OncologyLive Targeted Therapy News

Emerging targeted therapies are extending survival in many can-cers, but the cost of these new

treatments is often high. For example, sipuleucel-T (Provenge, Dendreon) for metastatic castration-resistant pros-tate cancer costs $93,000 a year. Ipili-mumab (Yervoy, Bristol-Myers Squibb), the first treatment for metastatic mel-

anoma to improve overall survival in more than 10 years, costs $120,000 for four infusions over a span of just three months. Everolimus (Afinitor, Novar-tis), for renal cell carcinoma and pan-creatic cancer, costs $10,000 a month.

Many of these medications are in-dicated at the final stage of cancer; on average, they extend lifespan by a

Feature

Targeted Therapies in Breast Cancer: Increasingly Promising—and Complicated

Feature

The Rising Cost of Cancer Care in the Era of Individualized TherapyA Q&A With Thomas J. Smith, MD

By Anna Azvolinsky, PhD

Treatment of breast cancer is becoming “horren-dously complicated,” said Brian Leyland-Jones, MD, PhD, director of the Winship Cancer Institute

at Emory University in Atlanta, Georgia. According to Leyland-Jones, as research on breast cancer progresses, the disease is seen as a set of many different diseases, each with distinct molecular and clinical features.

In February, Leyland-Jones spoke at the 9th Annual Northern New Jersey Breast Cancer Conference, held at the John Theurer Cancer Center, Hackensack, New Jersey, where he gave a broad overview of the current progress and direction of optimal therapies for breast cancer—individualized treatment based on specific molecular targets. Leyland-Jones noted that research in the field, both clinical trial data and new preclini-cal studies, is progressing so rapidly that it is almost im-possible to remember all of the new, targeted areas. “It is becoming clear that breast cancer has 50 to 80 targetable drivers,” he said. “This is a time of massive knowledge change in the entire field.”

(continued on page 23) (continued on page 7)

(continued on page 27)

Gastric and Colorectal Cancer

Better Understanding of Gastric Cancer Subtypes Needed for Targeting Treatment

Gastric cancer is not one disease. This was the theme highlighted by Manish A. Shah, MD, director of Gastrointestinal Oncology at Weill Cornell Medical College/New York Presbyterian Hospital, in New York City, during his talk at

the ASCO 2012 Gastrointestinal Cancers Symposium. Shah discussed the impor-tance of developing new, targeted therapies for gastric cancer based on new delin-eations and definitions of gastric cancer subtypes.

Hypothesis-driven development of targeted therapies for gastric cancer is an im-portant and yet elusive goal. Much more research is needed to define molecular subtypes of gastric cancer and identify appropriate targets for clinical use. Shah stressed that while it has been known for more than 40 years that there are distinct subtypes of gastric cancer, clinical practice and clinical trials continue to cluster these gastric cancer patients. Current progress includes the first targeted therapy for gastric cancer approved by the FDA in 2010: Trastuzumab (Herceptin) in combi-nation with chemotherapy is now an option for gastric cancer that overexpresses HER2.

Aside from trastuzumab, little progress has been made in over a decade. “It may have been appropriate to group all gastric cancer patients together when cytotoxic

For the Practicing Oncology Professional

In this issue...

Gastric and Colorectal Cancer• Imatinib Indication Expansion:

Approval for GIST • Regorafenib May Offer Option

for Metastatic Colorectal Cancer and GIST

Hematologic Malignancies• Targeting the PI3K/Akt/mTOR

Pathway for Lymphoma • Obinutuzumab Compares

Favorably With Rituximab in NHL Trial

• Nilotinib Beats Imatinib for CML in Two Phase III Trials

Renal Cell Carcinoma• Approval of Axitinib Adds

Another Therapy Option for Metastic RCC

Skin Cancer• New Laboratory Melanoma

Research Supports Ongoing Clinical Trials

Targeted TherapyNews

TM

www.TargetedTherapyOncology.com

(see page 22)

Breaking news from clinical trials, educational sessions, and seminars at this year’s meeting will focus on the latest advances in and practical advice for the use of new targeted treatments. Here’s what not to miss.

Patricia LoRusso, DO

Thomas J. Smith, MD

Brian Leyland-Jones, MD, PhD

10th International Congress on Targeted Therapies in CancerThe Mayflower Renaissance HotelWashington, DCAugust 17-18, 2012

06.12 ASCO: A Focus on Personalized Medicine

Activate

Amplify

Attack

Prostate cancer cell

PROVENGE- activated T cells

EXTEND SURVIVAL

TREAT fIRST LINE wITh PROVENGE TO

In advanced prostate cancer...

Activated T cell attacks prostate cancer

PROVENGE activating a T cell

Resting T cell

• PROVENGE extends median survival beyond 2 years1

• Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2

— The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2

• PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer

• The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3

IndIcatIon: provenge® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Important Safety InformatIon: provenge is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the provenge group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (grade 3) acute infusion reactions were reported in 3.5% of patients in the provenge group. reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. no grade 4 or 5 acute infusion reactions were reported in patients in the provenge group.The most common adverse events (incidence ≥15%) reported in the provenge group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.For more information on provenge, please see Brief Summary of prescribing Information on adjacent page.

www.provenge.com

• Explore the PROVENGE Interactive Experience• Create a personalized patient educational

poster for your office

visit us at Booth 22063

5654-1_Targeted_Therapy_Spread_L1.indd 1-2 4/30/12 4:18 PM

Activate

Amplify

Attack

Prostate cancer cell

PROVENGE- activated T cells

EXTEND SURVIVAL

TREAT fIRST LINE wITh PROVENGE TO

In advanced prostate cancer...

Activated T cell attacks prostate cancer

PROVENGE activating a T cell

Resting T cell

• PROVENGE extends median survival beyond 2 years1

• Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2

— The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2

• PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer

• The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3

IndIcatIon: provenge® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Important Safety InformatIon: provenge is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the provenge group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (grade 3) acute infusion reactions were reported in 3.5% of patients in the provenge group. reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. no grade 4 or 5 acute infusion reactions were reported in patients in the provenge group.The most common adverse events (incidence ≥15%) reported in the provenge group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.For more information on provenge, please see Brief Summary of prescribing Information on adjacent page.

www.provenge.com

• Explore the PROVENGE Interactive Experience• Create a personalized patient educational

poster for your office

visit us at Booth 22063

5654-1_Targeted_Therapy_Spread_L1.indd 1-2 4/30/12 4:18 PM

PROVENGE® (sipuleucel-T)Suspension for Intravenous Infusion Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION •For Autologous Use Only. •TherecommendedcourseoftherapyforPROVENGEis3completedoses,givenat

approximately2-weekintervals. •Premedicatepatientswithoralacetaminophenandanantihistaminesuchas

diphenhydramine. •Beforeinfusion,confirmthatthepatient’sidentitymatchesthepatientidentifiersonthe

infusion bag. •Do Not Initiate Infusion of Expired Product. •InfusePROVENGEintravenouslyoveraperiodofapproximately60minutes.

Do Not Use a Cell Filter. •Interruptorslowinfusionasnecessaryforacuteinfusionreactions,dependingonthe

severityofthereaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

•PROVENGE is intended solely for autologous use.

•Acute infusion reactions(reportedwithin1dayofinfusion)included,butwerenotlimitedto,fever,chills,respiratoryevents(dyspnea,hypoxia,andbronchospasm),nausea,vomiting,fatigue,hypertension,andtachycardia.Incontrolledclinicaltrials,71.2%ofpatientsinthePROVENGEgroupdevelopedanacuteinfusionreaction.

Incontrolledclinicaltrials,severe(Grade3)acuteinfusionreactionswerereportedin3.5%ofpatientsinthePROVENGEgroup.Reactionsincludedchills,fever,fatigue,asthenia,dyspnea,hypoxia,bronchospasm,dizziness,headache,hypertension,muscleache,nausea,andvomiting.Theincidenceofsevereeventswasgreaterfollowingthesecondinfusion(2.1%vs0.8%followingthefirstinfusion),anddecreasedto1.3%followingthethirdinfusion.Some(1.2%)patientsinthePROVENGEgroupwerehospitalizedwithin1dayofinfusionformanagementofacuteinfusionreactions.NoGrade4or5acuteinfusionreactionswerereported in patients in the PROVENGE group.

Closelymonitorpatientswithcardiacorpulmonaryconditions.Intheeventofanacuteinfusionreaction,theinfusionratemaybedecreased,ortheinfusionstopped,dependingontheseverityofthereaction.Appropriatemedicaltherapyshouldbeadministered as needed.

•Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely testedfortransmissibleinfectiousdiseases.Therefore,patientleukapheresismaterialand PROVENGE may carry the risk of transmitting infectious diseases to health care professionalshandlingtheproduct.Universalprecautionsshouldbefollowed.

•Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapyorimmunosuppressiveagents(suchassystemiccorticosteroids)givenconcurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGEisdesignedtostimulatetheimmunesystem,andconcurrentuseofimmunosuppressiveagentsmayaltertheefficacyand/orsafetyofPROVENGE.Therefore,patientsshouldbecarefullyevaluatedtodeterminewhetheritismedicallyappropriatetoreduceordiscontinueimmunosuppressiveagentspriortotreatmentwithPROVENGE.

•Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterilityresultsfromseveraltests:microbialcontaminationdeterminationbyGramstain,endotoxincontent,andin-processsterilitywitha2-dayincubationtodetermineabsenceofmicrobialgrowth.Thefinal(7-dayincubation)sterilitytestresultsarenotavailableatthetimeofinfusion.IfthesterilityresultsbecomepositiveformicrobialcontaminationafterPROVENGEhasbeenapprovedforinfusion,Dendreonwillnotifythetreatingphysician.Dendreonwillattempttoidentifythemicroorganism,performantibioticsensitivitytestingonrecoveredmicroorganisms,andcommunicatetheresultstothetreatingphysician.Dendreonmayrequestadditionalinformationfromthephysicianinordertodeterminethe source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONSBecauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.

ThesafetyevaluationofPROVENGEisbasedon601prostatecancerpatientsinthePROVENGEgroupwhounderwentatleast1leukapheresisprocedureinfourrandomized,controlledclinicaltrials.Thecontrolwasnon-activatedautologousperipheralbloodmononuclearcells.

Themostcommonadverseevents,reportedinpatientsinthePROVENGEgroupatarate≥15%,werechills,fatigue,fever,backpain,nausea,jointache,andheadache.Severe(Grade3)andlife-threatening(Grade4)adverseeventswerereportedin23.6%and4.0%ofpatientsinthePROVENGEgroupcomparedwith25.1%and3.3%ofpatientsinthecontrolgroup.Fatal(Grade5)adverseeventswerereportedin3.3%ofpatientsinthePROVENGEgroupcomparedwith3.6%ofpatientsinthecontrolgroup.

Seriousadverseeventswerereportedin24.0%ofpatientsinthePROVENGEgroupand25.1%ofpatientsinthecontrolgroup.SeriousadverseeventsinthePROVENGEgroupincludedacuteinfusion reactions (see Warnings and Precautions),cerebrovascularevents,andsinglecasereportsofeosinophilia,rhabdomyolysis,myastheniagravis,myositis,andtumorflare.

PROVENGEwasdiscontinuedin1.5%ofpatientsinStudy1(PROVENGEgroupn=341;Controlgroupn=171)duetoadverseevents.SomepatientswhorequiredcentralvenouscathetersfortreatmentwithPROVENGEdevelopedinfections,includingsepsis.Asmallnumberofthesepatientsdiscontinuedtreatmentasaresult.Monitoringforinfectioussequelaeinpatientswithcentralvenouscathetersisrecommended.

EachdoseofPROVENGErequiresastandardleukapheresisprocedureapproximately3dayspriortotheinfusion.Adverseeventsthatwerereported≤1dayfollowingaleukapheresisprocedurein≥5%ofpatientsincontrolledclinicaltrialsincludedcitratetoxicity(14.2%),oralparesthesia(12.6%),paresthesia(11.4%),andfatigue(8.3%).

Table1providesthefrequencyandseverityofadverseeventsreportedin≥5%ofpatientsinthePROVENGEgroupofrandomized,controlledtrialsofmenwithprostatecancer.Thepopulationincluded485patientswithmetastaticcastrateresistantprostatecancerand116patientswithnon-metastaticandrogendependentprostatecancerwhowerescheduledtoreceive3infusionsofPROVENGEatapproximately2-weekintervals.Thepopulationwasage40to91years(median70years),and90.6%ofpatientswereCaucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Any Adverse EventChillsFatigueFeverBackpainNauseaJoint acheHeadacheCitrate toxicityParesthesiaVomitingAnemiaConstipationPainParesthesia oralPain in extremityDizzinessMuscle acheAstheniaDiarrheaInfluenza-likeillnessMusculoskeletal painDyspneaEdema peripheralHot flushHematuriaMuscle spasms

591 (98.3)319(53.1)247(41.1)188(31.3)178(29.6)129(21.5)118(19.6)109(18.1)89(14.8)85(14.1)80(13.3)75(12.5)74(12.3)74(12.3)74(12.3)73(12.1)71(11.8)71(11.8)65(10.8)60(10.0)58(9.7)54(9.0)52(8.7)50(8.3)49(8.2)46(7.7)46(7.7)

186 (30.9)13(2.2)6(1.0)6(1.0)18(3.0)3(0.5)11(1.8)4(0.7)0(0.0)1(0.2)2(0.3)11(1.8)1(0.2)7(1.2)0(0.0)5(0.8)2(0.3)3(0.5)6(1.0)1(0.2)0(0.0)3(0.5)11(1.8)1(0.2)2(0.3)6(1.0)2(0.3)

291 (96.0)33(10.9)105(34.7)29(9.6)87(28.7)45(14.9)62(20.5)20(6.6)43(14.2)43(14.2)23(7.6)34(11.2)40(13.2)20(6.6)43(14.2)40(13.2)34(11.2)17(5.6)20(6.6)34(11.2)11(3.6)31(10.2)14(4.6)31(10.2)29(9.6)18(5.9)17(5.6)

97 (32.0)0(0.0)4(1.3)3(1.0)9(3.0)0(0.0)5(1.7)0(0.0)0(0.0)0(0.0)0(0.0)7(2.3)3(1.0)3(1.0)0(0.0)1(0.3)0(0.0)0(0.0)2(0.7)3(1.0)0(0.0)3(1.0)3(1.0)1(0.3)1(0.3)3(1.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

(Table 1 continued on next page.)

5654-1_Targeted_Therapy_BS_L1.indd 1 4/30/12 4:18 PM

Cerebrovascular Events.Incontrolledclinicaltrials,cerebrovascularevents,includinghemorrhagicandischemicstrokes,werereportedin3.5%ofpatientsinthePROVENGEgroupcomparedwith2.6%ofpatientsinthecontrolgroup.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


HypertensionAnorexiaBonepainUpper respiratory tract infectionInsomniaMusculoskeletal chest painCoughNeck painWeight decreasedUrinary tract infectionRashSweatingTremor

45(7.5)39(6.5)38(6.3)38(6.3)

37(6.2)36(6.0)

35(5.8)34(5.7)34(5.7)33(5.5)31(5.2)30(5.0)30(5.0)

3(0.5)1(0.2)4(0.7)0(0.0)

0(0.0)2(0.3)

0(0.0)3(0.5)2(0.3)1(0.2)0(0.0)1(0.2)0(0.0)

14(4.6)33(10.9)22(7.3)18(5.9)

22(7.3)23(7.6)

17(5.6)14(4.6)24(7.9)18(5.9)10(3.3)3(1.0)9(3.0)

0(0.0)3(1.0)3(1.0)0(0.0)

1(0.3)2(0.7)

0(0.0)2(0.7)1(0.3)2(0.7)0(0.0)0(0.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)


*Controlwasnon-activatedautologousperipheralbloodmononuclearcells.

©2012DendreonCorporation. Allrightsreserved.March2012.PrintedintheU.S.A. Dendreon,theDendreonlogo,andPROVENGE are registered trademarks ofDendreonCorporation.P-A-03.12-066.00

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.1.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed March 6, 2012.


Cerebrovascular Events.Incontrolledclinicaltrials,cerebrovascularevents,includinghemorrhagicandischemicstrokes,werereportedin3.5%ofpatientsinthePROVENGEgroupcomparedwith2.6%ofpatientsinthecontrolgroup.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


HypertensionAnorexiaBonepainUpper respiratory tract infectionInsomniaMusculoskeletal chest painCoughNeck painWeight decreasedUrinary tract infectionRashSweatingTremor

45(7.5)39(6.5)38(6.3)38(6.3)

37(6.2)36(6.0)

35(5.8)34(5.7)34(5.7)33(5.5)31(5.2)30(5.0)30(5.0)

3(0.5)1(0.2)4(0.7)0(0.0)

0(0.0)2(0.3)

0(0.0)3(0.5)2(0.3)1(0.2)0(0.0)1(0.2)0(0.0)

14(4.6)33(10.9)22(7.3)18(5.9)

22(7.3)23(7.6)

17(5.6)14(4.6)24(7.9)18(5.9)10(3.3)3(1.0)9(3.0)

0(0.0)3(1.0)3(1.0)0(0.0)

1(0.3)2(0.7)

0(0.0)2(0.7)1(0.3)2(0.7)0(0.0)0(0.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)


*Controlwasnon-activatedautologousperipheralbloodmononuclearcells.

©2012DendreonCorporation. Allrightsreserved.March2012.PrintedintheU.S.A. Dendreon,theDendreonlogo,andPROVENGE are registered trademarks ofDendreonCorporation.P-A-03.12-066.00

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.1.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed March 6, 2012.


In 2011, the FDA approved 35 new medicines—seven in oncology,

including the first new treatment for Hodgkin lymphoma in 30

years. By the end of the first quarter of 2012, the FDA had approved

two new cancer therapies. Many of the new oncology medications be-

ing approved are molecularly targeted therapies—and that has posed

a challenge for practicing oncologists: Treating patients with targeted

therapies requires new approaches to diagnosis, treatment, monitor-

ing, and management of adverse events.

Targeted Therapy News is aimed at helping oncologists meet

these challenges by providing the information and analyses they

need to best use targeted therapies in clinical practice.

In this, our premier issue, we focus on the latest developments

in targeted therapies. “ASCO: A Focus on Personalized Medicine”

highlights key presenta-

tions to watch for at this

year’s annual meeting

of the American Soci-

ety of Clinical Oncology,

including educational

seminars specifically

designed to help oncol-

ogists successfully use

novel therapies in pa-

tient care.

“The Rising Cost of

Cancer Care in the Era of

Individualized Therapy”

takes a look at contro-

versies over the costs of

these emerging treat-

ments, and “A New Look at Survival Data for Sipuleucel-T” goes beyond

the original analysis of clinical trial data for sipuleucel-T to suggest

that the prostate cancer vaccine may have delivered a greater overall

survival benefit than previously described.

Finally, our news section includes coverage of breaking develop-

ments in a wide range of cancers, including gastric, colorectal, skin,

and renal cell cancers, and hematologic malignancies.

Targeted Therapy News is one of the latest additions to our fam-

ily of oncology-focused publications and websites, along with The

International Journal of Targeted Therapies in Cancer, a new, peer-re-

viewed journal that also makes its debut this month.

We thank you for joining us, and we look forward to continuing

to provide you with the information and resources you need to

provide the best possible care to your cancer patients.

Peter Ciszewski

Targeted Therapy News: The Premier Issue

In 2011, the FDA approved 35 new medicines—seven in oncology, including the first new treatment for Hodgkin lymphoma in 30 years.

From the Publisher 3

Targeted Therapy News • 06.12

Editorial Board4

Jame Abraham, MDSection of Hematology/OncologyMary Babb Randolph Cancer CenterWest Virginia UniversityMorgantown, WV

Ross Abrams, MDDepartment of Radiation OncologyRush University Medical CenterChicago, IL

Alex A. Adjei, MD, PhDDepartment of MedicineRoswell Park Cancer InstituteBuffalo, NY

Lawrence Afrin, MDDivision of Hematology/OncologyMedical University of South CarolinaCharleston, SC

Sanjiv S. Agarwala, MDDivision of Oncology/HematologySt. Luke’s Hospital & Health NetworkBethlehem, PA

Nita Ahuja, MDSurgery & OncologyThe Johns Hopkins HospitalBaltimore, MD

Lowell Anthony, MDSection of Hematology & OncologyLouisiana State UniversityNew Orleans, LA

David Artz, MD, MBAInformation Systems Memorial Sloan-Kettering Cancer CenterNew York, NY

J. Robert Beck, MDFox Chase Cancer CenterPhiladelphia, PA

Tomasz Beer, MDProstate Cancer ProgramOregon Health & Science University Cancer InstitutePortland, OR

E. Roy Berger, MDNorth Shore Hematology AssociatesEast Setauket, NY

Ralph V. Boccia, MDCenter for Cancer and Blood DisordersBethesda, MD

Jeffrey Bumpous, MDDivision of Otolaryngology-HNS University of LouisvilleLouisville, KY

Barbara A. Burtness, MDHead and Neck Medical OncologyFox Chase Cancer CenterPhiladelphia, PA

John Caton Jr, MDMedical OncologyWillamette Valley Cancer CenterEugene, OR

Emily Chan, MD, PhDVanderbilt UniversityNashville, TN

Helen Chan, MDGI Surgical OncologyLakeland Regional Cancer CenterLakeland, FL

Tarek Chidiac, MDMid-Ohio Oncology/Hematology Inc, dbaThe Mark H. Zangmeister CenterColumbus, OH

Patrick Wayne Cobb, MDHematology-Oncology Centers of the Northern RockiesBillings, MT

Ezra E. W. Cohen, MDSection of Hematology/OncologyUniversity of ChicagoChicago, IL

Richard Cohen, MDCohen Hufford Koltzova MedicalSan Francisco, CA

Allan Cohn, MDRocky Mountain Cancer CenterDenver, CO

Sandra Cuellar, PharmD, BCOPDepartment of Pharmacy PracticeUniversity of Illinois at ChicagoChicago, IL

Mary Daly, MD, PhDPopulation ScienceFox Chase Cancer CenterPhiladelphia, PA

Don Dizon, MDProgram in Women’s OncologyWomen & Infants HospitalProvidence, RI

Habib Doss, MDTennessee Oncology, PLLCNashville, TN

Anthony Elias, MDBreast Cancer & Sarcoma ProgramsUniversity of Colorado Cancer CenterAurora, CO

Fadi Estephan, MDMedical OncologyHutchinson ClinicHutchinson, KS

Evelyn Fleming, MDGynecologic OncologyDartmouth-Hitchcock Medical CenterLebanon, NH

Michele Fox, MDPathologyMyeloma Institute for Research & TherapyUniversity of Arkansas for Medical SciencesLittle Rock, AR

Sharon L. Francz, BHA, BS, ONational Coalition of Oncology Nurse NavigatorsRockville, MD

David R. Gandara, MDDivision of Hematology and OncologyUC Davis Cancer CenterSacramento, CA

Leonard G. Gomella, MDDepartment of UrologyThomas Jefferson UniversityPhiladelphia, PA

Andre Goy, MD, MSJohn Theurer Cancer Center Hackensack University Medical CenterHackensack, NJ

David Graham, MDClinical Trials Carle Clinic AssociationUrbana, IL

Gregory Griffin, MDDivision of Hematology/OncologyAlfred I. duPont Hospital for ChildrenWilmington, DE

Reuben Guerrero, MDDivision of Oncology/HematologyStraub Clinic & HospitalHonolulu, HI

Mahendra Gupta, MDMedical OncologyInnovis HealthFargo, ND

Daniel Hamstra, MD, PhDPediatric Radiation OncologyGenitourinary Radiation OncologyUniversity of MichiganAnn Arbor, MI

Robin Hanson, MD, PhDCardinal Kids Cancer CenterSt. John’s Mercy Medical CenterCreve Coeur, MO

Roy S. Herbst, MD, PhDDivision of Medical OncologyYale School of MedicineNew Haven, CT

William Hocking, MDHematology/OncologyMarshfield ClinicMarshfield, WI

Clifford A. Hudis, MDBreast Cancer Medicine ServicesMemorial Sloan-Kettering Cancer CenterNew York, NY

Dennie Jones, Jr, MDNew Mexico Cancer Care AllianceUniversity of New MexicoAlbuquerque, NM

Emad Kandil, MDDepartment of SurgerySection of Endocrine & Oncological SurgeryTulane Cancer CenterNew Orleans, LA

Song Kang, MDVirginia Oncology AssociatesSentara Careplex HospitalHampton, VA

Gary Lyman, MD, MPH, FRCP(Edin)Duke University Medical CenterDurham, NC

David G. Maloney, MD, PhDClinical Research DivisionFred Hutchinson Cancer Research CenterSeattle, WA

Maurie Markman, MDClinical Affairs & Medical Oncology Cancer Treatment Centers of AmericaPhiladelphia, PA

Robert Meister, MDArlington-Fairfax HematologyArlington, VA

Wilson Mertens, MDCancer ServicesBaystate HealthSpringfield, MA

Joseph Mikhael, MDDivision of Hematology/OncologyDepartment of Internal MedicineMayo ClinicScottsdale, AZ

Mohamed Mitwally, MDDepartment of Obstetrics & Gynecology University of MinnesotaMinneapolis, MN

Janaki Moni, MDMichiana Hematology OncologySouth Bend, IN

Hyman Muss, MDUniversity of Vermont and Vermont Cancer CenterHematology Oncology UnitBurlington, VT

Leigh Neumayer, MDIntegrated Breast ProgramHuntsman Cancer InstituteSalt Lake City, UT

Anthony Nguyen, MDMedical OncologyComprehensive Cancer Centers of Nevada-SienaHenderson, NV

Joyce A. O’Shaughnessy, MDDivision of Breast Cancer ResearchTexas Oncology/US OncologyDallas, TX

Daniel A. Osman, MDBreast Cancer SurgeonMiami, FL

Andrew L. Pecora, MDJohn Theurer Cancer Center Hackensack University Medical CenterHackensack, NJ

Edith A. Perez, MDDepartment of Hematology/OncologyMayo ClinicJacksonville, FL

Roman Perez-Soler, MDDivision of OncologyAlbert Einstein College of MedicineBronx, NY

Daniel P. Petrylak, MDGenitourinary Oncology SectionColumbia University Medical CenterNew York, NY

Aarati Rao, MDDivision of Pediatric Hematology/OncologyUniversity of South AlabamaMobile, AL

Douglas Reding, MD, MPHMarshfield CenterMarshfield, WI

John Rhee, MDMedical Oncology & Hematology, PCYale-New Haven HospitalNew Haven, CT

Adam I. Riker, MDCancer ServicesOchsner Cancer InstituteNew Orleans, LA

Steven Rosen, MDRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IL

Richard J. Rosenbluth, MD John Theurer Cancer CenterHackensack University Medical CenterHackensack, NJ

Oliver Sartor, MDDepartment of UrologyTulane Cancer CenterNew Orleans, LA

Lee Schwartzberg, MDThe West ClinicMemphis, TN

Maureen Sheehan, MDKansas City Cancer CenterKansas City, MO

Edibaldo Silva, MD, PhDDivision of Surgical OncologyEppley Cancer Center University of Nebraska Medical Center Omaha, NE

David Spigel, MD Lung Cancer ProgramThe Sarah Cannon Research InstituteNashville, TN Kellie Sprague, MDBone Marrow TransplantationTufts Medical CenterBoston, MA

Richard Tenglin, MDOncology AssociatesRapid City Regional HospitalRapid City, SD

J. Tate Thigpen, MDDivision of Medical OncologyUniversity of MississippiJackson, MS

Katherine Tkaczuk, MDMedicine & Oncology University of Maryland Cancer CenterBaltimore, MD

Debu Tripathy, MDWomen’s Cancer ProgramUniversity of Southern CaliforniaLos Angeles, CA

Philip Villiotte, MDSpectrum Medical GroupScarborough, ME

Roland Walter, MD, PhDClinical Research DivisionFred Hutchinson Cancer Research Center Seattle, WA

Ronald Walters, MD, MBA, MHAMedical Operations & InformaticsBreast Medical OncologyMD Anderson Cancer CenterHouston, TX

Richard Wein, MDDepartment of Otolaryngology-Head & Neck SurgeryTufts Medical CenterBoston, MA

H. Jack West, MDThoracic Oncology ProgramSwedish Cancer InstituteSeattle, WA

James Wheeler, MDRadiation Oncology ProgramGoshen Center for Cancer CareGoshen, IN

Andrew D. Zelenetz, MD, PhDDepartment of MedicineMemorial Sloan-Kettering Cancer CenterNew York, NY

Paul Zeltzer, MDNeurosurgeryDavid Geffen School of MedicineUniversity of California, Los AngelesLos Angeles, CA

Jeffrey Zonder, MDHematology/OncologyKarmanos Cancer CenterDetroit, MI

In This Issue... 5


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22 ASCO: A Focus on Personalized Medicine

By Anna Azvolinsky, PhD

23 The Rising Cost of Cancer Care in the Era of Individualized Therapy

A Q&A With Thomas J. Smith, MD By Anna Azvolinsky, PhD

26 A New Look at Survival Data for Sipuleucel-T

By Anita T. Shaffer

27 Targeted Therapies in Breast Cancer: Increasingly Promising— and Complicated

35 Research Profile: Leonard M. Neckers, PhD

36 Trials in Progress

40 Evidence-Based Oncology Breakthroughs in Targeted Therapies Not Applicable If Not Cost-Effective

By Marie Rosenthal, MS

Features News

Departments

GASTRIC AND COLORECTAL CANCER6 Imatinib Indication Expansion: Approval for GIST

6 Regorafenib May Offer Option for Metastatic Colorectal Cancer and GIST

7 Better Understanding of Gastric Cancer Subtypes Needed for Targeting Treatment

GyNECOLOGIC MALIGNANCIES8 PARP Inhibitors Intriguing Despite Research Setbacks

HEAD AND NECK CANCER9 Hypothyroidism Risks With MKIs Examined

9 Reolysin Trial Reaches Enrollment Milestone

HEMATOLOGIC MALIGNANCIES12 Subcutaneous Dosing of Bortezomib Approved

12 Targeting the PI3K/Akt/mTOR Pathway for Lymphoma

13 Bruton’s Tyrosine Kinase Inhibitor PCI-32765: Durable Responses in Refractory CLL

13 Obinutuzumab Compares Favorably With Rituximab in NHL Trial

14 Nilotinib Beats Imatinib for CML in Two Phase III Trials

PROSTATE CANCER19 Zytiga Study Unblinded After Interim Analysis

19 Sipuleucel-T Stimulates Response in Localized Setting, Study Finds

RENAL CELL CARCINOMA20 Approval of Axitinib Adds Another Therapy Option

for Metastic RCC

SKIN CANCER21 New Laboratory Melanoma Research

Supports Ongoing Clinical Trials

21 First-Ever Drug Approved for Advanced Form of Most Common Skin Cancer

The content contained in this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. Targeted Therapy News makes no representations or warranties of any kind about the complete-ness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. Targeted Thera-py News reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. Targeted Therapy News further dis-claims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of Targeted Therapy News.

News


6

In January of this year, the FDA ap-proved the use of imatinib (Gleevec, Novartis Pharmaceuticals) for adult

patients with CD117-positive gastroin-testinal stromal tumors (GIST) follow-ing surgical removal. Updated clinical trial data supporting a longer treat-ment schedule were also disclosed; the label now includes study data showing prolonged overall patient survival and relapse-free survival over a 36-month adjuvant treatment compared with the standard-of-care, 12-month adjuvant

Results from two phase III trials in metastatic colorectal cancer (mCRC) and unresectable gastro-

intestinal stromal tumors (GIST) that have progressed despite prior treat-ment indicate that the multi-tyrosine kinase inhibitor regorafenib may offer some benefit.

The phase III international CORRECT trial showed that regorafenib may be a new treatment option that achieves disease control in mCRC that has pro-gressed on multiple lines of standard therapy including 5-fluorouracil (FU), oxaliplatin, irinotecan, bevacizumab, and cetuximab. The trial achieved a statistically significant improvement in

cologists (ASCO) meeting in June 2011. The open-label, multicenter, random-ized phase III study evenly divided 400 patients with KIT-positive GIST into two groups to receive imatinib for ei-ther 12 months or 36 months. The pri-mary endpoint was recurrence-free survival.

After 54 months of follow-up, study results showed that patients who re-ceived imatinib for 36 months were 54% less likely to experience recurrence (hazard ratio [HR] 0.46; 95% confidence

regimen in high-risk GIST patients. Imatinib was first approved in 2001

for chronic myeloid leukemia. The drug was granted accelerated approval for advanced and metastatic GIST in 2002. In 2008, a label was approved for adju-vant use in patients who had surgical removal of their GIST but who are at risk for recurrence.

The latest approval stems from the results of the SSGXVIII/AIO study, which were first presented at the an-nual American Society of Clinical On-

interval [CI], 0.32-0.65; P < .0001) com-pared with patients who received the drug for 12 months. The study also found that the chance of death as a re-sult of GIST was 55% lower in the group that received imatinib for 36 months (HR 0.45; 95% CI, 0.22-0.89; P = .019) compared with the group receiving the drug for 12 months. After five years, 92% of patients in the 36-month imatinib group were alive compared with 81.7% of patients in the 12-month arm of the study. TTN

Imatinib Indication Expansion: Approval for GIST

Regorafenib May Offer Option for Metastatic Colorectal Cancer and GIST

overall survival (OS). The trial was un-blinded in October 2011 after an interim analysis of patients in the placebo arm were offered regorafenib therapy. The full results of the trial were presented at the American Society of Clinical On-cology (ASCO) 2012 Gastrointestinal Cancers Symposium in January 2012. The trial has since been expanded to a phase IIIb open-label protocol for mCRC patients who have progressed following standard of care. Follow-up results will be presented at the upcoming ASCO An-nual Meeting in June 2012.

A total of 760 patients with mCRC who had progressed despite therapy were randomized 2:1 to receive either regorafenib or placebo. Both study arms also received best supportive care. Pa-tients received regorafenib 160 mg (n=505) or placebo (n=255) once daily for three weeks, followed by one week with no treatment.

Median OS was 6.4 months for rego-rafenib and 5.0 months for the placebo arm, an improvement of 29%. The es-timated hazard ratio for OS was 0.773 (one-sided P = .0051). Median progres-sion-free survival was 1.9 months and 1.7 months for the regorafenib and pla-cebo arms, respectively. The most fre-quent grade 3 or higher adverse events included hand-foot skin reaction in 17%, fatigue in 15%, and diarrhea in 8% of patients. Some patients had their dosages reduced to manage side effects.

“This is the first small-molecule ki-

nase inhibitor with proof of efficacy in colorectal cancer and is a potential new standard of care in this patient population,” said lead author Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota. “The main emphasis of these findings is that this drug delays disease progression, achieving a much higher disease control rate than place-bo,” Grothey added. The disease control rate was 44% for regorafenib and 15% for placebo (P < .000001).

Regorafenib is a multikinase inhibi-tor that shows antiangiogenic activ-ity against vascular endothelial growth factor receptor 2 (VEGFR2) and TIE2. The inhibitor blocks various kinases in-volved in tumor cell proliferation, new blood vessel formation, and the interac-tion between tumor cells and the mi-croenvironment.

Study findings showed no difference in response in patients treated with two versus three or four lines of prior thera-py, according to Grothey. Previous small-molecule multikinase inhibitors were investigated in conjunction with chemo-therapy but showed no benefit in mCRC.

Grothey believes that regorafenib worked because it was used as a single agent. He speculated that because tu-mors evolve due to therapy exposure, a “promiscuous” multitargeted therapy may be needed in a last-line setting. The drug is under investigation in com-bination with FOLFIRI chemotherapy as a second-line treatment for mCRC in a

phase II trial. “A lot of pharmaceutical companies

shy away from this very sick patient population, but this is a population in need, and we can do drug development here,” Grothey said. He added that the CORRECT trial shows that placebo-con-trolled trials are feasible in a population with unmet needs, particularly refrac-tory colorectal cancer.

Regorafenib also holds promise for patients with GIST. In April 2012 it was announced that the phase III GRID trial met its primary endpoint of a statisti-cally significant improvment in pro-gression-free survival in patients with metastatic and/or unresectable GIST whose disease had progressed despite prior therapy. Full trial results will be presented at the upcoming ASCO an-nual meeting in June 2012.

Finally, regorafenib is being investi-gated in phase II trials for treatment-naïve patients with metastatic renal cell carcinoma and liver cancer. TTN

Key ResearchGrothey A, Sobrero AF, Siena S, et al. Results of

a phase III randomized, double-blind, placebo-

controlled, multicenter trial (CORRECT) of

regorafenib plus best supportive care (BSC)

versus placebo plus BSC in patients (pts) with

metastatic colorectal cancer (mCRC) who have

progressed after standard therapies. Presented at

the ASCO Gastrointestinal Cancers Symposium;

January 19-21, 2012; San Francisco, CA. J Clin Oncol. 2012;(suppl 4; abstr LBA385).

Axel Grothey, MD

Targeted Therapies: Gastric and Colorectal Cancer

therapeutics like 5-FU were being stud-ied,” Shah said. “But when we talk about targeted therapies for gastric cancer, the subtypes matter, and they will mat-ter more as we design trials for targeted therapies for this disease.”

According to the National Cancer Institute, there will be approximately 21,320 new cases of gastric cancer in 2012, and 10,540 patients are estimated to die of the disease. It is the seventh leading cause of cancer death in the US and the second leading cause of cancer death worldwide.

Epidemiology and risk factor studies, response to therapy, and genetic analy-ses all provide evidence that distinct

subpopulations of gastric cancer ex-ist. Epidemiologic studies have shown that gastric cancer in Asian countries is different from gastric cancer in the US in terms of location of tumor, stage at diagnosis, postoperative mortality, re-sponse to therapy, and outcomes.

One step in the right direction is anal-ysis of clinical trials based on patient subtypes in order to identify patients who are more likely to respond to treat-ment. Shah presented survival analy-sis according to gastric cancer subtype in the AVAGAST trial testing first-line capecitabine and cisplatin plus bevaci-zumab or placebo in patients with ad-vanced forms of the disease. The trial was a phase III worldwide trial, in which more than 50% of the patients were re-cruited from Asia. Subanalysis showed that patients from the Americas and Europe exhibited more evidence of ben-efit compared with patients from the Asia-Pacific region. Patient outcomes were also analyzed based on the molec-ular expression profiles for gastric can-cer: proximal nondiffuse gastric can-cer (type 1), diffuse (type 2), and distal nondiffuse (type 3). These three tumor subtypes have different genetic and his-tological patterns.

The presented subanalysis showed that patients with the type 3 subtypes had a better prognosis, independent of geography. Bevacizumab had a higher benefit in non-Asian patients with type 2 and type 3 gastric cancer. The data support the view that gastric cancer subtypes may be important predictors of outcomes and need to be investigat-ed further.

Shah also described a study that com-pared gastric cancers among Koreans and Americans from one institution in each country. After adjusting for all known risk factors, disease-specific sur-vival for Korean patients with gastric cancer was significantly higher than in the US patients by about 20% to 30%.

Results showed that the tumors in Korean patients were mainly in the middle and lower stomach. In contrast, the tumors of American patients were mainly in the gastroesophageal and up-per gastrointestinal tract. Cancer was

generally diagnosed at an earlier stage in Korean patients, while the diagnosis was evenly split among four stages in the American patients. Postoperative mortality was 0.2% in Korean patients and 2% in American patients. Five-year disease-specific survival was 82% in Ko-rean patients and 74% in American pa-tients.

“This suggests a different biology [in Asians and Americans],” Shah said. However, there may be inherent biologi-cal and genetic differences between Ko-reans and Americans that were not ac-counted for in this study.

A 2011 study by Wang et al analyzed 22 matched pairs of gastric cancer spec-imens and normal tissue. The authors showed that these tumors are geneti-cally diverse, with the gastric cancer tis-sues exhibiting mutations in chromatin modifiers, cell junction genes, and cell cycle regulation genes.

A second group of investigators, Tan and colleagues, identified a 171-gene signature that could robustly classify tumors to predominantly intestinal or diffuse gastric cancer subtypes. “These authors were setting up a dichotomy,” Shah explained. The implication is that the different subtypes of the cancer respond differently and have different disease kinetics due to different mo-lecular drivers and therapeutic targets. The future of gastric cancer should be targeted therapies, said Shah.

Supporting the notion that gastric cancers, like many other cancers, con-sists of distinct subtype is a small phase II study by Shah et al of 44 patients with gastric cancer treated with anti-angiogenic therapy at Memorial Sloan-Kettering Cancer Center, New York City. The study showed variation in the six-month progression-free survival (PFS) for the three subtypes of gastric cancer. Proximal gastric cancers had the best PFS, distal tumors had intermediate PFS, and diffuse gastric cancers had the worst PFS. The study underscores the need to focus research on the genetic profiles of gastric cancer and to use the current knowledge about the three gas-tric subtypes to better design clinical trials. TTN

Key ResearchAVAGAST: A randomized, double-blind,

placebo-controlled, phase III study of first-line

capecitabine and cisplatin plus bevacizumab or

placebo in patients with advanced gastric cancer

(AGC). Presented at the ASCO Annual Meet-

ing; June 4-8, 2010; Chicago, IL. J Clin Oncol. 2010;28:(suppl; abstr LBA4007).

Shah MA, Jhawer M, Ilson DH, et al. Phase

II study of modified docetaxel, cisplatin, and

fluorouracil with bevacizumab in patients with

metastatic gastroesophageal adenocarcinoma.

J Clin Oncol. 2011;29(7):868-874.

Strong VE, Song KY, Park CH, et al. Comparison

of gastric cancer survival following R0 resec-

tion in the United States and Korea using an

internationally validated nomogram. Ann Surg.

2010;251(4):640-646.

Tan IB, Ivanova T, Lim KH, et al. Intrinsic subtypes

of gastric cancer, based on gene expression

pattern, predict survival and respond differ-

ently to chemotherapy. Gastroenterology.

2011;141(2):476-485.

Wang K, Kan J, Yuen, ST, et al. Exome sequenc-

ing identifies frequent mutation of ARID1A in

molecular subtypes of gastric cancer. Nat Genet. 2011;43(12):1219-1223.

News


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Targeted Therapies: Gastric and Colorectal Cancer

Gastric Cancer(continued from cover)

Manish A. Shah, MD

“When we talk about targeted therapies for gastric cancer, the subtypes matter, and they will matter more as we design trials for targeted therapies for this disease.”

–Manish, A. Shah, MD

Epidemiology and risk factor studies, response to therapy, and genetic analyses all provide evidence that distinct subpopulations of gastric cancer exist.

News8

Early excitement over the potential for using PARP inhibitors in the treatment of patients with ovar-

ian cancer has dissipated amid disap-pointing findings on overall survival, but the class of novel therapeutics re-mains under active investigation for pa-tients with this tumor type.

At least three pharmaceutical compa-nies are continuing development programs with various PARP agents, noted Michael J. Birrer, MD, PhD, professor of Medicine, Harvard Medical School and director, Gy-necologic Medical Oncology, director, Gynecologic Cancer Research Program, Mas-sachusetts General Hospital Cancer Center in Boston, in a recent interview. He spoke shortly after AstraZeneca announced its de-cision to halt studies of olaparib for main-tenance treatment of serous ovarian cancer.

“I haven’t given up hope on this,” said Birrer, referring to the class of PARP inhibi-tors as a whole. “I think you’ll see trials with PARP inhibitors testing the ability and activ-ity of bringing the PARP inhibitor up front in newly diagnosed patients in combination with chemotherapy. Most of those trials will also include a maintenance phase. In conjunction with that, there will be selec-tive trials in BRCA1- and BRCA2-mutated patients with recurrent resistant disease.”

PARP, poly(adenosine diphosphate [ADP]–ribose) polymerase, plays an impor-tant role in the repair of single-strand DNA breaks. Birrer said single-strand breaks can become double-strand breaks that

results in The New England Journal of Medi-cine. They reported median progression-free survival of 8.4 months with olaparib versus 4.8 months on placebo. Adverse events were more prevalent among those who received olaparib, but most of those events were grade 1/2, with nausea, fa-tigue, vomiting, and anemia among the most frequently reported effects.

However, the interim survival analysis, conducted after 38% of the participants had died, did not show a significant ad-vantage for olaparib, which demonstrat-ed a hazard ratio of 0.94 (95% confidence interval, 0.63-1.39; P = 0.75).

“Maintenance treatment with olapa-rib was associated with a significant im-provement in progression-free survival among patients with platinum-sensi-tive, relapsed, high-grade serous ovar-ian cancer,” the researchers concluded. “However, at the interim analysis, this did not translate into an overall survival benefit. As of this writing, 21% of the pa-tients were still receiving olaparib (and 3% were still receiving placebo), which indicates that the disease is controlled for a prolonged period in some patients.”

Birrer said the trial results presented at ASCO were “remarkable,” but that the FDA would want to see an overall sur-vival advantage before approving a new drug. He said there also remains “a fair amount of confusion” about what would be the best dosage for patients, with studies evaluating doses ranging from 100 mg to 400 mg twice daily.

Meanwhile, companies that are con-tinuing to study PARP inhibitors in ovar-ian cancer include Abbott Laboratories, which is studying veliparib (ABT-888) as monotherapy for patients with relapsed ovarian cancer with a BRCA mutation; Clovis Oncology, which is exploring ruca-parib (CO-338) in BRCA-associated ovar-ian cancer; and BioMarin Pharmaceutical Inc, which is investigating BMN-673 in patients with advanced or recurrent solid tumors, including ovarian cancers. TTN

Key ResearchLedermann JA, Harter P, Gourley C, et al. Phase

II randomized placebo-controlled study of olapa-

rib (AZD2281) in patients with platinum-sensitive

relapsed serous ovarian cancer. J Clin Oncol. 2011;29(suppl; abstr 5003).

Ledermann J, Harter P, Gourley C, et al. Olaparib main-

tenance therapy in platinum-sensitive relapsed ovar-

ian cancer [published online ahead of print March 27,

2012]. N Engl J Med. doi: 10.1056/NEJMoa1105535.

are, in turn, repaired by a complex that contains BRCA1 and BRCA2. Thus, he said, researchers have theorized that inhibiting the PARP enzyme should selectively kill cells with those genetic abnormalities.

Earlier studies had demonstrated higher antitumor activity and objective response rates for patients with and without BRCA1/2 mutations, a phase II trial highlighted at the 2011 American Society of Clinical On-cology Annual Meeting did not require that mutation status. Eligible patients had recurrent, platinum-sensitive ovarian or fallopian-tube cancer or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or a serous component.

The trial, which AstraZeneca sponsored, demonstrated that olaparib improved medi-an progression-free survival by 65% among the 136 patients randomized to receive 400-mg doses twice daily, compared with 129 participants on placebo. Investigators believed the compound showed promise as monotherapy for this patient population.

In December, however, AstraZeneca an-nounced the company would not move forward with phase III development in the maintenance setting after interim data “indicated that the previously reported progression-free survival benefit is unlike-ly to translate into an overall survival ben-efit, the definitive measure of patient ben-efit in ovarian cancer. In addition, attempts to identify a suitable tablet dose for use in phase III studies have not been successful.”

In March, researchers detailed those

PARP Inhibitors Intriguing Despite Research SetbacksBy Anita T. Shaffer

Targeted Therapies: Gynecologic Malignancies

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This illustration depicts ovarian cancer at stage IIC. One noteworthy PARP study included patients with grade 2 or 3 serous ovarian cancer.

Bladder

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Ovary

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Sigmoid colon

Malignant cells in aperitoneal washing

Stage IIC Cancer


Michael J. Birrer, MD, PhD

News


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A retrospective analysis of the risks of hypothyroidism in patients in Germany who received sunitinib

and sorafenib is gaining attention in the field of head and neck cancers, where the drugs are being evaluated for clini-cal use.

A study published in the European Jour-nal of Cancer earlier this year found that 13.7% of patients on sunitinib and 6.3% of those who took sorafenib were treated with thyroid hormone (TH) therapy typi-cally prescribed to treat hypothyroidism. The study, with findings based on pre-scription data from 2509 patients, is be-lieved to be the largest database exami-nation of the endocrine disorder among people taking either of the drugs.

TH before the study period, those who were not registered in the database, and those who received TH within 29 days of the initial index date were excluded. Data for the remaining 2509 patients were examined based on TH prescrip-tions written during an observation pe-riod that began 30 days after the initial index date through August 31, 2009.

In all, 178 of 1295 patients taking suni-tinib (13.7%) and 77 of 1214 patients tak-ing sorafenib (6.3%) received TH thera-py. Incidence rates were 24.2 per 100 person-years for sunitinib patients and 12.1 per 100 person-years for sorafenib patients, with the unadjusted hazard ratio for TH therapy calculated as 2.0 (95% confidence interval [CI], 1.5-2.6) for sunitinib as compared with sorafenib.

Sherman said hypothyroidism has been observed in patients, but that the study marks the first time that there are enough concrete data to make the nec-essary recommendations.

The German research team suggested clinicians exercise caution in prescrib-ing TH for cancer patients with slightly increased serum-TSH levels who are not displaying symptoms. “If clinical hypothyroidism occurs, it can be treat-ed with TH, which leads to fast and complete correction of increased TSH values and should not restrict the use

Both drugs are multikinase inhibi-tors (MKIs) that the FDA has approved for the treatment of advanced renal cell carcinoma (RCC). Sunitinib (Sutent) also is approved to treat certain gastrointes-tinal stromal tumors (GIST) and pan-creatic neuroendocrine tumors while sorafenib (Nexavar) is additionally in-dicated for hepatocellular carcinoma. A number of phase II trials are under way studying the efficacy of sunitinib and sorafenib in the treatment of thy-roid cancer.

In reviewing the study, Eric J. Sher-man, MD, Head and Neck Oncology, Me-morial Sloan-Kettering Cancer Center, New York City, said the findings are no-table in his field because MKIs represent a promising class of drugs for thyroid patients. “This study is clinically rel-evant to anyone treating a patient with thyroid cancer,” he said.

Using prescription data from more than 80% of German pharmacies, inves-tigators started with an index of 6444 patients for whom one of the two an-ticancer therapies had been prescribed from July 1, 2006, through December 31, 2007. Clinical hypothyroidism requir-ing TH therapy was defined as thyroid-stimulating hormone (TSH) levels >10 mIU/L.

Patients who had been prescribed

Hypothyroidism Risks With MKIs ExaminedBy Ben Leach

Reolysin Trial Reaches Enrollment Milestone

Targeted Therapies: Head & Neck Cancer

The first stage of enrollment has been completed in a phase III clin-ical trial that will examine the use

of a human reovirus, in combination with chemotherapy, in patients with head and neck cancer. Oncolytics Bio-tech Inc. announced April 2 that it has enrolled 80 patients in the trial of Reo-lysin, a variant of the respiratory enteric orphan virus. The patients, who have platinum-refractory head and neck can-cers, will receive Reolysin in combina-tion with paclitaxel and carboplatin.

“This is an important milestone for this study,” Brad Thompson, PhD, president and CEO of Oncolytics in Calgary, Cana-da, said in a press release. “A data analy-sis that will involve examining evolving progression-free survival will now be performed on this patient group to de-termine the probability of success in the second stage of the study.”

The randomized, double-blind trial

will assess the intravenous administra-tion of Reolysin with the two chemother-apy drugs versus chemotherapy alone in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, or squamous cell cancer of the nasopharynx, who have progressed on or after prior platinum-based chemother-apy. It is being conducted in 80 centers in 12 countries in North America and Europe. The primary endpoint is overall survival.

Reolysin works by infecting patients with the reovirus, to which most people have been exposed by adulthood, and which typically causes few or no symp-toms, the company said. Normal cells are able to fight the infection, but cancer cells with Ras gene mutations cannot, and the unchecked multiplication of the virus kills them by causing them to rupture. Then, the virus moves on to destroy near-by tumor cells. (NCT01166542) TTNIll

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of sunitinib and sorafenib in malignant diseases in general,” they concluded.

The FDA-approved prescribing infor-mation (PI) for Sutent includes a rec-ommendation for a baseline laboratory measurement of thyroid function prior to the start of treatment and advice about monitoring patients for signs of such problems. In May 2011, the PI was updated to include reports of higher rates of hypothyroidism than with pla-cebo among small groups of patients.

The PI for Nexavar describes hypo-thyroidism as an “uncommon” adverse drug reaction and does not include it among the most serious reactions.

Sherman said that while hypothyroid-ism does pose a serious risk to the patient, it is also a very treatable condition. TH can be started as soon as hypothyroidism is identified, and dose rates are monitored throughout treatment. If a patient is taken off sorafenib or sunitinib, it is possible for thyroid levels to return to normal.

“It’s very easy to treat,” Sherman said. “It’s just one of those things that you want to make sure you don’t miss.” TTN

Feldt S, Schüssel K, Quinzler R, et al. Incidence of

thyroid hormone therapy in patients treated with

sunitinib or sorafenib: a cohort study [published

online ahead of print February 28, 2012]. Eur J Cancer. doi:10.1016/j.ejca.2012.01.036.

Eric J. Sherman, MD

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News


12

The FDA has approved subcutane-ous injection as a safe method for delivering bortezomib (Velcade,

Takeda Pharmaceuticals) for patients with multiple myeloma and mantle cell lymphoma who have received one prior therapy, expanding the potential number of patients who can receive the medication.

Bortezomib by intravenous injection is already approved (since 2003) to treat both multiple myeloma and mantle cell lymphoma. The subcutaneous delivery reduces the risk of adverse events as-sociated with the intravenous form.

The new approval is based on a piv-otal 222-patient, randomized phase III trial published in The Lancet Oncol-

One of the major developments in cancer treatment in recent years has been the potential of

drugs that target the oncogenic phos-phatidylinositol-3-kinase (PI3K)/Akt pathway and the mammalian target of rapamycin (mTOR), a downstream ef-fector of the pathway. The intracellular pathway is central to cell proliferation, growth, and angiogenesis, so it’s no sur-prise that it’s implicated in a number of different tumor types, including breast, non-small cell lung, and renal cell can-cer. Mutations and changes in expres-sion have been found in every major node of the pathway. Typical mutations include mutation or amplification of PI3K, overexpression of the oncogene AKT, or inactivation of the tumor sup-pressor phosphatase and tensin homo-log (PTEN). Research has shown that alteration of normal PI3K pathway sig-naling translates to a poor patient prog-nosis and resistance to available treat-ments. This makes the role of the PI3K pathway in tumor evolution particular-ly important to understand.

This multifunctional pathway has been recognized as a particularly attrac-tive target for patients with lymphoma. “The PI3K pathway appears continu-ously deregulated among lymphoma malignancies,” said Sonali M. Smith, MD, director of the Lymphoma Program at the University of Chicago Medical Center, Illinois. Molecular abnormali-

This is an important benefit, accord-ing to Sundar Jagannath, MD, director of the Multiple Myeloma Program and professor of Medicine in Hematology and Medical Oncology at Mount Sinai Medical Center in New York City. “In a newly diagnosed myeloma patient at this time, we really don’t want to cre-

progression-free survival (hazard ra-tio [HR] = 0.44; P = .0009) compared with the investigator’s choice. Objec-tive response was 22% among patients receiving temsirolimus and 2% in the control group. The study established an effective clinical dose for temsirolimus monotherapy—the trial tested two dif-ferent once-weekly dosages—and the results led to approval of the agent in Europe for relapsed or refractory MCL in 2009.

“The challenge with the classic mTOR inhibitors is that there is a lot of resis-tance,” said Smith, who was one of the investigators in the phase III study. It is not yet clear why only certain patients respond and why the responses are not durable. Smith believes that second-generation mTOR inhibitors, although still in early-stage trials, may be more promising for MCL.

Another approach that exploits the PI3K/mTOR pathway is targeting PI3 ki-nase, the major switch that signals to mTOR. The compound GS-1101 (Gilead) specifically inhibits the delta isoform of PI3K and is in clinical trials for MCL and other types of lymphoma. The com-pound has “a lot of activity” in MCL, ac-cording to Smith.

MCL is one of the most difficult-to -treat subtypes of non-Hodgkin lym-phoma. Between 2% and 7% of all pa-tients with non-Hodgkin lymphoma have MCL. The disease is often diag-

ogy in May 2011. The trial compared subcutaneous and intravenous injec-tions of bortezomib in patients with relapsed multiple myeloma who were bortezomib-naïve, finding similar effi-cacy regardless of the delivery method. The patients receiving subcutaneous injections had an overall response rate (ORR) of 43% and a complete response (CR) rate of 7%. This is compared to a 42% ORR and an 8% CR in patients re-ceiving the intravenous drug.

In addition to a noninferior efficacy compared with standard intravenous delivery, subcutaneous bortezomib injection had a lower incidence of pe-ripheral neuropathy, a common side effect of bortezomib therapy.

ties linked to abnormal PI3K pathway signaling have been demonstrated in mantle cell lymphoma (MCL), a mature B-cell non-Hodgkin lymphoma, as well as in Hodgkin lymphoma. Specifically, mTOR, a serine/threonine kinase that is a key downstream target of the PI3K pathway, as well as an important regu-lator of normal development, has been associated with lymphomagenesis.

“[mTOR] appears to be an excellent target in MCL,” Smith said. “Overex-pression of the protein cyclin D1 is the hallmark of mantle cell lymphoma. This protein is controlled in part by mTOR. So this is a very nice rationale for test-ing mTOR inhibitors in this cancer.” Smith added that the entire PI3K/Akt/mTOR pathway, not just mTOR, is valid as a target in MCL.

Temsirolimus (Torisel, Pfizer), an mTOR inhibitor, has been studied in pa-tients with MCL in phase II trials. The response rate in these trials was about 40% and lasted six months, according to Smith. This led to combination tri-als, including temsirolimus combined with rituximab (Rituxan, Genentech) and everolimus (Afinitor, Novartis) com-bined with the CHOP chemotherapy regimen.

In a phase III trial testing the efficacy of temsirolimus compared to choice of therapy in 162 heavily pretreated pa-tients with relapsed or refractory MCL, temsirolimus significantly improved

ate peripheral neuropathy if a better option is available,” Jagannath said. “I think this novel method of administra-tion is really helpful.”

A total of 53% of patients in the in-travenous arm experienced peripheral neuropathy of any grade, compared with 38% of patients in the subcutane-ous arm; 16% of patients in the intra-venous arm compared with 6% in the subcutaneous arm had grade 3 or high-er peripheral neuropathy.

Additional grade 3 events included thrombocytopenia (19% vs 13% in the intravenous and subcutaneous arms, respectively) and neuralgia (9% vs 3% in the intravenous and subcutaneous, arms, respectively). TTN

nosed at stage IV and is most common in men age 60 years and over. Because this older patient population is more likely to have comorbidities, they are not candidates for more intensive treat-ments, even though cytotoxic chemo-therapy regimens—including rituximab and the chemotherapy regimen CHOP—appear to be effective in achieving a re-sponse, and even complete remission in many cases. Additionally, many pa-tients relapse after receiving front-line treatments. TTN

Key ResearchHess G, Smith SM, Berkenblit A, Coiffier B.

Temsirolimus in mantle cell lymphoma and other

non-Hodgkin lymphoma subtypes. Semin Oncol. 2009; 36(suppl 3):S37-S45.

Subcutaneous Dosing of Bortezomib Approved

Targeted Therapies: Hematologic Malignancies

Targeting the PI3K/Akt/mTOR Pathway for Lymphoma

Sonali M. Smith, MD

News


13

Updated results from a phase Ib/II clinical trial in patients with chronic lymphocytic leukemia/small lym-

phocytic lymphoma (CLL/SLL) showed that the new Bruton’s tyrosine kinase (BTK) in-hibitor PCI-32765 could be an important ap-proach for these patients.

BTK is a cytoplasmic tyrosine kinase important for B-lymphocyte development, signaling, and differentiation; it is a central mediator of B-cell receptor signaling, es-sential for normal B-cell development. PCI-32765 is an oral, irreversible inhibitor of BTK that induces apoptosis and inhibits cellu-lar migration and adhesion in malignant B-cells. The initial phase Ib/II data showed the therapy to be highly active and tolerable for CLL patients. These original data were presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting.

Both previously untreated and relapsed

molecular risk features. Most (82%) patients were still being treated on the trial, while only 8% had progressive disease at the time of data presentation. The six-month pro-gression-free survival was 92% in the 420-mg cohort and 90% in the 840-mg cohort.

The therapy was well tolerated. Two pa-tients discontinued therapy, and six had their dosage lowered. Approximately 21% of patients had a grade 3 adverse event potentially related to the investigational therapy. Most patients experienced a tran-sient high lymphocyte count during the first two months of treatment and resolved over time.

Data at the ASH meeting on PCI-32765 also showed a high rate of OR in patients with relapsed or refractory mantle cell lym-phoma (MCL) in a phase II trial. Phase III trials in MCL patients are being planned. In-terim data from phase IB/II trials of patients

or refractory patients who had at least two prior therapies were treated with the tyro-sine kinase inhibitor until disease progres-sion. Two doses, 420 mg and 840 mg, were tested. Sixty-one patients with relapsed or refractory CLL were enrolled in the trial. Pa-tients in the 420-mg cohort had a median of three prior therapies. The median number of prior therapies was five for the 840-mg cohort. The trial results were presented at the American Society of Hematology (ASH) Annual Meeting in December 2011.

In the 420-mg cohort, the objective re-sponse (OR) was 70% with a 10.2-month median follow-up. The OR was 44% in the 840-mg group with a 6.5 month median follow-up. Another 19% and 35% of patients in the 420-mg and 840-mg cohorts, respec-tively, had a nodal partial response with re-sidual lymphocytosis. ORR, according to the trial authors, appears to be independent of

with treatment-naïve chronic lymphocytic leukemia (CLL) and combination therapy of PCI-32765 and atumumab in patients with chronic lymphocytic leukemia will be presented at the upcoming ASCO Annual Meeting in June 2012.

PCI-32765 is being jointly developed by Janssen Biotech, Inc., owned by Johnson & Johnson, and Pharmacyclics Inc. The two companies have a 50/50 profit/loss agree-ment and will share development and com-mercialization activities. TTN

Key ResearchO’Brien S, Burger JA, Blum KA, et al. The Bruton’s Tyro-

sine Kinase (BTK) Inhibitor PCI-32765 induces durable

responses in relapsed or refractory (R/R) chronic

lymphocytic leukemia/small lymphocytic lymphoma

(CLL/SLL): Follow-up of a phase Ib/II study. Presented

at the ASH Annual Meeting; December 10-13, 2011;

San Diego, CA. Blood. 2011;118(21): abstr 983.

Bruton’s Tyrosine Kinase Inhibitor PCI-32765: Durable Responses in Refractory CLL

Targeted Therapies: Hematologic Malignancies

Obinutuzumab Compares Favorably With Rituximab in NHL Trial

Treatment with obinutuzumab (GA101) showed higher response rates compared to rituximab in pa-

tients with relapsed or refractory non-Hodgkin lymphoma (NHL) in a phase II randomized trial. Patients in the trial had a previous complete response (CR) or uncon-firmed complete response (CRu) to a ritux-imab-containing regimen. Both obinutu-zumab and rituximab antibody therapies target the CD20 protein expressed on can-cerous B-cells. Obinutuzumab is designed to bind CD20, a major lymphoma biomark-er on the surface of B-cells selectively and with higher affinity. The drug is a novel glyco-engineered anti-CD20 monoclonal antibody that causes cell death of cancer-ous B-cells that express CD20 by activating the patient’s immune cells to attack the cancer cells or by inducing apoptosis of the cancerous cells.

Rituximab (Rituxan, Roche), a chimeric antibody against CD20, is approved as a first-line treatment for CD20-positive B-cell NHL in combination with chemotherapy and as a maintenance monotherapy fol-lowing the rituximab plus chemotherapy combination treatment for patients who achieve a response. Rituximab and other therapies have improved survival rates in patients with NHL. Still, relapse of the dis-

ease and resistance to treatments remains a major hurdle.

Although obinutuzumab has shown activity against lymphoma in single-arm studies, the current GAUSS trial is the first comparing the therapy to an approved NHL treatment. The results of the GAUSS inter-national trial were reported by Laurie H. Sehn, MD, MPH, a medical oncologist at the British Columbia Cancer Agency and clini-cal associate professor at the University of British Columbia, in Vancouver, BC, Cana-da, at the American Society of Hematology (ASH) Annual Meeting in December 2011.

“This is the first head-to-head trial of GA101 against rituximab in patients with relapsed, indolent NHL,” said Sehn. “GA101 demonstrated promising efficacy with a trend towards higher response rates, with-out appreciable differences in safety,” she added. The study was not powered to show superiority of obinutuzumab over ritux-imab. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety outcomes in patients receiving both treatments.

A total of 175 patients (149 follicular [FL] and 26 nonfollicular indolent NHL) were randomized to receive four weekly infusions of either obinutuzumab or ritux-

imab. Patients had received an average of two prior lines of therapy—all containing rituximab. Patients without evidence of progression following induction therapy received ongoing treatment with GA101 or rituximab every two months for up to two years at the same dose. The groups were balanced, although at baseline patients re-ceiving obinutuzumab had a larger volume of disease.

The primary efficacy analysis was con-ducted in the FL population (n=149) at the end of the induction phase. The ORR was 44.6% in the obinutuzumab arm compared with 33.3% in the rituximab arm; there were 11.3% more responses in the experi-mental agent arm. A complete remission (CR) or unconfirmed complete remission (CRu) was seen in 12.2% versus 5.3% of patients in the obinutuzumab and ritux-imab arms, respectively. The best overall response in the FL population was CR/CRu for 35.1% of the obinutuzumab group and 18.7% of the rituximab group.

While there were more infusion-related reactions with obinutuzumab (74% vs 51%), both agents were well tolerated. Infusion-related reactions are common with anti-body treatments and were generally mild and did not result in significant differences in treatment discontinuations, according

to Sehn. Grade 3 infusion-related reactions were 11% and 6% in the obinutuzumab and rituximab arms, respectively.

“Based on these data, we believe that phase III trials to truly test the efficacy of this agent are warranted, and they are now under way,” she said. A large phase III study testing obinutuzumab in combi-nation with chemotherapy compared to rituximab with chemotherapy in patients with advanced indolent NHL is ongoing. Another phase III trial is testing the drug in combination with CHOP chemotherapy in patients with large B-cell lymphoma whose cancer cells express CD20. Obinu-tuzumab is also being investigated in pa-tients with treatment-naïve chronic lym-phocytic leukemia. TTN

Key ResearchSehn LH, Goy A, Offner FC, et al. Randomized phase

II trial comparing GA101 (obinutuzumab) with ritux-

imab in patients with relapsed CD20 indolent B-cell

non-Hodgkin lymphoma: preliminary analysis of the

GAUSS study. Presented at the ASH Annual Meet-

ing; December 10-13, 2011; San Diego, CA. Blood.

2011;118(21): abstr 269.

Laurie H. Sehn, MD, MPH

News


14

Data presented at the American Society of Hematology (ASH) An-nual Meeting in December 2011

showed that nilotinib (Tasigna) contin-ues to exhibit better molecular response levels in patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) compared with imatinib mesylate (Gleevec). Imatinib, approved in 2001 for CML, is considered the established standard of care; nilo-tinib was approved in 2011.

The ENEST (Evaluating Nilotinib Ef-ficacy and Safety in clinical Trials) re-search program aims to assess the ef-ficacy of nilotinib, a next-generation tyrosine kinase inhibitor (TKI) in pa-tients with CML who have developed resistance to or are unable to tolerate imatinib. Three-year follow-up data from the ENESTnd confirmed the supe-riority of nilotinib over imatinib and ac-ceptable tolerability for patients newly diagnosed with Ph+CML. The second result from this program presented at ASH showed that switching patients with Ph+CML from imatinib to nilotinib led to faster and better molecular re-sponses. This ENESTcmr trial aimed to test whether switching patients from imatinib to nilotinib would be more ef-ficacious for CML patients on long-term imatinib therapy. The ENEST program is funded by Novartis Pharmaceuticals, the manufacturer of both medications.

The Philadelphia chromosome is a fusion of the abl protein with bcr, lead-ing to a constitutive activation of the abl tyrosine kinase, the hallmark of CML. Imatinib selectively binds and inhibits

experienced grade 3 or 4 events. The authors of the study concluded that the deeper molecular responses with ni-lotinib could increase the eligibility of patients to enroll in tyrosine kinase dis-continuation studies. A discontinuation study is currently ongoing.

The ENESTnd trial studied the effec-tiveness of nilotinib at two different dose levels compared with imatinib in patients with newly diagnosed Ph+ CML in chronic phase. The study randomized 846 patients to receive nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg once daily (n = 283). The three-year follow-up results showed that fewer pa-tients taking nilotinib experienced dis-ease progression to accelerated phase

the activity of the mutated abl protein. Nilotinib also blocks bcr-abl activity—based on in vitro studies, nilotinib has a greater binding potency for bcr-abl compared with imatinib and has activ-ity against many of the imatinib-resis-tant bcr-abl mutations. The other next-generation bcr-abl inhibitor is dasatinib (Sprycel, Bristol-Myers Squibb), also ap-proved for resistant and relapsed CML after imatinib treatment.

Recent studies have demonstrated that about 40% of very highly selected Ph+ CML patients treated with imatinib achieved durable CMR and may be able to cease therapy without disease recur-rence. However, most patients with CML do not achieve CMR on imatinib, even with long-term therapy, mostly due to resistance to the TKI.

The ENESTcmr trial enrolled 207 pa-tients who had been treated with ima-tinib for at least two years. The primary endpoint was confirmed CMR (unde-tectable levels of bcr-abl by 12 mo). Of the intention-to-treat group still in the study at 12 months, 14.9% of patients on nilotinib and 6.1% of patients on ima-tinib achieved a confirmed CMR (P = .04). The results showed 23% (n = 24) of pa-tients who received nilotinib at 400 mg twice daily had undetectable levels of the bcr-abl protein in a blood test after 12 months. This level was higher than the 11% of patients (n = 11) taking ima-tinib once daily (P = .02). Adverse events were higher in the nilotinib group, but consistent with previous studies: 29% of nilotinib-treated patients compared with 2% of imatinib-treated patients

or blast crisis, whether in the 300-mg arm (n =2) or the 400-mg arm (n = 3) compared with the group taking ima-tinib (n =12). Among patients taking nilotinib 400 mg twice daily, 97% were alive at the three-year mark (8 patient deaths) compared with 94% of patients on imatinib (17 patient deaths). Nilo-tinib was superior to imatinib in all ma-jor efficacy endpoints, including CMR and major molecular response.

Nilotinib was also associated with fewer CML-related deaths. The study found that five patients taking nilotinib 300 mg twice daily and four patients taking nilotinib 400 mg twice daily died of CML-related issues in the follow-up period compared with 14 patients in the imatinib arm. Overall, 28% of patients taking nilotinib 400 mg twice daily achieved the deepest levels of response compared with 15% of patients taking imatinib (P = .0003). TTN

Key ResearchHughes TP, Lipton JH, Leber BL, et al. Complete

molecular response (CMR) rate with nilotinib in

patients (pts) with chronic myeloid leukemia in

chronic phase (CML-CP) without CMR after ≥2

years on imatinib: preliminary results from the

randomized ENESTcmr trial of nilotinib 400 mg

twice daily (BID) vs imatinib. Presented at the

ASH Annual Meeting; December 10-13, 2011; San

Diego, CA. Blood. 2011;118(21): abstr 606.

Saglio G, LeCoutre PD, Pasquini R, et al. Nilotinib

versus imatinib in patients (pts) with newly

diagnosed Philadelphia chromosome-positive

(Ph+) chronic myeloid leukemia in chronic phase

(CML-CP): ENESTnd 36-month (mo) follow-up.

Presented at the ASH Annual Meeting; December

10-13, 2011; San Diego, CA. Blood. 2011;118(21):

abstr 452.

Nilotinib Beats Imatinib for CML in Two Phase III TrialsTargeted Therapies: Hematologic Malignancies

ENESTnd Study Design

Patients diagnosed with Ph-positive CP-CML

within 6 months

(N = 846)

Stratified by Sokal risk score

year 3

5-year follow-up

Nilotinib 300 mg BID

(n = 282)

Nilotinib 400 mg BID

(n = 281)

Nilotinib 400 mg QD

(n = 283)

Randomization

Cabozantinib (60 mg qd)

Prednisone

KEY ELIGIBILITY CRITERIA•Diagnosis of CRPC •Presence of bone metastases•Prior treatment with docetaxel•�Prior treatment with abiraterone and/or MDV3100 (enzalutamide)•No limit to the number of prior therapies

COMET-1

PRIMARY ENDPOINT Confirmed Pain Response

COMET-2

PRIMARY ENDPOINTOverall Survival

Randomized, double-blind, controlled trial Randomized, double-blind, controlled trial

Visit www.COMETClinicalTrials.com/TT or call 1-855-85-COMET to learn more about these trials.

Randomization

Cabozantinib (60 mg qd)

Mitoxantrone + Prednisone

Cabozantinib (XL184) phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases

CabOzantinib MET Inhibition CRPC Efficacy Trials

© 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 05/12

CRPC (N=960)

•��Prior docetaxel treatment•��Prior abiraterone and/or MDV3100 treatment•��No limit to number of prior therapies

CRPC(N=246)

•��Prior docetaxel treatment•��Prior abiraterone and/or MDV3100 treatment•��No limit to number of prior therapies•��Pain related to bone metastases

S:6.75”

S:9.75”

T:8.25”

T:10.875”

B:9”

B:11.125”

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Time to Death (Months)ZYTIGA® 797 736 657 520 282 68 2 0Placebo 398 355 306 210 105 30 3 0

The median duration of treatment with ZYTIGA® was 8 months.

% S

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ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS)

Mechanism of action

PROSTATE TUMOR TISSUE

ADRENALS

TESTES

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively)

In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy

Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.

Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

* Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival.†552 events.‡775 events.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

Janssen Biotech, Inc.© Janssen Biotech, Inc. 2012 3/12 08Z12066B

08Z

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% S

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ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS)

Mechanism of action

PROSTATE TUMOR TISSUE

ADRENALS

TESTES

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively)

In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy

Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.

Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

* Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival.†552 events.‡775 events.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Please see adjacent pages for brief summary of full Prescribing Information.

www.zytiga.com

Janssen Biotech, Inc.© Janssen Biotech, Inc. 2012 3/12 08Z12066B

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Due to the positive results found in an interim review, research-ers unblinded a phase III study of

abiraterone acetate (Zytiga) plus predni-sone ahead of schedule. The drug com-bination is being tested in asymptom-atic or mildly symptomatic men with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.

The Independent Data Monitoring Committee (IDMC) unanimously rec-ommended unblinding the study (COU-AA-302) early after a planned interim analysis found clinical benefit in radio-graphic progression-free survival and overall survival, the primary endpoints of the study, according to Janssen Re-search & Development.

In addition, the committee found a fa-vorable safety profile among men in the treatment arm. The committee not only recommended unblinding the study, but also that patients on placebo be offered treatment with abiraterone, the com-pany said.

The international, multicenter, dou-ble-blind study included 1088 patients who were randomized to receive abi-raterone 1000 mg once a day with pred-nisone 5 mg administered twice daily or placebo plus the steroid.

A company official indicated that the IDMC analysis helps advance explora-tions of the drug. “The COU-AA-302 study has been a key priority for us as we expand our understanding of the utility of Zytiga in metastatic prostate cancer,” William N. Hait, MD, PhD, glob-al head of Janssen R&D, said in a press release.

The company did not provide more details of the results because it plans to submit them for publication in a peer-reviewed journal.

In April 2011, the FDA approved abi-raterone in combination with pred-nisone to treat men with metastatic CRPC who have received prior che-motherapy containing docetaxel. Later this year, Janssen plans to seek an ex-panded indication in men with CRPC

who have not received chemotherapy. Abiraterone, which inhibits the CYP17

enzyme, is a first-in-class agent target-ing testosterone, according to the Na-tional Cancer Institute. It blocks andro-gen production at three sources—the testes, the adrenal glands, and the tu-mor itself, the company said. TTN


19

Zytiga Study Unblinded After Interim Analysis

Sipuleucel-T Stimulates Response in Localized Setting, Study Finds

Targeted Therapies: Prostate Cancer

Molecular structure of abiraterone

By Ben Leach

The neoadjuvant administration of sipuleucel-T (Provenge) may stimulate an immune response in

patients with localized prostate cancer without adversely affecting their sur-geries, according to study results pre-sented at the 2012 Genitourinary Can-cers Symposium. The study explored the possibility of using the vaccine earlier in the treatment timeline than its current approved indication for pa-tients with asymptomatic or minimally symptomatic metastatic castration- resistant prostate cancer.

In a phase II trial, 42 patients with localized prostate cancer who were slated for radical prostatectomy were given sipuleucel-T in three infusions administered 6 to 7 weeks prior to their surgeries. Prostate cell specimens were collected prior to and following treat-ment with sipuleucel-T. Patients were

followed for 72 weeks, and also ran-domly assigned to receive a booster treatment with the vaccine or no fur-ther treatment.

At the time of the presentation in Feb-ruary, immunohistochemistry analysis had been completed on 19 patients. “Significant increases (>2-fold) in CD3-positive and CD4-positive T-cell popula-tions were observed at the tumor rim, where benign and malignant glands interface, compared with the pretreat-ment biopsy,” researchers said in their abstract. Surgical impact was measured by operative complications, procedure time, and estimated blood loss.

In a companion abstract, investiga-tors reported a “robust immune system activation,” including antigen-present-ing cells and memory and activated ma-ture B cells.

Although the results are preliminary, the study suggests more work should be done to explore the potential benefits in patients who have an earlier-stage prostate cancer, according to Leonard G. Gomella, MD, Bernard W. Godwin Jr. Professor of Prostate Cancer, chairman, Department of Urology, and director, Clinical Affairs, Kimmel Cancer Center Thomas Jefferson University, Philadel-phia, Pennsylvania. Gomella served as chair of the conference program com-mittee at the American Society of Clini-cal Oncology symposium.

“This is very exciting because if im-munotherapies work, they tend to work when there’s a minimal amount of dis-ease,” Gomella said.

He also said the study found tumor

Leonard G. Gomeela, MD

markers through which the impact of the treatment could be evaluated.

“One of the challenges that we have when we look at all immunotherapy, and particularly when we look at the sipuleucel-T immunotherapies, is that we don’t have a specific marker for re-sponse,” Gomella said. “This is very en-couraging and very positive news that this study was able to show that there were specific markers of an immune re-sponse in the prostate.”

He noted that the study is among ear-ly-phase investigations into stimulating the immune cells in the preprostateco-my setting, but that major clinical trials are “a long way off.”

Investigators said in their abstract that “work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.” TTN

ReferencesFong L, Weinberg VK, Corman JM, et al. Immune

responses in prostate tumor tissue following

neoadjuvant sipuleucel-T in patients with local-

ized prostate cancer. J Clin Oncol. 2012;30:(suppl

5). Abstr 181.

Sheikh NA, Wesley JD, Perdue N, et al. Evalua-

tion of immune activation following neoadjuvant

sipuleucel-T in subjects with localized prostate

cancer. J Clin Oncol. 2012;30:(suppl 5). Abstr 178.Illus

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Axitinib (Inlyta, Pfizer) is the seventh drug approved for the treatment of advanced renal cell carcinoma

(RCC) since 2005. The small-molecule ty-rosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor re-ceptors (VEGFR-1, 2, 3), platelet-derived growth factor receptor (PDGFR), and c-KIT was approved by the FDA in January of this year as a second-line treatment. Axitinib joins three other multi-tyrosine kinase inhibitors, two mTOR inhibitors, and an antiangiogenic therapy as avail-able treatments for metastatic RCC.

“We went from almost no therapies to many promising therapies. Now, patients with metastatic disease are living more than twice as long as they did before—two years on average. It’s harder to measure quality of life and how much better they feel, but they feel better being alive than not, and that’s the ultimate test,” said Bri-an Rini, MD, associate professor of Medi-cine at Case Western Reserve University and a practicing oncologist at the Cleve-land Clinic Taussig Cancer Institute in Cleveland, Ohio. Rini was the principal in-vestigator of the pivotal phase III AXIS trial that led to the approval of axitinib in RCC.

Rini presented AXIS trial secondary re-sults at the American Society of Clinical Oncology (ASCO) 2012 Genitourinary Can-cers Symposium. The original trial results were presented at the annual 2011 ASCO conference. The 723 patients on the trial who had failed an initial systemic therapy (either sunitinib, bevacizumab plus inter-feron-alpha, temsirolimus, or cytokines) for treatment of their metastatic clear-cell RCC were randomized to either 5 mg of axitinib or 400 mg of sorafenib (Nexavar, Bayer)—both administered twice a day (BID). The majority of patients (54%) had

therapeutic levels with the standard 5-mg BID dose, a dose-titration strategy was ap-plied to normalize plasma levels of axitinib exposure. In the phase III study, criteria for dose titration included no toxicity great-er than grade 2 for two weeks or more, a blood pressure of <150/90 mmHg, and no antihypertensive medication. Investiga-tors had the discretion to titrate axitinib to 7 mg, and then to 10 mg, depending on patient reaction to the drug. A total of 25% of patients experienced dosage reductions or progression, and one-third did not need any dosage changes. Thirty-seven percent received escalating doses of ixitinib—17% to 7 mg and 20% to 10 mg.

The phase IIII secondary analysis pre-sented by Rini showed a roughly equiva-lent PFS in the titrated group compared with the nontitrated group of axitinib-treated patients. Both subgroups had a su-perior PFS compared with patients treated with sorafenib. Adverse events were con-sistent among the titrated and nontitrated patients.

“One would expect this,” Rini said. “Both groups had similar blood levels of the drug,” No difference in PFS was observed in the axitinib-treated groups who had a prior response to sunitinib, but PFS im-proved in sorafenib-treated patients with a prior response to sunitinib. “This is a small subset of patients,” he said. A further subanalysis of patients from the AXIS trial who had initially received cytokine thera-py will be presented at the upcoming 2012 ASCO meeting in June.

Axitinib is currently being tested in the front-line metastatic RCC setting. The fully-accrued trial is testing axitinib given at a 5-mg dose twice daily compared with sorafenib at 400 mg twice daily, the same dose as in the second-line study. After four weeks, axitinib-treated patients are segregated to either a dose-titration or a steady 5-mg dose subgroup. Results of the trial are expected in 2013. Data from the phase II first-line trial of axitinib will be presented at the 2012 ASCO annual meet-ing by Rini.

RCC researchers are getting more comfortable with axitinib titration, ac-cording to Daniel C. Cho, MD, of the Beth Israel Deaconess Medical Center in Bos-ton, Massachusetts. Cho believes that this titration approach should also be applied to other therapies. He noted that sorafenib is too toxic at higher doses, but that the newer TKIs may be more ame-nable to dose titration.

Despite the progress in new treatments, the field has a long way to go, Rini said.

received sunitinib as their initial therapy. Treatment was discontinued in 14 of 359 patients receiving axitinib and in 29 of 355 patients receiving sorafenib.

Patients in the axitinib arm began with a 5-mg dose; those who tolerated this dose could be titrated up to a 10-mg dose, de-pending on tolerability. The outcome and frequency of adverse events were similar in both patients whose axitinib dose was titrated and those who received a constant dose: Both subgroups showed superior responses compared with sorafenib. Pro-gression-free survival (PFS), the primary outcome, favored the axitinib arm, which had a median PFS of 6.7 months com-pared with 4.7 months for the sorafenib arm (hazard ratio [HR] = 0.665; P < .0001). Prior treatment did not affect outcomes; both patients previously treated with sunitinib and cytokine therapy had a ro-bust response to axitinib. The objective re-sponse rates were 19.4% for patients tak-ing axitinib compared with 9.4% for those on sunitinib (P = .0001).

The AXIS trial was the first trial for kid-ney cancer to compare two kidney cancer drugs. “I started working with this drug eight years ago, so it’s been a long road,” Rini said. “Thousands, if not tens of thou-sands, of people must come together to make trials like this happen, not to men-tion the patients,” he said. “This is the fun part, when we get to the end and get re-sults like this. It’s gratifying for all the hard work people have put in along the way.” Rini was also involved in the phase III trial of bevacizumab combined with standard-of-care interferon-alfa that resulted in ap-proval of the combination by the FDA in 2009 for metastatic RCC.

Because earlier-stage trials showed intra-patient variability on the ability to achieve

New therapies have extended patients’ lives, but resistance is a major issue. The researcher is determined to continue to develop unique approaches and new drugs for RCC. Thankfully, new potential treatments are in the pipeline, with some already in phase III trials.

A phase III IMPACT global trial is testing a therapeutic vaccine, IMA901, in combi-nation with sunitinib compared to suni-tinib alone in treatment-naïve metastatic RCC patients. IMA901 is a combination of multiple tumor-associated peptides. The vaccine is being developed by immatics biotechnologies GmbH.

The primary endpoint of the trial is overall survival. Phase II data had shown

both promising immune response and survival in patients with advanced RCC. Another trial, at the Cleveland Clinic, is a sunitinib-dosing study. The phase II pi-lot study started last year to test whether giving sunitinib for six months, and then giving the patients a break from the drug for two months, may be more efficacious than continuous drug therapy. The ratio-nale is that the two-month break may pro-vide a better quality of life for patients. The long-term on-off schedule may be more sustainable compared to ongoing therapy that results in intolerable side effects that result in discontinuation of treatment. TTN

Key ResearchRini BI, Escudier B, Tomczak P, et al. Comparative

effectiveness of axitinib versus sorafenib in ad-

vanced renal cell carcinoma (AXIS): a randomised

phase 3 trial. Lancet. 2011;378:1931-1939.

Approval of Axitinib Adds Another Therapy Option for Metastatic RCC

Targeted Therapies: Renal Cell Carcinoma

“PFS was roughly equivalent in

the titrated and nontitrated groups of axitinib-treated

patients, and both groups had

superior PFS versus sorafenib in this

second-line setting.”–Brian I. Rini, MD

Brian I. Rini, MD

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Two new treatments for metastatic melanoma were approved in 2011—the first in more than a decade. Ipi-

limumab (Yervoy, Bristol-Myers Squibb), an immunotherapy, showed overall sur-vival improvement, leading the FDA to approve the therapy for both treatment-naïve and previously treated patients in March of that year. Five months later, vemurafenib (Zelboraf, Genentech), a targeted BRAF inhibitor, was approved for use in metastatic melanoma tumors that have the BRAFV600E mutation—about 40% of all patients with meatstatic mela-noma. Even before the formal approval of the BRAF inhibitor, the two compa-nies that manufacture ipilimumab and vemurafenib, Bristol-Myers Squibb and Genentech, respectively, entered into a collaboration to formally test the safety and efficacy of the combination therapy in patients with the BRAF mutation. The phase I/II, 50-person, dose-escalation trial formally started in November 2011.

At the 2012 American Association of Cancer Research annual meeting held at the end of March, melanoma re-searchers from the MD Anderson Can-cer Center in Houston, Texas, presented formal evidence supporting the combi-nation trial.1 Patrick Hwu, MD, head of MD Anderson’s Department of Mela-noma Medical Oncology, presented data showing that adding a BRAF inhibitor to immunotherapy can reverse the im-munosuppressive tumor microenviron-ment induced by the BRAF mutation.

Additionally, the researchers found that a BRAF inhibitor increased the im-

off-target effects, according to Gregory Lizée, PhD, of the same department, who was also a part of the study. Both human data and mouse models led to the con-clusion that the combination of a BRAF inhibitor with immunotherapy may act in a synergistic way.

Another recent study addresses mech-anisms of resistance to BRAF inhibitor treatment in patients with metastatic melanoma.2 Roger Lo, MD, PhD, and col-leagues at the Johnsson Comprehensive Cancer Center at the University of Cali-fornia in Los Angeles have discovered

mune response to a tumor in a mouse tu-mor model. The study provided evidence that the BRAF inhibitor targeted therapy does not prohibit the immune function of patients with metastatic melanoma. This is an important result, as evidence exists that kinase-targeted treatments can have detrimental off-target effects on the cells of the immune system. Vemurafenib may not because of its specificity and minimal

New Laboratory Melanoma Research Supports Ongoing Clinical Trials

Targeted Therapies: Skin Cancer

Basal cell carcinoma (BCC) makes up about 80% of all skin cancers and affects up to 2 million Ameri-

cans every year. This most common form of cancer is curable if the lesion is within a confined area and rarely progresses to a more advanced form. Still, until the ap-proval of vismodegib (Erivedge, Roche) this past January, there were few options for patients who had progressed to the metastatic form of the disease.

Vismodegib is not only the first treat-ment approved for advanced BCC (as

well as for adults with advanced BCC that cannot be treated with radiation or surgery), but the first inhibitor of the Hedgehog signaling pathway to gain au-thorization from the FDA.

The decision, based on the pivotal phase II ERIVANCE study, came after an expedited six-month review. Vismodegib showed a 43% objective response rate for locally advanced BCC and a 30% response rate for metastatic BCC. The median du-ration of response was 7.6 months.

Vismodegib is an oral medication that

First-Ever Drug Approved for Advanced Form of Most Common Skin Cancer

Patrick Hwu, MD

the other relapsed patients develop resis-tance by as yet unknown means. The next steps for Lo and his team will be to study each individual patient and find out what happens during relapse at the molecular level. This research will facilitate next-generation clinical trials and new thera-pies that can be combined for a more ro-bust response. It could also result in ways to avoid needing to overcome resistance. “The goal is to understand all possible mechanisms and deduce the common de-nominator molecules that can be targeted, together with mutant BRAF, in combinato-rial approaches,” Lo said. Already, the com-bination of a BRAF inhibitor with a MEK inhibitor is expected to be a “powerful two-hit,” increasing efficacy and reducing side effects, Lo said. TTN

References1. Hong DS, Vence L, Falchook G, et al.

BRAF(V600) inhibitor GSK2118436 targeted

inhibition of mutant BRAF in cancer patients

does not impair overall immune competency.

Clin Cancer Res. 2012;18:2326-2335.

2. Shi H, Moriceau G, Kong X, et al. Melanoma

whole-exome sequencing identifies (V600E)

B-RAF amplification-mediated acquired B-RAF

inhibitor resistance. Nat Commun. 2012;3:724.

3. Nazarian R, Shi H, Wang Q, et al. Melanomas

acquire resistance to B-RAF(V600E) inhibi-

tion by RTK or N-RAS upregulation. Nature.

2010;16;468(7326):973-977.

4. Poulikakos PI, Persaud Y, Janakiraman M, et al.

RAF inhibitor resistance is mediated by dimeriza-

tion of aberrantly spliced BRAF(V600E). Nature.

2011;480(7377):387-390.

selectively inhibits the smoothened re-ceptor (SMO) in the Hedgehog pathway. Abnormal signaling through the Hedge-hog pathway is the major underlying molecular driver of BCC. Genentech, a

part of the Roche Group, discovered the molecule and collaborated with Curis, Inc on preclinical studies. TTN

how tumor cells are able to stop respond-ing to treatment with vemurafenib. The team sequenced the protein-coding parts of the genome of tumors from patients treated with the drug. “Patient biopsy-oriented translational research is absolutely key to overcoming targeted drug resistance,” Lo stressed.

The research team found the tumors to have higher copy numbers of the BRAF gene, meaning the tumor is producing extra BRAF protein, rendering inhibition by the drug ineffective. About 20% of pa-tients (a total of 20 were sampled) who developed resistance had this amplifica-tion of the BRAF gene. Using cell lines, the researchers also found that the com-bination of a BRAF and MEK inhibitor could overcome the amplification-driven resistance. This combination treatment is currently in a phase I/II clinical trial for advanced melanoma.

“[In an earlier study], we initially found no evidence of secondary muta-tions in the BRAF gene,” said Lo.3 “This shifted the pharmaceutical community away from further drug development for alternative BRAF inhibitors that might circumvent mutated BRAFV600 harboring secondary mutations. The surprise is we have recently come full circle to find that alterations in BRAF—beyond the muta-tion that activates this oncogene—are important.” These BRAF mutations in-clude truncations in the gene4 and the newly described BRAF amplification.

Researchers have discovered resistance mechanisms that account for somewhere between 60% and 70% of resistance cases;

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Feature

The year 2011 marked a milestone of sorts for new drug approv-als by the FDA. Thirty-five new

medicines were approved—the second highest number of approvals in the last decade. Seven were oncology drugs, in-cluding the first one approved for Hodg-kin lymphoma in 30 years.

With the influx of these new drugs, awareness and education for oncolo-gists are paramount, and this year’s an-nual meeting of the American Society of Clinical Oncology (ASCO) will include educational seminars on these latest clinical advances. Leading researchers involved in the development of the on-cology drugs will provide practical ad-

• Axitinib (Inlyta, Pfizer), an oral small-molecule inhibitor of multiple tyrosine kinases including cKIT, VEGFR 1-3, and PDGFR, for treatment of relapsed ad-vanced renal cell carcinoma (RCC).

• Vismodegib (Erivedge, Genentech), an oral inhibitor of the Hedgehog pathway for the treatment of advanced basal cell carcinoma (BCC). Uninhibited signaling of the Hedgehog pathway is the molec-ular driver of BCC.

Another pre-meeting session will focus specifically on targeted therapy approaches. Patricia LoRusso, DO, of the Karmanos Cancer Institute, De-troit, Michigan, in the session “Where Did We Come From, Where Do We Go From Here?” will give a bird’s-eye view of targeted therapies, discussing past and present development and how to approach the next phase based on what targeted therapies have taught us thus far.

Because many of the new targeted therapies are oral medications that pa-tients take at home, the ways in which patients are educated about their treat-ments and monitored have fundamen-tally evolved. The management of side effects of targeted therapies will be discussed in a session by an oncology nurse, Peg Esper, MSN, MSA, RN, ANP-BC, AOCN, from the University of Michi-

vice on individual new therapies. This new feature is part of a set of pre-

meeting seminars that start one day be-fore the official meeting kick-off. Nota-bly, six of the seven drugs discussed are targeted treatments. Two of these treat-ments, axitinib and vismodegib, were approved by the FDA in 2012. Drugs to be discussed include:

• Vemurafenib (Zelboraf, Genentech), an oral, small-molecule BRAF inhibitor for pa-tients with metastatic melanoma whose tumors harbor a BRAFV600E mutation.

• Crizotinib (Xalkori, Pfizer), an oral, small-molecule, dual inhibitor of the c-MET and ALK receptor tyrosine kinases for advanced non-small cell lung cancer (NSCLC) that expresses the EML4-ALK fusion gene.

• Brentuximab vedotin (Adcetris, Se-attle Genetics), for intravenous infusion, an anti-CD30 antibody for the treatment of CD30-positive relapsed Hodgkin lym-phoma and relapsed systemic anaplas-tic large cell lymphoma.

• Abiraterone acetate (Zytiga, Janssen), an oral inhibitor of the cytochrome P450 17A1 protein (CYP17A1) for the treat-ment of metastatic castration-resistant prostate cancer (mCRPC) in men who have received prior chemotherapy.

gan School of Nursing, Ann Arbor. “Targeted therapies for such tumors

as metastatic melanoma, prostate cancer, and renal cell cancer will most likely be presented at the meeting,” said LoRusso. “There is also a lot of activity ongoing with other novel targets, such as agents targeting the PI3 kinase path-way and various isoforms of the PIK3CA mutation. Hopefully some of this data will be mature enough and presented as well.”

According to LoRusso, the face of melanoma has changed completely because of targeted and biologic treat-ments: “There has been a huge impact.” Phase III results of the effectiveness of vemurafenib for melanoma were pre-sented at last year’s ASCO plenary ses-sion. This compound has had a major impact on the BRAF-mutated subset of melanoma. Results of new targeted treatments and their combinations will likely be a highlight of this year’s meet-ing as well.

LoRusso sees combination therapies as the future of targeted therapies. “In metastatic disease, where we are go-ing for one major target because there is one major driver mutation—such as with basal cell cancers, ALK-mutated lung cancer, or BRAF-mutated melano-ma, for example—the majority of these patients will eventually go on to prog-ress despite continued therapy,” said


22

• Metastatic melanoma: Results of the phase III METRIC clinical trial of trametinib, a MEK inhibitor tested in a global, randomized trial of patients with metastatic mela-noma, the results of the phase III BREAK-3 trial of dabrafenib, a BRAF kinase inhibi-tor; also, an update on a phase I/II trial of dabrafenib combined with trametinib in treatment-naïve patients.

• RCC: Results of the global, randomized, phase III TIVO-1 clinical trial testing the ef-ficacy of tivozanib, a receptor tyrosine kinase inhibitor, against sorafenib, the current standard of care, as a first-line treatment for advanced RCC.

• Liver cancer, RCC, prostate cancer, and thyroid cancer: Four oral presentations of studies with cabozantinib (XL184) are expected during ASCO. Cabozantinib is a small-molecule inhibitor of the tyrosine kinases c-Met and VEGFR2. The four presen-tations will be: • Clinical data of a phase II randomized, discontinuation trial in hepatocellular carcinoma • Efficacy of cabozantinib in patients with metastatic, refractory RCC • Phase II nonrandomized, expansion cohort results in chemotherapy-pretreated

mCRPC • Full results of the pivotal phase III EXAM trial in medullary thyroid cancer patients

• Non-small cell lung cancer: Results of the pivotal phase III LUX-Lung 3 trial of afatinib in treatment-naïve patients with metastatic NSCLC with EGFR mutations. The trial compares the efficacy of afatinib, an irreversible ErbB family inhibitor, to peme-trexed/cisplatin. Mutations in EGFR, also known as ErbB1, are found in approximately 12% of Caucasians and as many as 40% of Asian patients with NSCLC.

• Acute myeloid leukemia and acute lymphoblastic leukemia: Six-month follow-up data from the pivotal PACE trial of ponatinib, a pan-BCR-ABL inhibitor, in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblas-tic leukemia (Ph+ ALL) who are resistant or intolerant to the currently approved BCR-ABL inhibitors dasatinib and nilotinib, or who have the T315I mutation. Positive preliminary data were presented at the American Society of Hematology (ASH) meeting in December 2011.

• Immunotherapy for melanoma, RCC, and lung cancer: Several abstracts will be presented on phase I and phase II clinical trials of MDX-1106/ BMS-936558, an anti-PD1 immunotherapy that is seen as the next generation of immunotherapy after ipi-limumab. Anti-PD1 is being developed by Bristol-Myers Squibb. Results are expected from the large expansion cohort data of the phase I/II solid tumor trial and potentially from the phase II RCC trial.

Targeted Therapy Presentations to Watch for at ASCO

ASCO: A Focus on Personalized MedicineBy Anna Azvolinsky, PhD

Patricia LoRusso, DO

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LoRusso. “Based on this evidence, com-bination targeted therapies is the way to go forward.”

Many monotherapies have not result-ed in robust responses, or at least not in long-term responses, according to LoRusso. “We are in the process of be-ing challenged to re-think how we give these targeted therapies, especially if combination data demonstrate better efficacy over monotherapy.” LoRusso also pointed out that because of the high potential cost of combining ther-apies, combinations will have to show robust efficacy in order to be widely uti-lized.

Science is what is driving the com-bination therapies. Hypothesis-driven clinical trials based on robust labora-tory research results is now much more prevalent, said LoRusso. The challenge will be to not only further develop new therapies, but to find better ways to measure progress and genomic evolu-tion of a tumor through the course of disease and treatment.

Serial biopsies are at times nec-essary and ultimately can benefit a patient by providing accurate infor-mation that influences further treat-ment. However, these biopsies can be invasive and come with many adverse effects. “We realize that the informa-tion biopsies provide is important for treatment decisions and assessment of disease. They are important but associ-ated with toxicities,” LoRusso said. New technologies such as assaying for cir-culating tumor cells or circulating DNA are in development as potential ways to access the cancer information less invasively—a topic to be discussed at the ASCO 2012 meeting.

Identifying patients who will benefit

most from a medication is also impor-tant, both for patient outcomes and to minimize cost of care, two major ongo-ing issues in oncology. “We need to fo-cus on what is best for the patient,” said LoRusso.

Provocative NCI Questions To Be Addressed A key theme at this year’s ASCO meet-ing will be sessions that aim to address some of the provocative questions that were assembled by the National Cancer Institute (NCI) in 2011. The goal of the questions is to identify and address the most complex cancer care and research problems. The ASCO sessions will be a forum for the oncology community to discuss the problems and think of in-novative, “outside-the-box” ways to use laboratory, clinical, and population studies to begin to offer answers. Many educational sessions at ASCO will high-light these questions.

One of the proposed questions, “Why do many cancer cells die when sud-denly deprived of a protein encoded by an oncogene?” highlights the ability of targeted therapies to inhibit a spe-cific driver mutation within a tumor. The question also brings to light our relatively meager understanding of why inhibition of oncogenic drivers leads to cancer cell death for some tumor types but not others. Many broad and tumor type-specific sessions will address this question. Some of these sessions in-clude “Biologic Principles of Targeted Combination Therapy,” “Developing a Targeted Therapy: Issues in the Age of Personalized Therapy,” and “New Op-tions, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma.” TTN


23

Rising Cost(continued from cover)

(continued on next page)

few months at most. As a result, as new therapies become available in clinical practice, questions about costs ver-sus benefits are increasingly emerging. Among the often difficult questions be-ing asked: Are the survival gains worth the burden on the healthcare system and individual patients? How do we pay for new drugs, diagnostics, and technol-ogies—and who should pay?

Like it or not, economics are driving treatment choices for patients in the real world. Even when a drug is covered by insurance, many patients are not able to afford even the copay. Thus, de-spite advances in innovation and care, cost is hindering use of new therapies.

To gain perspective on these issues, Targeted Therapy News spoke with Thom-as J. Smith, MD, director of Palliative Medicine at The Sidney Kimmel Com-

prehensive Cancer Center and professor of Oncology at Johns Hopkins Medical School in Baltimore, Maryland. Smith discussed the rising cost of cancer ther-apies, the burden of cost, and the cost-benefit analysis of end-of-life care, and will also speak about these issues at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in a session titled, “Costs of Cancer Care: Af-fordability, Access, and Policy.”

TTN: How can oncologists stay informed about the best decisions on care along-side their patients in the context of new high-cost targeted therapies?Smith: It is complicated. I think the first question we have to ask ourselves as oncologists is, “Does it work?” Is there a clear-cut improvement in over-all survival or disease-free survival, or quality of life that makes it better than other treatments? If the answer to this first question is yes, then the

next question is, “How much does it cost and to whom?” And these are re-ally difficult questions because some-times the cost can be extraordinary to society as a whole but very little to the patient. The patient may only have an annual $1000 copay for a $120,000 new melanoma treatment, for example. In other cases, they may need to pay up to 40% of the cost of treatment. Oncolo-gists need to discuss costs directly with their patients. I have learned to ask my patients, “What is your insurance cov-erage?” and “How much is this going to cost you?” before having the patient

Like it or not, economics are driving treatment choices for patients in the real world.

Treating patients with targeted therapies requires a new approach to diagnosis (using molecular biomarkers), monitoring of patients, management of new types of adverse events, and cost decisions due to high prices of these medications. We have witnessed a range of successes in the advancement of targeted therapy research and clinical trials, and approvals for different types of cancers. For example, lung cancer, breast cancer, and melanoma are now at the forefront of personalized medicine and targeted therapy options. The following ASCO 2012 educational meeting sessions will highlight the latest research developments in targeted treatments and new ways clinicians need to be thinking about this type of approach to cancer care.

Several sessions specifically highlight personalized medicine for different tumor types:

– “The Cost of Lung Cancer Care: Screening, Personalized Medicine, and Palliative Care” (Friday, June 1)

– “Personalized Medicine in Lung Cancer in 2012” (Saturday, June 2)

– “New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma” (Saturday, June 2)

– “‘Personalized’ Oncology for Colorectal Cancer: Ready for Prime Time or Stop the Train” (Tuesday, June 5)

– “Mechanisms of Resistance to Targeted Anticancer Agents” (Saturday, June 2)

– “Biologic Principles of Targeted Combination Therapy” (Sunday, June 3)

• Many TKIs are approved for a range of cancers, including imatinib and dasatinib for CML, gefitinib for breast and lung cancers, erlotinib for lung and pancreatic cancers, and sunitinib for RCC. “Laboratory and Clinical Insights into Resistance to Tyrosine Kinase Inhibitors” (Sunday, June 3) will address a key issue in the use of TKIs.

• A novel view on targeted therapies will be discussed on Monday, June 4, in the ses-sion “Targeting Critical Molecular Aberrations Early in the Course of Solid Tumors: Is It About Time?” Targeted therapies are now predominantly utilized in the advanced cancer and metastatic setting, but this session will discuss moving these agents into the adjuvant setting, and potentially even to earlier-stage settings.

• A “Meet the Professor” session on Monday, June 4, “Bringing Personalized Cancer Thera-py into Routine Use,” will focus on the practical aspect of personalized care for clinicians.

ASCO: Targeted Therapy Educational Sessions

receive a $120,000 bill they cannot pay. For example, aromatase inhibitors for

breast cancer cost $450 a month even though there are three of them on the market and all of them are essentially interchangeable. This gets to an issue of compliance. Some patients simply can-not afford the 20% copay.

TTN: The cost of the end-of-life care is very high for cancer patients. How do oncologists reconcile these costs

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TTN: What are some of the ways that oncologists can curb costs while pro-viding good care for patients at the end of life?Smith: There are a couple of strategies for oncologists that make good sense. One is to get people into a care system that keeps them out of the hospital near the end of life. The best way to do this is hospice. ASCO and many of us who are practicing oncologists are now rec-ommending that when patients have about three to six months left to live, they should visit a hospice for informa-tion. This does a few things. It makes it

real for the patient and the family that this is where things are headed and it is time to plan. It introduces the hos-pice team as the best way to take care of people at the end of life—which all professional societies agree on, every single one. It introduces the hospice care team as part of the regular oncol-ogy care plan. Integrating the hospice early is now part of best practices for most oncologists. It makes the transi-tion easier, so that when a patient has tried a third-line chemotherapy in lung cancer or colorectal cancer without success, the oncologist can say, “Now is the time for you to switch to the hos-pice care,” with the nurses and social workers that the patient has already met.

TTN: ASCO released palliative care guid-ance in March of this year. How do you see this being implemented?Smith: Palliative care should be a part of the care of anyone with a serious ill-ness. The uptake should not be slow. All of us who are practicing oncolo-gists work with hospice providers. I like to use the analogy of we know the radiation therapist and our surgeons very well. We know their phone num-bers and their fax numbers probably by heart. For the hospice providers, it tends to be a love-hate relationship. It shouldn’t be that way. It should be part of the normal process of care. I

with providing the best treatment for their patients, while also recogniz-ing whether the quality of life may be more important for a patient with advanced-stage cancer? Smith: Many of us were trained to treat the disease and as long as there is some-thing that can be done, to keep treating as long as it does not make the patient deathly ill. This has worked for our pa-tients for the most part. Sometimes, I think the deathly ill part gets neglected a little bit because we tend to ask less about our patients’ quality of life than we should.

TTN: What role does palliative care play?Smith: Palliative care was always de-signed to improve patients’ symptoms and coping, to lessen depression, and to lessen caregiver burden. It is only an interesting sidebar that it results in cost savings. The cost savings are substan-tial. It could be anywhere from 20% to 50% of the cost in the last month or six months of life that can be reduced. This type of care allows patients to get out of the hospital, where most people don’t want to be.

TTN: How does this affect our current healthcare spending as a whole?Smith: There are really imperative rea-sons to have this cost discussion. First, our cancer care system is simply not sustainable. Even though it is only 5% of the national budget, in the insured population it is 15% to 20%, a substan-tial amount. The cost per person per year in the US is $8100. It is $4500 in Canada for exactly the same amount of health benefit. The cost of insurance for a family of four has gone from $6000 in the year 2000 to over $15,000 in the year 2012. Insurance premiums went up 8% to 9% last year, and that is simply not sustainable either. There were close to a million, if not more, medical bankrupt-cies last year alone. So we need to do something. The question is, “What can we do that will cause as little harm as possible?”

think oncologists like me should be calling the hospice providers and say-ing, “We actually work a lot together. Let’s figure out what we can both do to improve the care our patients get.” Hospice providers like to see patients when they have at least a month to live rather than a day left to live. It is a terrible process of care when we simply avoid having this conversation until the patient is bed-bound, in re-nal failure, and has an infection and two days left to live. In this situation, hospice is just scurrying around and doesn’t even have a chance to speak to the patient, and is left to pick up the pieces for bereavement and grief counseling. Patients in hospice care and with palliative care tend to live longer rather than shorter.

Oncologists should speak to the hos-pice providers to understand how they can do better. We should ask them how our statistics compare to the national average in terms of referral time. As on-cologists, we need to be having realistic conversations about how many treat-ment types a patient can go through be-fore we run out of options. Saying that there is a limit to treatments and there will be a time when treatment will only do more harm than good is necessary. This conversation needs to happen ear-ly and be reinforced throughout treat-ment.

TTN: Who are the other players that need to be involved in these cost decisions on a policy level?Smith: This is a big point. I don’t think that cost control should fall to the in-dividual oncologist. I think one of the worst things would be that no one at the insurance or government or societal level wants to make these decisions, so it is all a burden on the individual oncologist. I don’t think individual on-cologists should be the only ones hav-ing difficult conversations with patients because no one else wants to do it. But, as oncologists, we need to be prepared to ask our patients about cost.

TTN: What is the current level of change and awareness on a government and policy level?Smith: Change is already happen-ing. Insurance companies are making decisions about what they cover and don’t cover. Medicare makes decisions by basically not making decisions on whether Medicare will pay for an FDA-approved indication. But we do need to be having more adult conversations about what we can and cannot pay for. This extends beyond cancer to ventric-ular assist devices, $100,000 pulmonary hypertension treatment, and the ex-pensive rheumatologic drugs. We can-not continue to spend the way we have been spending.


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“ASCO and many of us who are practicing oncologists are now recommending that

when patients have about three to six months left to live, they should visit a

hospice for information.”—Thomas J. Smith, MD

TTN: The US highly values new scien-tific innovation. The FDA last year ap-proved 35 new, innovative drugs. Most of these approvals were the first glob-al approvals. How do we reconcile the need and benefit of new innovations in spite of cost?Smith: I think it is fascinating that the average cost of a new therapy has gone up by hundreds of percentage points while the improvement in overall sur-vival or disease-free survival has stayed at about 1%. I would like to see data showing that [the cost increases are] due to the increased cost of clinical tri-als, but it seems hard to imagine. I think companies are doing what we would like them to be doing from a business perspective. They are valuing their drugs at what they think the market will bear. It is great for the company, but it is impossible to sustain.

There may be instances where target-ed therapies or testing will actually save money. A good example is the Oncotype DX 21 [21 gene assay] in breast cancer, which we use routinely. The data are quite convincing that this allows us to spare chemotherapy in many situations and simply treat patients with a hor-monal agent. To me, there is not an ob-vious correlation between a high price and the fact that a therapy is targeted. Many of these drugs are in the meta-static setting at the end of life. We as a society need to step up and say, “How much of this can we actually afford?”

As an individual oncologist, I can’t fix the cost of targeted therapies. What I can fix as a regular oncologist is the high cost of end-of-life care, much of which is not desired by the patient. I can fix this part by having an open and honest conver-sation with patients and their families about the reality of the situation. Keep-ing patients out of the hospital in the last one or two months of life would save billions of dollars for insurance compa-nies and Medicare, and it is what many patients want. This cost savings will al-low us to better afford many of these innovative and exciting therapies, all of which I want to keep using.

TTN: Are we going in the right direction and having this discussion?Smith: I think that it is fascinating to see what is being proposed on the fed-eral level. A lot of the plans being pro-posed will actually turn over the benefit determination to insurance companies. It will not be Medicare making the deci-sion, but it will contract with an insur-ance company that will determine what is covered. Somehow, that is thought to be better at this point. Medicare is al-ready divided into regions. Coverage is determined by someone, whether a bu-reaucrat or at a large company. I think things will get worse before they get better. TTN

NOW ENROLLING

An Open-Label Two-Stage Study to Determine Efficacy and Safety of Orally Administered BKM120

STUDY DESIGN

PRIMARY ENDPOINT• Progression-Free Survival

FOR MORE INFORMATION ABOUT STUDY DESIGN OR ENROLLMENT:• US residents can visit www.clinicaltrials.gov [NCT01297491]• For countries outside of the US, please contact your local

Novartis Medical Representative

BKM120 is an investigational compound. Efficacy and safety have not been established. There is no guarantee that BKM120 will become commercially available.

Up to 180 patients will be enrolledBiomarker prescreening can take place before formal eligibilityStudy population comprises 1 prior treatment for squamous histology and 1-2 prior treatments for non-squamous histology

SECONDARY ENDPOINTS• Objective Response Rate• Time to Response• Duration of Response• Disease Control Rate• Overall Survival• Safety

Stage 1

Group 1: SquamousNSCLC pretreated with 1 prior platinum-based chemotherapy

line for advanced disease

BKM120 BKM120 BKM120 BKM120Docetaxel Docetaxel or Pemetrexed

Group 1: SquamousNSCLC pretreated with 1 prior platinum-based chemotherapy

line for advanced disease

Group 2: Non-SquamousNSCLC pretreated with 1 or 2 prior antineoplastic therapies

for advanced disease

Group 2: Non-SquamousNSCLC pretreated with 1 or 2 prior antineoplastic therapies

for advanced disease

Metastatic NSCLC Patients

End of Treatment due to toxicity Continue tumor assessments Progression-Free Survival and SurvivalOR

End of Treatment due to progression Progression-Free Survival and Survival

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Determine PI3K Pathway Activation

Screening

Enrollment

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936 –1080 © 2012 Novartis Printed in USA 5/12 ONC-1040998

Investigating BKM120 in Patients With Metastatic NSCLC and Activated PI3K Pathway (CBKM120D2201)

Basalt-1_JournalAD 2 TTN.indd 1 5/16/12 11:45 AM

Feature


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bo was prepared by culturing one-third of the leukapheresis collection without PA2024 at 2 degrees to 8 degrees C. The remaining cells collected from patients in the placebo arm were cryopreserved.

Such procedures not only made the placebo “a biologically significant differ-ent intervention that could have had dis-tinct clinical properties,” but also might have placed older patients at a disadvan-tage when it came to replacing cells lost in leukapheresis, according to the article by Huber et al. “Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss pro-vides a potential alternative explanation for the survival ‘benefit’” of sipuleucel-T, the authors said.

In his IPCC presentation, Gomella said that researchers are debating the impact of extracting immune cells, but that a study pending publication indicates the “number of immune cells you pull out of the body with leukapheresis is clinically insignificant.”

Meanwhile, Dendreon Corporation, the Seattle, Washington, company that developed sipuleucel-T, is continuing to investigate the vaccine for patients with earlier-stage disease. TTN

Key ResearchGomella LG, Nabhan C, Whitmore JB, et al. Post-

progression treatment with APC8015F may have

prolonged survival of subjects in the control arm

of sipuleucel-T phase III studies. Poster presented

at: 2011 ASCO Annual Meeting; June 3-7, 2011;

Chicago, IL. Abstract 4534.

Huber ML, Haynes L, Parker C, et al. Interdisciplin-

ary critique of sipuleucel-T as immunotherapy in

castration-resistant prostate cancer [published

online ahead of print January 9, 2012]. J Natl Inst. 2012;104(4):273-279.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-

T immunotherapy for castration-resistant prostate

cancer. N Engl J Med. 2010;363(5):411-422.

Nabhan C, Gomella LG, DeVries T, et al. An analysis to

quantify the overall survival (OS) benefit of sipuleucel-T

accounting for the crossover in the control arm of the

IMPACT study. J Clin Oncol. 2012;30(suppl 5;abstr 144).

data demonstrating that patients who took the vaccine experienced a median OS of 25.8 months versus 21.7 months for those who received placebo.

Sipuleucel-T is custom manufactured for each patient from antigen-presenting cells (APCs) that are harvested from the patient through the process of leukapher-esis, then cultured to activate immuno-genicity and infused into the patient. The treatment course consists of three intra-venous infusions.

In his analysis, Gomella looked more closely at participants in the control arms of three randomized, double-blind sipuleucel-T studies. Of 249 people in the control arms, 216 participants who expe-rienced disease progression had the op-tion of receiving APC8015F, an autologous immunotherapy with the same potency as sipuleucel-T, which was made for each patient and cryopreserved at the time the placebo was prepared.

For the 155 patients from the con-trol arm who received APC8015F, the median OS was 23.6 months from ran-domization and 20.0 months following disease progression, which compared favorably with the median OS in the sipuleucel-T arms of 25.4 months from randomization and 20.7 months after progression.

In contrast, the 61 participants from the control arm who experienced dis-ease progression but did not cross over to APC8015F had a median OS of 12.7 months from randomization and 9.8 months following disease progression.

“The survival difference was dramati-cally different,” Gomella said during his IPCC presentation. “So in a way, the sipu-leucel-T trials shot themselves in the foot because the frozen product was included. If you exclude the frozen product, you ac-tually get a much more dramatic and a

A further analysis of clinical trial data for sipuleucel-T (Provenge, Dendreon) suggests that the thera-

peutic prostate cancer vaccine may have delivered a greater overall survival (OS) benefit than previously described in the study that paved the way for its approval nearly two years ago, according to a lead-ing researcher.

In fact, the analysis indicated that the survival benefit may be significantly higher than the 4.1-month advantage re-ported in the IMPACT study when the ex-periences of patients in the control arm who crossed over to a cryopreserved form of the vaccine are considered, said Leon-ard G. Gomella, MD, chairman of the De-partment of Urology and director of Clini-cal Affairs at the Kimmel Cancer Center, Thomas Jefferson University, in Philadel-phia, Pennsylvania.

Gomella discussed his hypothesis at the 5th Annual Interdisciplinary Pros-tate Cancer Congress (IPCC) March 31 in New York City, for which he served as a program director. The research was pre-sented at the 2012 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO) in February and at the 2011 ASCO Annual Meeting.

Gomella’s comments come amid con-tinuing controversy over sipuleucel-T, including a recent commentary in the Journal of the National Cancer Institute that maintained that previously unpublished data cast doubt on the vaccine’s survival benefit partly because of factors involving patients in the placebo arm.

The FDA approved Provenge on April 29, 2010, for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant, hormone-refractory prostate cancer, based on clinical trial

much more robust response of about 10 to 12 months.”

In an interview, Gomella added, “From my viewpoint, the benefit of sipuleucel-T has been understated because many of the patients who received the frozen product who were on the control arm ac-tually enjoyed a longer survival, decreas-ing the difference between the control arm and the treatment arm.

“In fact, if you look at our analysis of the patients who received a frozen prod-uct on the control arm and those who did not receive it, there was a significant sur-vival advantage to those patients who did receive the frozen product,” said Gomella. “It made the difference between the con-trol arm and the actual treatment arm much closer. And if you take out those patients who did not receive the frozen product on the control arm, that survival difference actually approaches 10 to 11 months.”

Gomella’s analysis, however, stands in sharp contrast to the contentions of Huber et al, who argue that previously unpub-lished trial data show worse OS in older versus younger patients in the placebo groups, and that the difference may en-hance the sipuleucel-T survival advantage.

Patients on placebo who were younger than age 65 experienced an unexpected 11-month median survival advantage when compared with those over age 65 (28.2 mo vs 17.2 mo, respectively), the au-thors said.

All of the 512 patients in the IMPACT study were scheduled for three leuka-pheresis procedures followed by infu-sions with either sipuleucel-T or pla-cebo. While the antigen-presenting cells of patients in the sipuleucel-T arm were incubated at 37 degrees C with immune-activating proteins, including the recom-binant fusion protein PA2024, the place-

A New Look at Survival Data for Sipuleucel-TBy Anita T. Shaffer

Leonard G. Gomella, MD

Control Arm Flow Diagram

Randomizationto control group

249 control subjects in 3 mCRPC studies

216 with confirmed disease progression*

155 received APC8015F

61 did not receive APC8015F

Median time from randomization to first APC8015F infusion was 5.2 months (range, 1.8-33.1)

Median time from disease progression to first APC8015F infusion was 2.2 months (range, 0.5-14.6)

*10 control subjects did not have confirmed disease progression and were treated with APC8015F

Control Infusions APC8015F Infusions

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The genetic research is identifying new subpopulations of breast cancer to allow for better treatment options—some of the new subtypes could ben-efit from existing targeted agents and chemotherapy. This new breast cancer subtype clustering based on genetic and transcription data is also identify-ing new molecular drivers.

Translational research is using the new genetic data to develop drugs from a range of many newly identified tar-gets. Advances in both basic research and translational research are produc-ing a plethora of new targets, according to Leyland-Jones. “The number of tar-gets is shooting up, but fortunately we are getting the drugs to handle those targets,” he said.

Although identification of driver mu-tations such as HER2 overexpression in breast tumors has allowed for tailored therapies, many aggressive tumor types have no distinguishing genetic charac-teristics on which to base treatments. Research in this field is very active. A recent study published in the journal Nature characterized over 2000 breast tumors. The study revealed new breast cancer subgroups based on both genomic and transcription analyses.1 The authors of the study identified three new dele-tion mutations that correlated with al-ready known breast cancer subtypes. Re-searchers can now take advantage of this knowledge to identify patients with these mutations and test specific drugs that target specific mutations. These types of genomic breast tumor studies will lead to more precise diagnoses and tailored treatments that target the specific mo-lecular defects of a patient’s tumor.

Mapping the genetic landscape of a tumor allows for identification of bio-markers, which can be used to predict response to treatment or better predict patients with high-risk disease or re-

that is characterized by what they lack (no expression of estrogen or progester-one receptor and no HER2 overexpres-sion) rather than distinct and targetable genetic aberrations. Platinum-based chemotherapy is widely used as a treat-ment, but it exposes the patient to toxicity and does not help all patients. Identifying patients who would benefit would save many patients from the tox-ic effects of systemic therapies that will not be efficacious—and lower unneces-sary costs of treatment.

currence. For example, a research team at the Dana-Farber Cancer Institute in Boston, Massachusetts, has identified a marker of DNA damage in patients with triple-negative breast cancer that may be able to predict whether a patient has the potential to respond to platinum-based chemotherapy agents such as carboplatin and cisplatin.2

Currently, triple-negative breast can-cer does not have any targeted therapy options because the subtype is actually a heterogeneous group of tumor types

HER2 Targeting: Advancements Beyond TrastuzumabApproximately 20% of breast cancers produce too much HER2. These HER2-positive breast cancers are typically more aggressive compared with other types of breast cancer and are fast-growing. “When amplified, the expres-sion of HER2 goes way beyond its nor-mal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression. When overexpressed to this extent, it plays a dominant role in proliferation and motility and resistance to hormon-al control,” said Dennis Slamon, MD, PhD, director of Clinical/Translational Research, director of the Revlon/UCLA Women’s Cancer Research Program, and chief of the Division of Hematol-ogy/Oncology at the Jonsson Compre-hensive Cancer Center, University of California, Los Angeles.

The HER2 gene was discovered in the late 1970s and cloned in 1985 by sci-entists at Genentech. That same year, scientists at the National Institutes of Health discovered that the gene is fre-quently present in multiple copies in human breast tumors. Trastuzumab (Herceptin, Genentech) was created at Genentech in 1990. The antibody specif-


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Breast Cancer(continued from cover)

(continued on page 30)

“It is becoming clear that breast cancer has 50 to 80 targetable drivers. This is a time of massive knowledge change in the entire field.”—Brian Leyland-Jones, MD, PhD

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Members of the human epidermal growth factor receptor family.

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ically binds to the extracellular domain of the HER2 receptor. The drug was ap-proved for metastatic breast cancer that overexpresses the HER2 protein in 1998—either as a monotherapy for patients who have received at least one chemotherapy treatment or as a first-line therapy in combination with paclitaxel. Phase III trials showed the antibody reduced rates of recurrence by about 50%. Since then, it has become one of the most common therapeutic agents used in the treatment of breast cancer. Trastuzumab was subsequently approved as an adjuvant treatment for HER2-overexpressing, early-stage breast cancer.

HER2 Signaling BasicsHER2 is a receptor tyrosine kinase that is part of a signaling network that controls important cellular processes such as cell survival, proliferations, an-giogenesis, invasion, and metastasis. HER2 belongs to the human epider-mal growth factor family of receptors, along with HER1 or EGFR, HER3, and HER4. The basic signaling mechanism for this family involves dimerization—the coming together of two of the same receptors (homodimerization) or two different receptors (heterodimeriza-tion) within the plasma membrane. Heterodimers of HER2 and HER3 have been shown to be more potent com-pared with homodimers in activation of downstream targets. Activation re-sults in intracellular signaling through an important pathway also frequently mutated in cancer: the phosphati-dylinositol-3-kinase (PI3K)/Akt/mam-malian target of rapamycin (mTOR) pathway.

“HER2-HER3 dimerization is a partic-ularly important aspect of HER2 signal-ing, as these dimers potently signal to the PI3K survival pathway and are the main mechanism driving HER2-positive cancers,” said Carlos L. Arteaga, MD,

extracellular domain and can block ligand-dependent HER2 dimerization. As a single agent, trastuzumab is more effective than pertuzumab in inhibit-ing HER2-dependent growth in vitro and in vivo, according to Slamon, who had played a major role in the development of trastuzumab.

“But when you hit the receptor twice, it appears you have even better activ-ity. We had preclinical data from our lab from several years ago that demonstrat-ed this. So, it appears that two assaults on the receptor gives you synergistic ac-tivity,” Slamon explained.

Pertuzumab is currently being stud-ied in patients with early and advanced HER2-positive breast cancer and ad-vanced HER2-positive gastric cancer.

Pertuzumab has limited activity as a single agent, but the synergistic ef-fect of trastuzumab plus pertuzumab that was demonstrated in preclinical studies has been confirmed in phase II trials in patients who had disease progression after trastuzumab mono-therapy.

The phase II NeoSphere (Neoadju-vant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) trial

director of the Breast Cancer Research Program at the Vanderbilt-Ingram Can-cer Center in Nashville, Tennessee. Arteaga’s research focuses on the role of signaling by oncogenes in the progres-sion of breast tumor cells and molecu-lar therapies in breast cancer.

Next-Generation HER2 Therapies in Development Although it was a great advance that led to improvement in survival of patients with an aggressive form of breast can-cer, trastuzumab is not a “magic bullet.” Significant problems of resistance to the therapy and relapse require next-gener-ation solutions, despite the availability of trastuzumab and lapatinib (Tykerb, GlaxoSmithKline), another inhibitor of the HER2 pathway.

One of the mechanisms of resistance to trastuzumab may be an incomplete blockade of HER2 signaling. Trastuzum-ab blocks ligand-independent signaling, but not ligand-dependent signaling that results in HER2-HER3 dimerization. The monoclonal antibody pertuzumab, also developed by Genentech, may overcome this form of resistance. Pertuzumab binds to a different region of the HER2

showed higher pathologic complete re-sponse (pCR) rates in newly diagnosed patients with HER2-positive breast can-cer treated with a triple combination of pertuzumab, trastuzumab, and chemo-therapy.3 The trial demonstrated that chemotherapy may not be necessary, as pertuzumab plus trastuzumab without chemotherapy also produced higher pCR rates. These results suggest that if it were possible to predict which patients would respond to the dual HER2-targeted com-bination, it may be possible to treat pa-tients effectively without chemotherapy.

Subsequently, the phase III CLEOPA-TRA (CLinical Evaluation Of Pertuzu-mab and TRAstuzumab) trial compared the triple combination of pertuzumab, trastuzumab, and docetaxel chemo-therapy to trastuzumab and docetaxel alone in 808 patients with HER2-positive metastatic breast cancer who had not been previously treated.4 Patients who received the triple combination had a 38% reduction in the risk of their disease worsening. The median progression-free survival (PFS) was 18.5 months for the triple combination compared with 12.4 months for trastuzumab plus chemo-therapy (P < .0001)— an increase of 6.1 months. The overall survival data were still immature when the trial data were presented but favored the triple com-bination. The objective response was 80.2% in the triple-therapy group com-pared with 69.3% in the control group.

Leyland-Jones called the survival im-pact demonstrated in the study “prac-tice-changing.” Arteaga believes that the results are due to a comprehensive blockade of HER2 signaling. “Frankly, I think these results were expected and, as strongly suggested by the mecha-nistic and preclinical data, the results could almost have been written before the trial,” he added.

The CLEOPATRA trial results were published in The New England Journal of Medicine in January. The combination has


30

Breast Cancer(continued from 27)

• One of the four abstracts selected to be presented during the plenary session of the meeting: Results of the EMILIA phase III study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer who have previously been treated with trastuzumab and a taxane.

• Results of the phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3K or PTEN altered HER2-positive metastatic breast cancer, at a clinical science symposium oral session.

• Results of the SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER-positive/HER2-negative metastatic breast cancer, at a clinical science symposium oral session.

• A 13-gene signature to predict rapid development of brain metastases in patients with HER2-positive advanced breast cancer, at an oral session.

• The National Surgical Adjuvant Breast And Bowel Project (NSABP) protocol, evaluation of lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer, at an oral session.

HER2-Positive Studies To Be Featured at ASCO 2012 Annual Meeting

“When amplified, the expression of HER2 goes way beyond its normal dynamic range—there is a wide range of normal HER2 expression—so that you get pathologic overexpression.”—Dennis Slamon, MD, PhD

Feature

been submitted for approval in both the US and in Europe for previously untreat-ed, HER2-positive, metastatic breast can-cer. The decision from the Food and Drug Administration (FDA) is expected June 8, 2012, based on a priority review.

The pertuzumab, trastuzumab, and chemotherapy combination is also be-ing investigated in a phase III trial as adjuvant therapy in nearly 4000 pa-tients with HER2-positive breast cancer.

In addition to trastuzumab and per-tuzumab, other agents such as HER2 dimerization inhibitors are in develop-ment. “Overall, these represent an im-portant class of agents as they disrupt a central mechanism of signaling by the HER2 receptor,” said Arteaga. These therapies include the monoclonal anti-body MM-21 (SAR256212; sanofi-aven-tis and Merrimack Pharmaceuticals), which disrupts HER3-ligand-induced HER2-HER3 dimerization. MM-121 is un-der clinical development in a variety of settings, including in combination with cetuximab and irinotecan in colorectal,

head and neck, non-small cell lung, and triple-negative breast cancers.

Another agent is a fully human anti-HER3 monoclonal antibody, U3-1287/AMG-888 (Daiichi Sankyo Co Ltd, U3 Pharma, and Amgen), which is current-ly being studied in a phase Ib/II trial in combination with trastuzumab and pa-clitaxel in patients with newly diagnosed HER2-positive metastatic breast cancer.

Additionally, Arteaga highlighted data on a novel HER3 antibody developed by Novartis that has shown the abil-ity to block both ligand-dependent and ligand-independent formation of HER2-HER3 dimers. “The preclinical data sug-gested this monoclonal antibody could be mechanistically superior to the other two HER3 antibodies, but it has not been tested in patients yet,” he said.

Other dual HER2-blockade approach-es include trastuzumab in combination with a PI3K inhibitor. “The ‘dual’ ap-proach targets different molecules or nodes in the HER2 pathway, the HER2 receptor, and PI3K immediately down-stream,” said Arteaga.

2012. Patients in the trial were previously treated with trastuzumab and chemo-therapy. Roche and Genentech will sub-mit applications for approval of T-DM1 to both the FDA and the European Medi-cines Agency (EMA) this year.

Another ongoing three-arm, phase III study is the MARIANNE trial comparing T-DM1 with and without pertuzumab to trastuzumab plus a taxane chemother-apy in 1000 patients with HER2-positive, previously untreated metastatic breast cancer. The primary endpoint of the trial is PFS.

Other Pathway TargetsMany additional targets are under de-velopment for breast cancer therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors may have efficacy in BRCA-associated cancer. In a phase III trial published in January 2011, the PARP inhibitor iniparib (BiPar-Sciences/sanofi-aventis) did not meet the primary dual endpoints of over-all survival (OS) and PFS in metastatic

triple-negative breast cancer. However, a prespecified subgroup analysis sug-gested improvements in OS and PFS in the second- and third-line settings. Researchers are continuing to investi-gate potential uses for iniparib and to discover which patients will most likely respond to PARP inhibitors.

Iniparib is considered a relatively weak PARP inhibitor, said Leyland-Jones. Other PARP inhibitors under de-velopment include rucaparib (Clovis), for BRCA-positive, post-neoadjuvant, triple-negative breast cancer; olaparib (AstraZeneca), for BRCA-positive breast cancer; and veliparib (ABT-888; Abbott), for BRCA-positive, triple-negative breast cancer.

Advances in basic research are lead-ing to a greater understanding of the tumor microenvironment, noted Ley-land-Jones. New therapeutic targets as a result of these advances include meta-bolic pathways (serine, glycine synthe-sis); JAK2 in triple-negative and poten-tially other breast cancers; androgen receptors in HER2-positive breast can-

Another approach is the combination of trastuzumab plus lapatinib used in the phase III NeoALTTO trial in women with HER2-positive primary breast can-cer.5 This trial demonstrated that the combination of trastuzumab plus lapa-tinib is more efficacious in achieving pCR compared with lapatinib alone.

A Novel Approach to Combin-ing a HER2-Targeted Drug With Chemotherapy Another promising agent for HER2-positive disease is T-DM1 (trastuzum-ab emtansine, Genentech). This novel therapeutic is an antibody drug conju-gate that combines trastuzumab with the chemotherapy agent DM1 through a linker designed to stabilize the anti-body-chemotherapy combination. The goal is for the T-DM1 to specifically reach its HER2 target without signifi-cant off-target effects, as occur with the administration of chemotherapy.

Results of a phase II trial, presented at the San Antonio Breast Cancer Sympo-

sium (SABCS), in December 2011, com-pared the combination of trastuzumab plus docetaxel with T-DM1 in HER2-positive metastatic breast cancer as a first-line therapy. T-DMI significantly improved PFS (median PFS for trastu-zumab/docetaxel was 9.2 mo vs 14.2 mo for T-DM1; HR = 0.594; P = .0353) com-pared with the trastuzumab/docetaxel combination. Toxicity was significantly less with T-DM1, presumably because the chemotherapy was delivered spe-cifically to HER2-expressing tumors.

T-DM1 has since shown efficacy in a phase III trial. Roche, Genentech’s parent company, announced at the end of March that the phase III EMILIA trial in 991 pa-tients met one of its primary endpoints: T-DM1 showed a significant improvement in PFS. The overall data for the trial are still immature. The trial compared T-DM1 therapy to a combination of capecitabine and lapatinib. The full trial results will be presented as a late-breaking abstract at the plenary session of the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting to be held in June

cer; and Src in trastuzumab resistance. The use of large-scale siRNA screens

to identify and validate targets is also under way. Translational research has recently facilitated research to over-come endocrine therapy resistance, overcoming HER2-targeted therapy re-sistance, and classification and progno-sis in triple-negative breast cancer.

Over the next five years, therapy will be increasingly based on genome se-quencing, said Leyland-Jones. As the cost of sequencing keeps dropping, ge-netic analysis of a patient’s tumor could become routine, with results available as quickly as two weeks.

While the approach to treatment of breast cancer continues to rapidly evolve, and our understanding of the drivers of the disease increase, there is still a long way to go. Many more aca-demic studies are needed on the genet-ics of breast cancer—particularly on un-derstanding the many types of diseases within the current category of triple-negative breast cancer. TTN

References1. Curtis C, Shah SP, Chin SF, et al. The genomic

and transcriptomic architecture of 2,000 breast

tumours reveals novel subgroups [published

online ahead of print April 18, 2012]. Nature. 2012.

doi:10.1038/nature10983.

2. Birkbak N, Wang ZC, Kim J-Y, et al. Telomeric allelic

imbalance indicates defective DNA repair and sen-

sitivity to DNA-damaging agents. Cancer Discovery.

2012. doi: 10.1158/2159-8290.CD-11-020.

3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and

safety of neoadjuvant pertuzumab and trastuzum-

ab in women with locally advanced, inflammatory,

or early HER2-positive breast cancer (NeoSphere):

a randomised multicentre, open-label, phase 2

trial [published online ahead of print December 6,

2011]. Lancet Oncol. 2012;13:25-32.

4. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus

trastuzumab plus docetaxel for metastatic breast

cancer [published online ahead of print December

7, 2012]. N Engl J Med. 2012;366:109-119.5. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib

with trastuzumab for HER2-positive early breast

cancer (NeoALTTO): a randomised, open-label,

multicentre, phase 3 trial [published online ahead

of print 17 January 17, 2012]. Lancet. 2012;379:633-

640. doi:10.1016/S0140-6736(11)61847-3.


31

“HER2-HER3 dimerization is a particularly important aspect of HER2 signaling, as these dimers potently signal to the PI3K survival pathway and are the main mechanism driving HER2-positive cancers.”—Carlos L. Arteaga, MD

JAK targeted to make a difference

Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

150

100

50

0

-50

-100

Ch

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e Fr

om

Bas

elin

e (%

)

IMP

RO

VE

ME

NT

WO

RS

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50% Improvement

Upper 50th Percentile Upper 50th Percentile

Placebo (n = 145)Jaka� (n = 145)



80

60

40

20

0

-20

-40

-60

-80

Ch

ang

e Fr

om

Bas

elin

e (%

)

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

IMP

RO

VE

ME

NT

WO

RS

EN

ING

35% Reduction

Jaka� ™ (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

JAK2

JAK1

* Intermediate or high-risk MF.

REDUCEsplenomegaly and symptoms of MF

REGULATEJAK signalingJAK signaling

References: 1. Jaka� Prescribing Information. Incyte Corporation. November 2011. 2. Data on � le. Incyte Corporation.

Jaka� is a trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved. RUX-1008U 05/12

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jakafi can cause hematologic adverse reactions,

including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

Please see Brief Summary of Full Prescribing Information on the following page.

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions. Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

and initiate appropriate treatment promptly• A dose modifi cation is recommended when administering Jakafi

with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modi� ed Myelo� brosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jaka� group and 16.5 in the placebo group.1,2

Jaka�

At Week 24, signi� cantly more patients receiving Jaka� vs placebo had

— A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a

— A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b

Reductions in spleen volume and improvements in TSS were seen with Jaka� in both JAK2V617F-positive patients and JAK2V617F-negative patients, relative to placebo2

Visit www.jaka� .com/explorefor more information on Jaka� and MF, plus valuable educational resources.

Jaka� demonstrated superior reductions in spleen volume andimprovements in symptom scores at Week 241,2,a,b

In these charts, each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

73934ha_c.indd 1 5/9/12 10:21 PM

JAK targeted to make a difference

Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

150

100

50

0

-50

-100

Ch

ang

e Fr

om

Bas

elin

e (%

)

IMP

RO

VE

ME

NT

WO

RS

EN

ING

50% Improvement





80

60

40

20

0

-20

-40

-60

-80

Ch

ang

e Fr

om

Bas

elin

e (%

)

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

IMP

RO

VE

ME

NT

WO

RS

EN

ING

35% Reduction

Jaka� ™ (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

JAK2

JAK1

* Intermediate or high-risk MF.

REDUCEsplenomegaly and symptoms of MF

REGULATEJAK signalingJAK signaling

References: 1. Jaka� Prescribing Information. Incyte Corporation. November 2011. 2. Data on � le. Incyte Corporation.

Jaka� is a trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved. RUX-1008U 05/12

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jakafi can cause hematologic adverse reactions,

including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

Please see Brief Summary of Full Prescribing Information on the following page.

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions. Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

and initiate appropriate treatment promptly• A dose modifi cation is recommended when administering Jakafi

with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modi� ed Myelo� brosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jaka� group and 16.5 in the placebo group.1,2

Jaka�

At Week 24, signi� cantly more patients receiving Jaka� vs placebo had

— A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a

— A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b

Reductions in spleen volume and improvements in TSS were seen with Jaka� in both JAK2V617F-positive patients and JAK2V617F-negative patients, relative to placebo2

Visit www.jaka� .com/explorefor more information on Jaka� and MF, plus valuable educational resources.

Jaka� demonstrated superior reductions in spleen volume andimprovements in symptom scores at Week 241,2,a,b

In these charts, each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

73934ha_c.indd 1 5/9/12 10:21 PM

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3%Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.A complete blood count must be performed before initiating therapy with Jakafi [see Dosage andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040

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Research Profile 35

Hsp90 is recognized as a crucial facilitator of oncogene addiction and

cancer cell survival.—Leonard M. Neckers, PhD

Leonard M. Neckers, PhD

TTN: What role does Hsp90 play in nor-mal cells?Molecular chaperones help nascent polypeptides fold correctly and multi-meric protein complexes assemble pro-ductively, while minimizing the dan-ger of aggregation in the protein-rich intracellular environment. Heat shock protein 90 (Hsp90) is an evolutionarily conserved molecular chaperone that participates in stabilizing and activat-ing more than 200 proteins—referred to as Hsp90 “clients”—many of which are essential for constitutive cell signal-ing and adaptive responses to stress. To accomplish this task, Hsp90, the chaperone Hsp70, and additional pro-teins termed co-chaperones form the dynamic complex known as the Hsp90 chaperone machine.

TTN: How is Hsp90 implicated in the de-velopment of cancer?Cancer cells use the Hsp90 chaper-one machinery to protect an array of mutated and overexpressed oncopro-teins from misfolding and degradation. Hsp90 is recognized as a crucial facili-tator of oncogene addiction and cancer cell survival.

TTN: How has the role of Hsp90 been exploited in cancer research and drug development?Like the prototypic Hsp90 inhibitor gel-danamycin (which was identified in 1994), Hsp90 inhibitors currently under clinical evaluation interact with Hsp90’s N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cy-cle, leading to client protein degradation.

Hsp90 inhibitors have proven to be very useful as probes of Hsp90 func-tion in both normal and cancer cells. Progress has been made in the clinical evaluation of targeting Hsp90 in can-cer. Patient selection based on tumor molecular characterization indicating

heightened dependence on Hsp90 and sensitivity to Hsp90 inhibition is prov-ing fruitful, as exemplified by RECIST re-sponses in a recent clinical trial involv-ing patients whose non-small cell lung cancers expressed EML4-ALK fusion protein, and in a trial involving HER2-positive breast cancer patients.

Another strategy that has shown promising results is the combination of Hsp90 and proteasome inhibitors to treat multiple myeloma. The first Hsp90 inhibitor, 17-AAG (tanespimycin), en-tered clinical trials in 1999. In 2004, a second Hsp90 inhibitor, 17-DMAG (al-

vespimycin), entered a first-in-human study. Owing to extensive efforts in ra-tional drug design and discovery, 13 ad-ditional Hsp90 inhibitors are currently undergoing clinical evaluation in cancer patients. Ten of these agents have en-tered the clinic in the past three years.

TTN: Can Hsp90 be used as a biomarker or prognostic indicator in cancer?Numerous published studies have re-ported elevated Hsp90 expression to be a characteristic of cancer cells in vivo. Further, a recent study reported a signif-icant inverse correlation between pro-longed survival and tumor Hsp90 level in patients with non-small cell lung

cancer. Studies are now in progress to confirm the link between tumor Hsp90 expression and tumor grade.

TTN: What is the future of research with regard to our understanding of Hsp90 or the development of Hsp90-targeted can-cer therapy?Although many Hsp90 clients are on-cogenes, and many of the compensa-tory mechanisms used by tumors to overcome other molecularly targeted and cytotoxic therapies are vulnerable to Hsp90 inhibition, it is now apparent that Hsp90 is also a key regulator of host

cell biology at the systems level. These systemic effects can either enhance or antagonize the antitumor activity of Hsp90 inhibitors in cancer patients.

Studies of the impact of targeted ther-apy in oncology trials have tended to fo-cus on the predicted effects of the drug on the tumor without consideration of the impact of therapy on the host, and the evaluation of Hsp90 inhibitors is no exception. As we move forward in de-veloping these agents, it will be critical-ly important to consider the impact of Hsp90 inhibitors on the patient as well as on the tumor, in order to identify the most fruitful indications for Hsp90 in-hibitor therapy in oncology. TTN

Leonard M. Neckers, PhD, is chief of the Tumor Cell Biology Section, Urologic Oncology Branch of the National Cancer Institute, Rockville, Maryland. His lab has been studying the role of the molecular chaperone Hsp90 in signal transduction and the translational development of Hsp90-targeted anticancer agents for two decades. Research con-ducted in his laboratory uncovered the importance of Hsp90 in the growth and survival of cancer cells and led to the first clinical trials of Hsp90 inhibitors. Targeted Therapy News spoke with him about the role of his work in cancer research.Leonard M. Neckers, PhD


Trials in ProgressTargeted Therapy

The Trials in Progress section is intended to stimulate discussion about ongoing clinical trials and to promote collaboration across the oncology community. Each issue, Targeted Therapy News will present summaries of ongoing research in a broad range of cancer types.

Breast CancerEndocrine Therapy With or Without Anti-VEGF Therapy for Advanced Breast CancerThis phase III study will examine the use of tamoxifen or letrozole alone or combined with beva-cizumab in women with hormone receptor-positive stage III or IV breast cancer. Participants will be randomized to receive either tamoxifen citrate or letrozole once daily on days 1 to 21 or tamoxifen or letrozole once daily on days 1 to 21 plus bevacizumab intravenously (IV) on day 1. In both arms, treatment is repeated every 21 days in the absence of disease progression or unac-ceptable toxicity. The primary outcome measures include progression-free survival, the rate of adverse events (especially stroke, proteinuria, thrombosis, and hypertension in patients treated with tamoxifen), and toxicity. The target recruitment for the study is 502 patients.Sponsor: Cancer and Leukemia Group B ClinicalTrials.gov Identifier:NCT00601900

Lung CancerSunitinib Maintenance Therapy in Advanced Lung CancerThis phase III study is comparing sunitinib with placebo as maintenance therapy in patients with stage IIIB or IV non-small cell lung cancer who have stable or responding disease after prior treatment with 4 courses of platinum-based chemotherapy. Participants are stratified according to ECOG performance status, disease stage, prior treatment with bevacizumab, and gender. After the completion of treatment, patients will be followed every 3 months for 1 year, every 6 months for 1 year, and periodically for 3 years. The primary outcome measure is progression-free survival. Secondary outcome measures include grade and type of toxicity, response rate, and overall survival. The study has a target recruitment of 244 patients. Sponsor: Cancer and Leukemia Group BClinicalTrials.gov Identifier: NCT00693992

Renal CancerSunitinib or Placebo for Patients at High Risk of Recurrent Renal Cell Cancer This phase III study is comparing sunitinib with placebo as adjuvant treatment in patients at high risk of recurrent kidney cancer per modified University of California Los Angeles Integrated Staging System (UISS) criteria after surgery. Subjects are Eastern Cooperative Oncology Group (ECOG) grade 0 to 2 and have predominant clear cell histology. In addition, they have not undergone prior anti-cancer treatment but have had their kidney tumor removed with no evidence of macroscopic disease following surgery. Approximately 720 patients will be randomized to sunitinib 50 mg PO or placebo on a 4/2 schedule: 4 weeks on, 2 weeks off for 1 year or until disease recurrence or occurrence of a secondary malignancy, significant toxicity, or withdrawal of consent. The primary outcome measure is disease-free survival. Investigators will also determine overall survival, safety, tolerability, and patient-reported outcomes. Sponsor: Pfizer ClinicalTrials.gov Identifier: NCT00375674

Axitinib (AG-013736) for the Treatment of Metastatic Renal Cell CancerThe phase III study is designed to determine whether axitinib is superior to sorafenib in delaying tumor progression in patients with metastatic renal cell cancer. Participants are required to have histologically documented metastatic renal cell cancer with a component of clear cell histology and evidence of measurable disease. They cannot have received prior systemic first-line therapy or must have progressive disease per Response Evaluation Criteria In Solid Tumors (RECIST) - version 1.0 after one prior systemic first-line regimen for metastatic disease containing sunitinib, cytokine(s), or both. Subjects will be randomized to axitinib at a starting dose of 5 mg bid with continuous dosing or sorafenib at a dose of 400 mg bid with continuous dosing. The primary outcome measure is pro-gression-free survival. Secondary outcome measures include overall survival, response rate, safety and tolerability, duration of response, and kidney-specific symptoms and health status. Sponsor: PfizerClinicalTrials.gov Identifier: NCT00920816

Hematologic CancerLenalidomide and Dexamethasone With or Without Bortezomib in Multiple Myeloma This phase III study will determine the efficacy of lenalidomide and low-dose dexamethasone with or without bortezomib for induction in patients with previously untreated multiple myeloma. Patients are stratified according to the International Staging System and intent to undergo transplantation at relapse. The primary outcome measure is progression-free survival. Secondary outcome measures include re-sponse rates, overall survival, and the correlation of genetic polymorphisms with biology and prognosis. In both arms, patients who intend to undergo transplantation at relapse undergo peripheral blood stem cell collection, preferably after course two. The study has an estimated enrollment of 440 patients.Sponsor: Southwest Oncology GroupClinicalTrials.gov Identifier: NCT00644228

Rituximab and Combination Chemotherapy for Diffuse Large B-Cell Non-Hodgkin Lymphoma This phase III study will compare R-CHOP (rituximab, cyclophosphamide, doxorubicin, vin-cristine, and prednisone) with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in patients with previously untreated, histologi-cally confirmed de novo diffuse large B-cell non-Hodgkin lymphoma. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years. The primary outcome measure is event-free survival 5 years after completion of study treatment. Secondary outcome measures include R-CHOP and dose-adjusted-EPOCH-R molecular predictors of outcome as measured by cDNA microarray 5 years after completion of study treatment. A total of 478 patients will be recruited for the study. Sponsor: Cancer and Leukemia Group BClinicalTrials.gov Identifier: NCT00118209

Head and Neck CancerEfficacy of Reolysin with Paclitaxel and Carboplatin in Platinum-Refractory Head and Neck CancerThis phase III study is comparing intravenous administration of Reolysin (Reovirus Serotype 3 Dearing) combined with paclitaxel and carboplatin or chemotherapy treatment alone in pa-tients with metastatic or recurrent squamous cell carcinoma of the head and neck who have progressed on or after prior platinum-based chemotherapy. Reolysin is an unmodified oncolytic reovirus that selectively replicates in Ras-activated cancer cells while not causing any significant human illness in its wild form. The primary outcome measure is overall survival. Patients will be evaluated clinically after each treatment course and radiologically every 6 weeks during and after treatment. The safety of the paclitaxel and carboplatin with intravenous blinded placebo or intra-venous blinded Reolysin will also be assessed. The study aims to recruit 280 patients.Sponsor: Oncolytics Biotech ClinicalTrials.gov Identifier: NCT01166542

Prostate CancerOral MDV3100 in Chemotherapy-Naïve Patients with Metastatic Prostate Cancer This phase III study will test the efficacy and safety of the novel androgen signaling inhibitor MDV3100 in chemotherapy-naïve patients who have progressive metastatic prostate cancer despite androgen depriva-tion therapy (ADT) as defined by rising prostate specific antigen levels or progressive soft tissue or bony disease. Study participants are asymptomatic or mildly symptomatic from prostate cancer. The primary outcome measures are overall survival and progression-free survival. Secondary outcome measures are time to first skeletal-related event and time to initiation of cytotoxic chemotherapy. An estimated 1680 men will participate in the study, which has a targeted primary completion date of September 2014.Sponsor: Medivation, IncClinicalTrials.gov Identifier: NCT01212991

36

Are you getting the full picture?

At diagnosis of metastatic colorectal cancer (mCRC)

Name: George Age: 58 Cancer: mCRC Specialty: Storyteller Biomarker Status:

Not an actual patient.

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T e s T T o p l a n

At diagnosis of mCRC, testing a patient’s tumors for biomarkers can help determine predictive and/or prognostic information1

Colorectal cancer is the 3rd leading cause of cancer death in men and women in the U.S.2

Understanding the patient’s biomarker profile helps define the characteristics of the patient’s disease and their overall prognosis.1 Knowing a patient’s biomarker status at diagnosis may help guide clinical decisions.3,4

Understanding the biomarker pathways involved in mCRC tumorigenesis can help inform appropriate treatment planning.3,5,6

KRAS and BRAF signaling are involved with colorectal tumorigenesis and tumor progression3

The KRAS gene may be mutated or wild-type. When KRAS is mutated, it is permanently switched on, whereas wild-type KRAS protein is activated when the EGFR is stimulated.3,5 Increased BRAF signaling may occur due to mutations in the BRAF gene.5 BRAF mutations are limited to those tumors that do not have KRAS exon 2 mutations.7

EGFR = epidermal growth factor receptor. *In a CLIA-certified laboratory.

References: 1. Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. 2. American Cancer Society. Cancer Facts & Figures: 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveillance/documents/document/acspc-029771.pdf. Accessed March 1, 2012. 3. Monzon FA, Ogino S, Hammond EH, et al. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med. 2009;133(10):1600-1606. 4. Grossman AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy. Arch Pathol Lab Med. 2011;135:1278-1282. 5. Krasinskas AM. EGFR signaling in colorectal carcinoma. Pathol Res Int. 2011;2011:1-6. http://www.hindawi.com/journals/pri/2011/932932/cta. Accessed January 6, 2012. 6. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Accessed March 15, 2012.

©2012 Bristol-Myers Squibb. All rights reserved. 693US12AB00111 04/12 Printed in USA.

Testing of biomarkers at diagnosis of mCRC is important for treatment planning3,7*

Are you getting the full picture?

Name: George Age: 58 Cancer: mCRC Specialty: Storyteller Biomarker Status:

693US12AB00111 Trim size: 10.75” x 13” Publication:693US12AB00111_BioMarker_Advertorial_10.75x13.indd 2 5/17/12 7:28 PM

Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]Surgery and Wound Healing ComplicationsThe incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 GlioblastomaAvastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

1.4 Metastatic Renal Cell Carcinoma (mRCC)Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing ComplicationsAvastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 HemorrhageAvastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non‑Gastrointestinal Fistula FormationSerious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic EventsSerious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy

was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 HypertensionThe incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion ReactionsInfusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian FailureThe incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

• Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1 Clinical Trial 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 below reflect exposure to Avastin in 3795 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing ComplicationsThe incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

73523ha_lota.indd 1 2/14/12 11:35 AM

Evidence-Based Oncology


40Targeted Therapy

Before the oncology treatment par-adigm can move from a one-size-fits-all model to true personalized

medicine, the medical establishment must find a cost-effective way to iden-tify biomarkers that determine which therapies patients should receive.

That is the message in a recent report by two Colorado researchers who per-formed a cost-effectiveness analysis of targeted therapies for lung cancer, us-ing the biomarker ALK and the targeted therapy crizotinib (Xalkori, Pfizer) to build their model.

In the analysis, published recently in the British Journal of Cancer, the re-searchers found that costs rose consid-erably as more people were tested who didn’t have the biological abnormality being sought. However, when the re-searchers controlled costs by applying methods to target patients for screen-ing who were more likely to test posi-tive, they missed a significant propor-tion of the patients who could have benefited from targeted therapy.1

D. Ross Camidge, MD, PhD, who per-formed the analysis with Adam J. Ather-ly, PhD, said that cost-effectiveness of screening has to be considered when de-termining the costs of treatment with tar-geted therapy, and that the high costs of a “test-everyone” approach may not be fea-sible in today’s healthcare environment.

“The big advances in lung cancer (and many other cancers) have come from not giving one drug to everyone, but develop-ing tests to find out in advance who will get maximal benefit from the drug. If you don’t, the average benefit is very poor. However, the cost of testing now has to be factored into the calculations of de-termining the cost-effectiveness of any drug used in this way. Bringing down the cost per positive is essential,” explained Camidge, who was involved in early re-search for the development of crizotinib and helped to develop one of the assays used to test for the ALK gene alteration.

“Assuming you only treat those who come up positive on a test, your cost-effectiveness goes down as you screen more people who don’t have the abnor-mality you are looking for. It increases the up-front costs of finding those positives,” Camidge said. “For a $1000 test, if the

group you screen has a 50% hit rate, you have to add $2000 to the costs of treating every patient. If it is 1%, you have to add $100,000 up front as the money you spend to find even one patient who is positive.

“For me, the message is to the wider community of doctors, insurers, health-care providers, and patients. Break-throughs will not be feasibly applicable unless we make the cost-effectiveness realistic.”

In the initial modeling, the researchers explored a range of costs, assuming that costs would vary over time. They found that, if all patients with advanced non–small cell lung cancer were screened for ALK, and the assay cost around $1400, screening would be $106,707 per quality-adjusted life-year (QALY) before any drug-related costs were considered. If the pop-ulation could be narrowed to only those more likely to test positive, the QALY cost would fall to $4756. However, physicians would miss more than half the patients who would benefit from treatment.

“When you start to think like this, the cost-effectiveness of these break-throughs becomes a real problem,” Camidge said. “We can either enrich the population being screened by other means but run the risk of missing some people, or bring down the cost of find-ing each positive patient, such as by re-ducing the cost of the individual test or multiplexing the tests so you get more positives (even if in different markers) per dollar spent.” TTN

Reference1. Atherly AJ, Camidge DR. The cost-effectiveness

of screening lung cancer patients for targeted

drug sensitivity markers. Br J Cancer. 2012;

106(6):1100-1106. doi:10.1038/bjc.2012.60.

Breakthroughs in Targeted Therapies Not Applicable If Not Cost-EffectiveBy Marie Rosenthal, MS

D. Ross Camidge, MD, PhD

HemorrhageThe incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic EventsThe overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Neutropenia and InfectionThe incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%.

ProteinuriaGrade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).]

Congestive Heart FailureThe incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer MBC, an indication for which Avastin is not approved, the incidence of Grade 3–4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Metastatic Colorectal Cancer (mCRC)The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL ++ Placebo IFL ++ Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7

(Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 );

tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaMusculoskeletal: Osteonecrosis of the jawRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphoniaSystemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive PotentialAvastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

01/12 AVA000076590110127309

Initial U.S.Approval: February 2004Code Revision Date: December 2011Avastin® is a registered trademark

of Genentech, Inc. ©2012 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

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Think AvastinBecause anti-angiogenesis mattersAvastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

To confront a common threat across approved indications...

Clinically meaningful activity in 4 distinct tumor types1

VEGF=vascular endothelial growth factor. * The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

IndicationsAvastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS Gastrointestinal (GI) perforation

— Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls

— The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal

complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is

fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined

— Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention

Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central

nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%

— Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood)

— Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included

— Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included

— Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were

— Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage

Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin

For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection

In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

†Avastin is not approved for use in combination with irinotecan.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information. Genentech, Inc. December 2011.

www.avastin.com©2012 Genentech USA, Inc. All rights reserved. AVA0000488401 Printed in USA. (01/12)

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