. Li served as Editor-in-Chief of the journal Cancer Epidemiology Biomarkers & Prevention and was on the editorial boards of numerous professional publications, including Cancer Research, the Journal of Clini-cal Oncology, and the American Jour-nal of Medical Genetics. In 1999, he was awarded the American Cancer Society Medal of Honor in Clinical Research. n

Frederick Pei Li, MD

Collaborators were drawn not only to the scientific ideas generated by Fred, but also by his friendly, calm, and

thoughtful demeanor and his generosity of spirit. —Joseph Fraumeni, MD, MSc

In Memoriam

Frederick Pei Li, MD1940 – 2015

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