Transcript
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Pan-ErbB blocker tops standard chemo
in lung cancer
CASE STUDY
Capecitabine
in advancedgastric cancer
NEWS
Asian study unveilsmechanism of HBV
integraon in HCC
CONFERENCE
Beer strategies neededfor ALL in adolescents
and young adults
INDUSTRY UPDATE
First-line temsirolimus
improves survival in
poor-prognosis
mRCC paents
June 2012July- August 2012
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Pan-ErbB blocker tops standard chemo in
lung cancer
Christina Lau
Afatinib, an investigational drug that
irreversibly blocks EGFR (ErbB1),
HER2 (ErbB2), HER3 (ErbB3) and
HER4 (ErbB4), signicantly extended pro-
gression-free survival (PFS) vs pemetrexed
plus cisplatin in the largest phase III trial in
EGFR mutation-positive advanced lung ade-
nocarcinoma. [ASCO 2012; abstract LBA7500]
The oral pan-ErbB inhibitor was particu-
larly benecial for patients with deletion 19
or L858R common mutations that together
accounted for 89 percent of all EGFR muta-
tions in the trial.
Unlike reversible EGFR tyrosine kinase
inhibitors such as getinib and erlotinib,
afatanib blocks the entire ErbB family of
receptors permanently, said lead inves-
tigator Dr. James Yang of the National Tai-
wan University Hospital. While getinib
and erlotinib have demonstrated signicant
benets vs rst-line chemotherapy, LUX-
Lung3 is the rst trial in EGFR mutation-pos-
itive lung cancer to use pemetrexed/cisplatin
as a chemotherapy comparator.The global trial included 345 treatment-
nave patients from 25 countries who had
stage IIIB (wet) or IV disease (median age,
61 years; ECOG performance status, 0-1;
East Asians, 72 percent; never-smokers,
68 percent). Patients were randomized
2:1 to receive afatinib (40 mg) once daily
or pemetrexed (500 mg/m2) plus cisplatin
(75 mg/m2
) q21d until progression.The trial met its primary endpoint of PFS.
Aer a median follow-up of 8 months, patients
receiving afatinib had a signicant 4.2-month
improvement in PFS. Median PFS was 11.1
months with afatinib vs 6.9 months with
pemetrexed/cisplatin [hazard ratio (HR), 0.58;
p=0.0004], Yang reported. Twelve-month
PFS rate was 47 vs 22 percent.
Importantly, the PFS benet of afatanib
was consistent in all relevant subgroups, in-
cluding gender, age at baseline, race (Asian
or non-Asian), baseline ECOG performance
status, and smoking history (never smoked,
or smoked 1
year).
The benet of afatinib was even great-
er in patients with deletion 19 or L858RV
[n=308], he continued. In these patients,
afatinib doubled PFS to 13.6 months vs 6.9
months with pemetrexed/cisplatin [HR, 0.47;
p
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Cancer drug shortages a global problem
Naomi Rodrig
The European Hematology Association
(EHA), the American Society of Hema-
tology (ASH) and the European Can-
cer Patient Coalition (ECPC) issued a joint call
to action to address the looming crisis of can-
cer drug shortage. The announcement, issued
at the recent 2012 EHA Congress, comes onthe footsteps of the American Society of Clini-
cal Oncology (ASCO) 2012 Annual Meeting,
which also highlighted the problem.
According to ASCO ocials, disrupted
manufacturing and quality control are the
main culprits behind the shortages that have
le many cancer patients without necessary
treatments. Were never sure when a generic
drug is suddenly going to go out of supply,said Dr. Richard Schilsky, Chair of the ASCO
Government Relations Commiee.
Hundreds of drugs have been in short sup-
ply in the US over the past year, including
methotrexate, used frequently for leukemia;
liposomal doxorubicin, which treats ovarian
cancer; paclitaxel, used in a variety of cancers;
mustargen, used to treat lymphoma; and 5-u-orouracil (5-FU), a key component of adjuvant
therapy for colorectal and other cancers.
The situation in Europe seems to be
even more serious. In the US, legislation is
under way that may curb drug shortages,
but in Europe we do not even have a proper
understanding of the scope of the problem,
remarked EHA President, Dr. Ulrich Jager.
The US FDA is draing legislation requir-ing mandatory 6-month advance notication
cent], paronychia [11.4 vs 0 percent], and dry
skin [0.4 vs 0 percent], said Yang. These
adverse events were as expected with EG-
FR-targeting therapies, and were manage-
able and reversible. It is also important tonote that patients in the afatinib arm re-
ceived 16 cycles of therapy, vs 6 cycles in the
pemetrexed/cisplatin arm.
In LUX-Lung3, only 7.9 percent of
patients discontinued afatinib due to treat-
ment-related adverse events (vs 11.7 per-
cent with pemetrexed/cisplatin), and onlyabout 1 percent discontinued the drug due to
diarrhea.
PERSPECTIVESDr. Kwok-Chi LamDepartment of Clinical Oncology, Prince of Wales Hospital
The LUX-Lung3 trial has echoed what we have seen in other randomized phase III trials, with consistent HR or
progression-ree survival. It is dicult to compare the treatment ecacy o dierent EGFR TKIs across dierent trials.Aatinib can be one o the treatment options or patients with EGFR mutation-positive tumors. We might know which
EGFR TKI is better as results o the LUX-Lung7 trial (comparing aatinib with geftinib in EGFR mutation-positive che-
monave non-small cell lung cancer) become available in uture.
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Increasing numbers of high-quality cancer genetics studies conducted in Asia are mak-
ing it into prestigious journals, arming the regions position as an upcoming hub of
advanced oncology research.
In the current issue, we report three stories of innovative research from Asia, as inves-
tigators from Hong Kong, China and Singapore are shedding new light on carcinogenesispathways. One of the studies focused on reversal of apoptosis, which may induce oncogenic
transformation in various cell types, while the others looked at specic cancers hepatocel-
lular carcinoma and an aggressive type of lymphoma that is common in China and Korea.
The expanding industry funding for basic research in Asia also reects increasing con-
dence in its quality as well as a fresh enthusiasm for long-term R&D investment in the region.
Although many of these studies are still at the preclinical stage, some may eventually lead to
new therapeutic or diagnostic products. The global pharma industry is now willing to stay
the course, which may give an even greater boost to Asian medical and life-science research.
The Editor
Big strides in cancer genetics researchin Asia
by drug companies for withdra-wals or man-
ufacturing interruption, with penalties for
non-reporting. Early alerts may enable gov-
ernment agencies to source the same or alter-native drugs from overseas manufacturers.
The situation in Europe is undoubt-
edly more complex. We are not one country;
we are 27 countries, each with its own rules
and regulations, noted Dr. Anton Hagen-
beek, The Netherlands, who emphasized that
drug supply and pricing are subject to gov-
ernment policies.
Asian countries have not been spared ei-ther. In my opinion, cancer drug shortage is
a global problem, and Hong Kong is aected
as well, commented Dr. Carol Kwok of the
Department of Oncology, Princess Margaret
Hospital. Just a few months ago, three com-
monly used cytotoxic drugs doxorubicin,
epirubicin and 5-FU were out of supply in
HA hospitals. The solution was substitution;
for example, epirubicin was used to substitute
doxorubicin and vice versa. For 5-FU, we usedother brands.
While the supply of these drugs has been
back to normal now, liposomal doxorubi-
cin, which is commonly used in second-line
treatment of recurrent ovarian cancer, has
been out of supply for almost a year. We
have to use topotecan, a more toxic drug,
for this indication, she said.
I guess the main reason for the shortagesis on the manufacturing side, such as lack of
raw materials. In other situations, the drug
company ceased to produce the drug because
it is not commonly used, such as mitotane for
adrenocortical carcinoma, a very rare can-
cer, Kwok suggested.
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Asian study unveils mechanism of HBV
integration in HCC
Naomi Rodrig
The Asian Cancer Research Group
(ACRG) in collaboration with the
Shenzhen-based genomics company
BGI recently published the results of a ge-
nome-wide study unveiling the mechanism of
recurrent hepatitis B virus (HBV) integration
in hepatocellular carcinoma (HCC) genomes.[Nature Genetics 2012. DOI: 10.1038/ng.2295]
HBV integration is thought to be one of
the major causes underlying HCC develop-
ment, as previous studies have shown that
it may induce chromosomal instability, lead-
ing to carcinogenesis and tumor recurrence.
However, this is the rst whole-genome se-
quencing study to systematically investigate
the breakpoints of HBV DNA and the humangenes which are aected by such integration
in a large sample of 88 pairs of HCC tumor
and non-tumor liver tissue obtained from 88
patients operated at Queen Mary Hospital
[QMH], said Professor Ronnie Poon, Chief
of the Division of Hepatobiliary & Pancreatic
Surgery at the University of Hong Kong (HKU)
who was one of the study investigators. The
study was initiated by Dr. John Luk, a corre-sponding author of the paper, when he was
working at HKU. He subsequently moved to
the National University of Singapore where
he recruited talents in bioinformatics analysis
for the project.
In the study, which enrolled 81 HBV-pos-
itive and seven HBV-negative patients with
HCC, HBV integration was observed more
frequently in tumors than in normal tissues
(86.4 vs 30.7 percent).
The researchers also identied a specic
region of the viral genome that is most com-
monly cleaved during integration into the
host genome. Approximately 40 percent of
HBV breakpoints within the HBV genome
were located at a 1,800-bp region where the
viral enhancer, X gene and core gene are lo-cated, they wrote.
In addition to the previously reported
human genes TERT and MLL4, they discov-
ered three novel genes associated with recur-
rent HBV integration CCNE1, SENP5 and
ROCK1. All these genes are known to play
an important role in cancer development and
progression, and showed upregulated expres-
sion in tumor vs normal tissue.Another observation was that the number
of HBV integration events was positively cor-
related with tumor size, and serum levels of
hepatitis B surface antigen (HBsAg) and al-
pha-fetoprotein.
The number of HBV integrations was also
associated with patient survival. Patients with
3 integrations, suggest-
ing that the number of integrations may be a
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prognostic indicator in HCC patients. This
is the rst study that correlated the HBV in-
tegration paerns with clinical outcome in
patients with HBV-related HCC, Poon toldOncology Tribune.
Notably, a higher frequency of HBV inte-
gration was observed in HCC patients who
were in their twenties or thirties, which may
explain the development of the tumors in
younger individuals without chronic hepati-
tis or cirrhosis.
According to Poon, over 6 percent of the 3,500
primary HCC cases who presented to QMH be-tween 2001 and 2010 were
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Reversal of apoptosis may drive carcinogenesis
Christina Lau
Arecent study from the Chinese Uni-
versity of Hong Kong (CUHK) dem-
onstrated that the process of apop-
tosis can be reversed even aer passing the
critical checkpoints of no return, which may
lead to genetic changes that contribute to car-
cinogenesis or resistance to cancer treatments.
[Mol Biol Cell 2012;23:2240-2252]
Accor ding to the researchers, this unan-ticipated rescue mechanism observed in both
normal and malignant cells may have impor-
tant applications in cancer treatment.
It is generally believed that apoptosis which
is a protective mechanism that eliminates dam-
aged cells through programmed cell death is
irreversible once cells pass certain checkpoints,
including cell shrinkage, mitochondrial frag-
mentation, nucleus condensation, DNA break-down and caspase-3 activation, said Professor
Ming-Chiu Fung of the Department of Biol-
ogy. Our previous work showed that human
cancer cells could evade the apoptotic process
even aer passing the presumed point of no re-
turn, and this may be one of the causes of can-
cer recurrence. [Br J Cancer 2009;100:118-122]
In their current study, Fung and colleagues
treated primary liver and heart cells, macro-phages, embryonic NIH 3T3 broblasts, cer-
vical cancer HeLa cells and brain cells with
apoptosis inducers.
Surprisingly, the vast majority of dying cells
arrested the apoptotic process and recovered
when the inducer was washed away.
More importantly, some cells acquired per-
manent genetic changes and underwent oncogen-
ic transformation aer the reversal of apoptosis,
Fung pointed out. In normal cells, these genetic
changes may cause new tumors to form aer can-
cer therapy. In cancer cells that undergo reversalof apoptosis aer treatment, new mutations may
develop, causing the cancer to become more
aggressive or metastatic.
The researchers proposed naming the rever-
sal of apoptosis as anastasis, a Greek term for
rising to life. While recent research indicates
that cancer stem cells [CSCs] are resistant to che-
motherapy and implicated in metastasis, our
observation is that anastasis occurs not only inCSCs, but also in most cancer cells, Fung told
Oncology Tribune. Further study is needed on
the relationship between CSCs and anastasis.
Although carcinogenesis represents a harm-
ful side eect of anastasis, anastasis may be con-
ducive to tissue repair and formation of new ge-
netic combinations. Our ndings suggest that
inhibiting anastasis may enhance the eect of
chemotherapy, while promoting anastasis mayfacilitate tissue recovery, said principal inves-
tigator Dr. Ho-Lam Tang of CUHKs School
of Life Sciences and John Hopkins University
School of Medicine.
For example, ongoing studies demonstrated
that genistein a predominant isoavone in soy-
bean with well-documented anticancer eects
could inhibit anastasis in cancer cells. This ef-
fect was observed at non-toxic concentrations of2.5-25 g/mL in our work with CUHKs Center
for Soybean Research, said Fung. Genistein
had a synergistic anti-cancer eect in combina-
tion with chemotherapy. Further investigation
will be carried out on the mechanism.
However, Fung warned against improper
use of herbal medicine with potential anti-
cancer properties, as they may drive cancer
progression or oncogenic transformation in
normal cells.
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Conference CoverageJul-Aug 20128
Better strategies needed for ALL in
adolescents and young adults
American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June 2012, Chicago, USA
Christina Lau
A
dolescents and young adults with
high-risk acute lymphoblastic leu-
kemia (ALL) have poorer survival
and higher toxicity from treatment than theiryounger counterparts, according to new data
from a major phase III study which highlights
the need for beer treatment strategies for
this group of patients. [Abstract CRA9508]
Historically, ALL patients older than 16
years have an inferior outcome compared
with patients aged 1 to 15 years because older
patients have higher rates of relapse and tox-
icity, said lead author Dr. Eric Larsen of theMaine Childrens Cancer Program in Scarbor-
ough, Maine, USA. In the Childrens Oncol-
ogy Group [COG] study ALL0232, we tested
dexamethasone vs prednisone during induc-
tion and high-dose methotrexate vs escalating
Capizzi methotrexate plus PEG asparaginase
during interim maintenance 1 in a 2 x 2 fac-
torial design. For the st time, patients aged
21-30 years were eligible for enrollment in anALL study.
ALL0232 enrolled patients with newly-di-
agnosed B-precursor high-risk ALL. Of 2,571
eligible patients, 501 (20 percent) were aged
16-30 years. This represents the largest co-
hort of adolescent and young adult ALL pa-
tients to date in a single clinical trial, he said.
At 5 years, patients aged 16-30 years had
signicantly poorer event-free survival (EFS)
and overall survival (OS) than those
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trial was to try to improve disease control in
the CNS.
Remission, dened as
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American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June 2012, Chicago, USA
Continuous androgen deprivation still
standard of care for prostate cancer
Yen Yen Yip
C
ontinuous androgen deprivation
remains standard of care in hor-
mone-sensitive metastatic prostate
cancer, according to a large multinationalphase III study. [Abstract 4]
Some doctors recommend intermient
hormonal therapy to men with metastatic pros-
tate cancer, believing it will reduce their risk of
side eects without compromising outcome,
but our ndings demonstrate a clear downside
to this approach for certain men, said lead in-
vestigator Dr. Maha Hussain from the Univer-
sity of Michigan, Ann Arbor, USA.The primary objective of the SWOG (South-
west Oncology Group) 9346 study, which
spanned 17 years, was to determine if inter-
mient androgen deprivation was non-inferi-
or to continuous therapy.
The study included more than 1,500 pa-
tients newly diagnosed with hormone-sen-
sitive prostate cancer, with prostate-specic
antigen (PSA) levels 5 ng/mL prior to initia-tion of androgen deprivation therapy, and a
SWOG performance status of 0 to 2. The sub-
jects were treated with goserelin and bicalu-
tamide for 7 months, and those who achieved
PSA 4 ng/mL at the 6th or 7th month were
then randomized to receive continuous or in-
termient therapy.
Aer a median follow-up of 9.2 years, the
primary endpoint of overall survival (OS) was
inferior in the intermient therapy group (5.1
years vs 5.8 years with continuous therapy; HR,
1.09). Among patients with minimal disease, OS
was signicantly beer for those who received
continuous therapy (7.1 vs 5.2 years; p=0.034).
However, in patients with extensive disease
spread, intermient and continuous therapieswere comparable.
Androgen deprivation therapy leads to sig-
nicant setbacks in quality of life, and is also
associated with increased fractures, decreased
cognitive function, increased risk of diabetes
and altered lipid proles. In addition, many
patients eventually progress to castration-re-
sistant disease, commented Dr. William Oh
from the Mount Sinai School of Medicine,New York, USA.
Previous preclinical data have suggested
that intermient therapy can re-induce apop-
tosis and prolong time to castration resistance.
[Cancer 1993;71:2782-2790]
The advantages of the intermient ap-
proach and its comparable ecacy were con-
rmed by at least 23 phase II trials, Oh noted.
However, these studies were essentially un-derpowered to evaluate survival.
The SWOG 9346 ndings will be practice
changing for many doctors who routinely use
intermient therapy, said Hussain.
Neither SWOG 9346 nor any randomized
trial has ever shown a superior cancer out-
come with intermient androgen deprivation
therapy, said Oh. This preclinical concept
[supporting intermient therapy] must no
longer be propagated.
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American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June 2012, Chicago, USA
Regorafenib offers hope for GIST patients
failing TKIs
Christina Lau
T
he multi-kinase inhibitor regorafenib
may represent the rst targeted treat-
ment option for patients with metastatic
and/or unresectable gastrointestinal stromaltumor (GIST) who progressed despite prior use
of both imatinib and sunitinib.
The phase III GRID (Regorafenib in Pro-
gressive Disease) trial included 199 patients
from 17 countries who failed at least imatinib
and sunitinib the only two drugs approved
for GIST worldwide. Patients were random-
ized to receive regorafenib 160 mg once daily
plus best supportive care (BSC) (n=133), orplacebo plus BSC (n=66), on a 3-weeks-on
1-week-o schedule. The trial was unblinded
on disease progression, when placebo-treated
patients were eligible for crossover to open-
label regorafenib and regorafenib-treated
patients continued on their treatment. On
the next progression, patients were taken o
treatment. [Abstract LBA10008]
The trial met its primary endpoint, withprogression-free survival [PFS] being four
times longer in the regorafenib arm. Median
PFS was 4.8 months for regorafenib vs 0.9
months for placebo [HR, 0.27; p
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Antidepressant relieves chemo-induced
neuropathic pain
American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, 1-5 June 2012, Chicago, USA
Yen Yen Yip
F
or the rst time, a randomized con-
trolled trial has found the serotonin-
norepinephrine reuptake inhibitor
(SNRI) duloxetine to be eective againstchronic neuropathic pain associated with tax-
ane- or platinum-based chemotherapy. [Ab-
stract CRA 9013]
In the study, duloxetine conferred a 30 per-
cent reduction in pain score for 33 percent of
patients. In the placebo group, only 17 percent
achieved a similar reduction in pain. A 30 per-
cent decrease in pain is clinically signicant
and important to patients, commented leadinvestigator Dr. Ellen Lavoie Smith, University
of Michigan School of Nursing, Ann Arbor,
USA.
A total of 220 patients with peripheral neu-
ropathic pain associated with paclitaxel or ox-
aliplatin were randomized to receive dulox-
etine (30 mg daily in the rst week, then 60 mg
daily for 4 weeks) or placebo.
Although mean pain scores fell in the pla-cebo group as well, patients who received du-
loxetine achieved a signicantly greater degree
of pain relief (p=0.003).
Overall, 59 percent of patients taking du-
loxetine achieved some degree of pain re-
lief vs 38 percent of placebo recipients. Pain
scores fell by half in 21 percent of patients onduloxetine vs 9 percent on placebo. However,
a small proportion of patients felt more pain
aer receiving treatment; fewer patients on
duloxetine experienced this eect compared
with the placebo group.
Not everyone responded to duloxetine,
Lavoie Smith said. Duloxetine... works by
increasing amounts of pain-inhibiting neu-
rotransmiers; we think patients who respondmay have some abnormalities in the way their
brain processes pain and we have to iden-
tify who might respond so we can target the
use of this drug.
The drug was generally well tolerated. Fa-
tigue, insomnia, nausea, somnolence and diz-
ziness were the most common adverse events.
Seven percent of recipients experienced se-
vere adverse events and 11 percent droppedout of the study as a result of side eects.
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ASCO 2012 Sa te l l i te Sympos iumJul-Aug 201214
Everolimus plus exemestane improves
PFS in advanced breast cancerUpdated data rom the BOLERO-2 trial
demonstrate that everolimus (Anitor, Novartis)
in combination with exemestane more than
doubled progression-ree survival (PFS) in women
with estrogen receptor positive (ER+), human
epidermal growth actor receptor 2-negative
(HER2-) advanced breast cancer who are resistant
to hormonal therapy. The data, presented at a Novartis-sponsored symposium held in
conjunction with the American Society o Clinical Oncology (ASCO) 2012 Annual Meeting,
conrm evidence rom previous analyses on the survival benets o adding everolimus to
exemestane.
Overcoming endocrine resistanceOver two-thirds o breast cancers
express the ER which contributes to tumor
growth and progression. Patients who are
ER+ benet rom endocrine therapeutic
agents, such as anti-estrogens that target
ERs. In postmenopausal patients, aroma-
tase inhibitors (AIs) are the rst-line treat-
ment choice. However, up to 25 percent o
all breast cancer patients do not respond
to endocrine therapy (de novo resistance),
whereas others will eventually relapse de-
spite an initial response due to either in-
trinsic or acquired resistance. [Clin Cancer
Res 2010;16:1979-1987] Molecular mech-
anisms o resistance are emerging. This
has led to the development o targeted
therapies. However, the challenge is to de-
ne which patients will most likely benet
rom these therapies, and which do not
need them, said Proessor Ian Smith o the
Royal Marsden Hospital and Institute o
Cancer Research in London, UK.
Everolimus: Targeting the PI3K/AKT/mTOR Pathway
Abnormalities in the phosphatidylinosi-
tol 3-kinase (PI3K)/AKT/mammalian target
o rapamycin (mTOR) pathway have been
implicated in several orms o human can-
cer. Activation o the AKT/mTOR pathway
leads to resistance to endocrine therapy
and their inhibition reverses the resis-
tance, explained Dr. Fabrice Andr o the
Institute Gustave Roussy Villejui, France.
Research on endocrine-resistant cells
showed that selective inhibitors o the PI3K/
AKT/mTOR pathway provide signicant
growth inhibition in long-term estrogen-
deprived breast cancer cells. [Nat Rev Drug
Discov2005;4:988-1004] Kinase activation
induced by long-term estrogen deprivation
and genomic alteration acquired during
the natural course o the disease may lead to
acquired resistance, said Andr.
We still have no idea how to identiy
patients who are resistant to endocrine
Pro. RugoDr. AndrPro. Smith
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ASCO 2012 Sa te l l i te Sympos iumJul-Aug 201215
therapy beore they relapse, or patients
who are more likely to respond to treat-
ments that may reverse resistance, said
Proessor Hope Rugo o the University o
Caliornia, San Francisco, USA.
Everolimus, an oral mTOR inhibitor, has
promising clinical activity in women with
HER2+, HER2-, and ER+ breast cancer when
combined with HER2-targeted therapy,
chemotherapy, and hormonal ther-
apy, respectively. [Pharmacotherapy
2012;32:383-396] The phase II TAM-
RAD trial, conducted by the Groupe
dInvestigateurs Nationaux pour lEtudedes Cancers Ovariens et du sein (GINECO
Group, France), was designed to evaluate
the ecacy and saety o everolimus in
combination with tamoxien vs tamoxien
alone in patients with hormone receptor-
positive (HR+), HER2- metastatic breast
cancer with prior exposure to AIs. Results
showed that addition o everolimus to
tamoxien delayed disease progressioncompared to tamoxien alone, with me-
dian time to disease progression o 8.6 vs
4.5 months. [Ann Oncol2012; 23(suppl 2):
ii17ii24; abstract 13O_PR]
BOLERO-2 studyBOLERO-2 (Breast cancer trials o OraL
EveROlimus-2) is an international, random-
ized phase III trial designed to evaluateeverolimus in combination with exemes-
tane vs exemestane alone in postmeno-
pausal women with ER+ HER2- advanced
breast cancer reractory to treatment with
nonsteroidal AIs (NSAIs) such as letrozole
or anastrozole. The study included 724 ad-
vanced breast cancer patients rom 189
sites worldwide. Eligible patients were ran-
domized (2:1) to exemestane (25 mg/day)with everolimus (10 mg/day) or placebo.
[Cancer Res 2011;71(24 suppl):abstract S3-
7; N Engl J Med2012;366:520-529]Updated results o an 18-month ollow-
up showed a median PFS o 7.8 months
or patients receiving exemestane plus
everolimus (n=485) (7.4 in the 12-month
ollow-up) vs 3.2 months or patients re-
ceiving exemestane alone (n=239). (Fig-
ure 1) An independent review showed a
PFS o 11 months in the combination arm
vs 4.1 months in the exemestane-onlyarm. Compared to 32.2 percent o patients
who died in the exemestane-only arm,
25.4 percent in the combination arm died.
[J Clin Oncol2012;30(suppl): abstract 559]
New subgroup analyses
The clinical benet o everolimus
was observed in all subgroups in the BO-
LERO-2 study. It is very encouraging thatthere are numerically ewer deaths in the
everolimus arm vs the placebo arm, and
this dierence has continued with the lat-
est analysis o data, said Rugo.
Delaying bone progression
Subgroup analysis showed that evero-
limus delayed bone progression in pa-
tients with or without bone metastasis atbaseline, said Rugo. The delay was more
Median PFS:
EVE + EXE: 7.8 months
PBO + EXE: 3.2 months
HR=0.45Log-rank p value
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ASCO 2012 Sa te l l i te Sympos iumJul-Aug 201216
signicant in patients with bone metastases
at baseline. [Eur J Cancer2012;48(suppl 1): ab-
stract LBA3]
NSAIs are associated with decrease inbone mineral density and increased risk o
ractures. Thereore, it is important to evalu-
ate whether new therapies in combination
with exemestane aect bone turnover. A
BOLERO-2 subanalysis evaluated the eect
o everolimus in combination with exemes-
tane vs exemestane alone on markers asso-
ciated with bone ormation and resorption.
Results showed that bone turnover markerswere reduced in the combination arm vs the
exemestane-alone arm during the rst 12
weeks o therapy, suggesting clinical benets
on bone health.
Maintaining quality o lie (QoL)
A subgroup o patients was assessed to de-
termine whether any disruption in health-re-
lated quality o lie (HRQoL) occurred with theeverolimus-exemestane combination. Re-
sults demonstrate that median time to deni-
tive deterioration in HRQoL was 8.3 months
or everolimus plus exemestane vs 5.8 or
exemestane alone, suggesting that adding
everolimus to exemestane maintained QoL
in the patients. (Figure 2) [Beck JT, et al. ASCO
2012; abstract 539]
In Asian patients
O 143 Asian patients in the BOLERO-2
study, 98 received everolimus plus exemes-
tane and 45 received exemestane alone. At
the time o database lock, 56 percent o Asian
patients in the combination arm had expe-
rienced disease progression vs 76 percent
in the exemestane-alone arm. Combination
therapy reduced the risk o disease progres-
sion by 44 percent vs exemestane alone
among Asian patients (HR=0.56; p
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201217
PISCES study: mRCC patients favor
pazopanib for better QoL
Pro.
Escudier
Pazopanib and sunitinib: Compa-rable ecacy, dierent saety
Pazopanib and sunitinib are both ap-
proved treatments or mRCC, with compara-
ble ecacy but dierences in terms o saety
prole, noted Escudier. An indirect compari-
son suggested that PFS rates associated
with pazopanib in treatment-nave subjects
were not signicantly dierent rom suni-
tinib (hazard ratio [HR], 0.93). However, pa-
zopanib was less toxic, with lower rates o
grade 3 or 4 adverse events (44 percent) as
compared with sunitinib (67 percent). [Mc-
Cann L. ASCO GU 2010; abstract 413]
Saety and tolerability takes on a
special signicance in mRCC, where pa-tients may have to be treated or many
months, or even years. While the evalua-
tion o drug tolerability is not easy, a strong
association between adverse events and
HRQoL suggests that patient preerence
is a legitimate and useul endpoint, said
Escudier. The PISCES (Patient Preerence
Study o Pazopanib vs Sunitinib in Ad-
vanced or Metastatic Kidney Cancer) wasthus designed to assess the impact o tol-
Pazopanib is an oral multi-kinase angiogenesis inhibitor which signicantly
improves progression-ree survival (PFS) in patients with metastatic renal cell
carcinoma (mRCC). It has also demonstrated a unique saety prole compared
with other approved agents or mRCC. As Proessor Bernard Escudier o the
Institut Gustave Roussy, France, elaborated at the American Society o Clinical
Oncology (ASCO) 2012 Annual Meeting, drug tolerability is a major determinant
o health-related quality o lie (HRQoL), which in turn determines patient
preerence or one therapy over another.
erability and HRQoL on a patients choice
o treatment.
PISCES: Are dierences in drugtolerability clinically meaningul orpatients?
PISCES was a double-blind, cross-
over study, in which 169 patients were
randomized 1:1 to receive pazopanib
800 mg or 10 weeks, ollowed by a 2-week
washout period, and then sunitinib 50 mg
or 10 weeks, or vice versa (sunitinib then pa-
zopanib). Patients were eligible i they had
previously untreated mRCC, any renal can-
cer histology, measurable or non-measur-
able disease, Eastern Cooperative Oncol-ogy Group (ECOG) perormance status 0 or
1, good or intermediate prognosis, no brain
metastases, and adequate cardiac and renal
unction. [Abstract CRA4502]
The subjects were stratied based on
their ECOG perormance status and the
number o metastatic sites (1 vs 2). CT
scans were perormed beore the start o
the trial, during the 2-week washout pe-riod, and again at the end o the second
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201218
treatment period.
Patients who had received 1 dose in
both treatment periods completed a ques-
tionnaire at the end o the study, whilethey were still blinded and beore end-
o-study imaging results were disclosed,
said Escudier. The primary endpoint o the
study was patient preerence, where the
subjects indicated which drug they pre-
erred to continue treatment with. Two ad-
ditional questions were asked to determine
the reasons that infuenced their choice,
and the single most important reason or
their preerence.
Other endpoints included physician pre-
erence, saety and quality o lie.
Patients preer pazopanib
Results showed that patients had a strong
preerence in avor o pazopanib, said Es-
cudier. In the primary endpoint analysis, 70
percent o patients said they preerred to
continue treatment with pazopanib vs 22
percent or sunitinib. Only 8 percent o pa-
tients did not have any preerence. These
dierences were statistically signicant
(p1 reason
0 10 20 30 40 50 60 70
Less hair colour change
Other
Less diarrhea
Less stomach pain
Less loss of appetite
Less soreness in hands/feet
Less nausea/vomiting
Less soreness in mouth/throat
Less changes in food tastes
Less fatigue
Better quality of life
Number of patients
Pazopanib preferred (n=80)
Sunitinib preferred (n=25)
i
i i i
Figure 2. Reasons infuencing patients choice o therapy
Adapted rom Escudier BJ, et al. ASCO 2012; abstract CRA4502.
70%(n=80)
22%
(n=25) 8%
Difference (pazopanib vssunitinib)
49.3%
p value < 0.001
Primary analysis population90
80
70
60
50
40
30
20
10
0Pazopanib preferred Sunitinib preferred No preference
Percentofpatients
(n=9)
Figure 1. PISCES primary endpoint: Patient preerence
Adapted rom Escudier BJ, et al. ASCO 2012; abstract CRA4502.
Primary analysis population
61%
22%
17%
Pazopanib preferred
Sunitinib preferred
No Preference
90
80
70
60
50
40
30
20
100
Percentofphysicians
Pazopanib preferred Sunitinib preferred No preference
Figure 3. Physician preerence in PISCES
Adapted rom Escudier BJ, et al. ASCO 2012; abstract CRA4502.
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201219
physicians preerred pazopanib, compared
with 22 percent who preerred sunitinib.
Seventeen percent o the physicians had no
preerence at all. (Figure 3)
Improved quality o lie and drug saety
Using the Functional Assessment o
Chronic Illness Therapy-Fatigue (FACIT-
F) tool to evaluate atigue, the PISCES in-
vestigators conrmed that patients were
signicantly less likely to experience
atigue when they received pazopanib
(p=0.002), said Escudier. A supplemen-
tary questionnaire that evaluated sore-
ness in the mouth/throat, hands and eet
also established pazopanibs superiority
over sunitinib (p
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Trastuzumab emtansine: A new
weapon against HER2-positive mBCApproximately 15 to 20 percent o all breast cancers involve human epidermal
growth actor receptor 2-positive (HER2+) disease. Targeted therapy options
or patients with HER2+ metastatic breast cancer (mBC) have been limited,
with a median time to progression o
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201221
Superior PFS
EMILIA met its primary endpoint oimproving PFS with T-DM1 treatment, de-
livering an absolute improvement o 3.2months in median PFS as compared withcapecitabine/lapatinib, reported Black-well. The median PFS or the two treat-ment arms was 9.6 months vs 6.4 months(p
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201223
Bevacizumab shows benefit in
platinum-resistant ovarian cancerPlatinum-resistant ovarian cancer is notoriously dicult to treat as therapeutic
options are limited in number and ecacy. This may change, as the phase
III AURELIA trial demonstrated that bevacizumab (Avastin Roche, Roche),
when added to standard chemotherapy, signicantly improves progression-
ree survival (PFS) in patients with platinum-resistant recurrent disease.
Results were presented recently at the American Society o Clinical Oncology
(ASCO) 2012 Annual Meeting by Proessor Eric Pujade-Lauraine o the Group
dInvestigateurs Nationaux pour lEtude des Cancers Ovariens (GINECO) and
Universit Paris Descartes in France.
Unmet need in dicult-to-treatdisease
Most patients with advanced ovariancancer will relapse. At rst relapse, 25 per-cent o patients have platinum-resistantdisease, and almost all patients with re-
current ovarian cancer will ultimately de-velop platinum resistance, said Pujade-Lauraine.
However, treatment options or plati-num-resistant ovarian cancer are limited.While single-agent weekly paclitaxel, pe-gylated liposomal doxorubicin (PLD) ortopotecan is the current standard o care,combination regimens have ailed to im-
prove ecacy vs monotherapy. Medianoverall survival [OS] is typically less than12 months, he pointed out.
Ovarian cancer is a highly VEGF-drivendisease. As bevacizumab has demonstrat-ed single-agent activity in platinum-resis-tant ovarian cancer, our objective was toevaluate the ecacy and saety o addingbevacizumab to chemotherapy in this set-ting, he said. [J Clin Oncol 2007;25:5180-
5186;J Clin Oncol2008;26:1773]
AURELIA: Bevacizumab in platinum-resistant recurrent disease
AURELIA is a multicenter, internation-al trial in 361 patients with epithelialovarian, primary peritoneal or allopiantube cancer whose disease progressed
within 6 months ater 4 cycles o plati-num-based therapy. Study patients hadreceived 2 prior anticancer regimens,and had no history o bowel obstruc-tion or abdominal istula, or clinical orradiological evidence o recto-sigmoidinvolvement. [Abstract LBA5002]
The patients were randomized 1:1 toreceive chemotherapy based on inves-
tigator choice (n=182), or bevacizumab(15 mg/kg q3w) in combination withchemotherapy (n=179). Chemotherapyoptions in the trial were paclitaxel (80mg/m2 days 1, 8, 15 and 22 q4w), topo-tecan (4 mg/m2 days 1, 8 and 15 q4w or1.25 mg/m2 days 1-5 q3w), and PLD (40mg/m2 day 1 q4w).
Treatment in both arms was contin-ued until progression or unacceptable
toxicity. At disease progression, patients
Pro.
Pujade-
Lauraine
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201224
in the chemotherapy-alone arm were al-lowed to cross over to bevacizumab mono-therapy, while those in the bevacizumab/
chemotherapy arm continued with theirchemotherapy without bevacizumab.The chemotherapy drugs used in the
trial are equally eective or resistantovarian cancer, diering only in their tox-icities. Investigators selected the chemo-therapy based on each patients previousexperience with the drugs, said Pujade-Lauraine. Baseline characteristics werewell balanced between the two treat-
ment arms.Signicant improvements in PFS and
response
The trial met its primary endpoint o PFS.PFS nearly doubled, with bevacizumab/che-motherapy reducing the risk o progressionby 52 percent vs chemotherapy alone. Thedierence was highly signicant, Pujade-Lauraine reported. The PFS benet was con-
sistent in all patient subgroups regardless oage, platinum-ree interval, tumor size, pres-ence o ascites, or assigned chemotherapy.(Figures 1 and 2)
Overall response rates (ORR) were alsosignicantly higher with bevacizumab/che-motherapy vs chemotherapy alone. (Figure3) The responses in the chemotherapy armare in line with whats expected in platinum-resistant patients, he noted.
OS data were not yet mature and will bereleased in 2013.
Saety and tolerabilityThe saety prole o bevacizumab was
consistent with ndings o pivotal trials obevacizumab across various tumor types.Grade 3 adverse events that were higherin the bevacizumab/chemotherapy arm in-cluded hypertension (7.3 vs 1.1 percent withchemotherapy alone), proteinuria (20.1 vs 6.6percent), gastrointestinal peroration (1.7 vs 0percent), and stula or abscess (1.1 vs 0 per-
cent). Other grade 3 adverse events, includ-ing bleeding, thromboembolic event, hema-tologic toxicity, wound-healing complication,reversible posterior leukoencephalopathysyndrome and cardiac disorders, were notsignicantly dierent between the two arms.
The rates o gastrointestinal peroration,stula or abscess were very low with bevaci-zumab/chemotherapy in the AURELIA trial,
noted Pujade-Lauraine. Excluding patientsat high risk o gastrointestinal perorationhelped limit the incidence o these adverseevents.
In the trial, atigue, abdominal pain,vomiting and dyspnea were less com-mon with bevacizumab/chemotherapy vschemotherapy alone.
Although peripheral sensory neuropathyand hand-oot syndrome were increased
CT BEV + CT
(n=182) (n=179)
Events, n (%) 166 (91%) 135 (75%)
Median PFS, months 3.4 6.7
HR (unadjusted) 0.48
Log-rank p-value
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201225
with bevacizumab/chemotherapy, Pujade-Lauraine pointed out that patients treatedwith bevacizumab/chemotherapy hadhigher exposure to chemotherapy than
those treated with chemotherapy alone.Bevacizumab delayed disease progression,allowing patients to be treated or a lon-ger period o time, which led to increasedcumulative toxicities o chemotherapy, heexplained. The other hypothesis that beva-cizumab could potentiate the toxicity o che-motherapy was unproven, because the timecourses o cumulative hand-oot syndrome
and cumulative neuropathy were similar
between bevacizumab/chemotherapy andchemotherapy alone.
Conclusions
AURELIA is the rst randomized phase IIItrial in platinum-resistant ovarian cancer todemonstrate a signicant benet with bio-logic therapy, and a signicant benet witha combination regimen vs mono-th-erapy,commented Pujade-Lauraine. In view othese signicant benets, bevacizumab incombination with chemotherapy shouldbe considered a new standard option in
platinum-resistant ovarian cancer.
Phase III trials on bevacizumabin ovarian cancer
Bevacizumab-based therapy has dem-onstrated signicant improvements inPFS in our phase III trials totaling nearly4,000 patients with newly-diagnosedor recurrent ovarian cancer. Adverseevents related to bevacizumab were as
expected, with no new saety signalsidentied.
First-line therapy in advanced disease
In the GOG-0218 (Gynecologic Oncol-ogy Group-0218) trial o patients withnewly-diagnosed stage III (incompletelyresectable) or IV disease who had un-dergone debulking surgery, median PFS
was 14.1 months with carboplatin/pacli-taxel plus concurrent and maintenancebevacizumab, vs 11.2 months with car-boplatin/paclitaxel plus concurrent bev-acizumab and 10.3 months with carbo-platin/paclitaxel plus placebo. [N Engl JMed 2011;365:2473-2483]
In the ICON-7 (International Collabo-ration on Ovarian Neoplasms-7) trial(stage IIIC or IV disease, 70 percent), me-
dian PFS was 19.8 months with carbopl-
atin/pacltaxel plus concurrent and main-tenance bevacizumab, vs 17.4 monthswith carboplatin/paclitaxel alone. [NEngl J Med 2011;365:2484-2496]
These results ormed the basis o theapproval o bevacizumab or treatmento ovarian cancer in Europe in December2011.
Previously-treated, recurrent disease
The OCEANS and AURELIA trials dem-onstrated signicant PFS improvementswith bevacizumab-based therapies inpatients with previously-treated, recur-rent ovarian cancer.
In the OCEANS trial o patients withplatinum-sensitive disease, bevaci-
zumab plus carboplatin/gemcitabineollowed by single-agent bevacizumabsignicantly increased PFS by 21 percentvs carboplatin/gemcitabine alone. [J ClinOncol 2011;29(June 20 suppl): abstractLBA5007]
Results o AURELIA oer hope orpatients with platinum-resistant dis-ease, with bevacizumab/chemotherapysignicantly extending PFS vs chemother-
apy alone.
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201226
Bevacizumab beyond progression
extends survival in mCRCResults rom a large phase III study conrm that continuing bevacizumab (BEV)
(Avastin Roche, Roche) beyond rst progression signicantly extends survival
in patients with metastatic colorectal cancer (mCRC) previously treated with
BEV plus chemotherapy. The ndings were presented recently at the American
Society o Clinical Oncology (ASCO) 2012 Annual Meeting by Proessor Dirk
Arnold o the University Cancer Center Hamburg, Germany.
ML18147 study
BEV in combination with fuoropyrimi-
dine-based chemotherapy is a standard o
care or mCRC in rst-line and, in BEV-nave
patients, second-line settings. In nonran-
domized observational studies o mCRC
patients, continuing BEV plus chemothera-
py beyond rst progression was associated
with prolonged survival vs stopping BEV,
said Arnold. [J Clin Oncol 2008;26:5326-
5334; J Clin Oncol 2010;28(15 suppl): ab-
stract 3596] However, the ecacy and
saety o continuing BEV ater rst pro-
gression had not been investigated in a
randomized clinical trial.
Design
The ML18147 study is the rst randomized
phase III trial that prospectively investigated
the impact o continued VEGF inhibition with
BEV in mCRC patients who progressed ater
rst-line BEV plus standard chemotherapy
(oxaliplatin- or irinotecan-based at physi-
cians discretion). The study included 820 pa-
tients who were randomized 1:1 to receive
oxaliplatin- or irinotecan-based chemother-
apy with or without BEV (2.5 mg/kg/week)
until urther disease progression. Patients
who received oxaliplatin-based chemother-
apy in the rst-line setting were switched to
irinotecan-based chemotherapy, and vice
versa. [Abstract CRA3503]
The study started as a national academic
trial rom the AIO Group [Working Group or
Medical Oncology o the German Cancer
Society] in Germany with progression-ree
survival [PFS] as primary endpoint. Subse-
quently, with growing interest throughout
Europe, more patients were enrolled, and
the primary endpoint was changed to over-
all survival [OS], said Arnold.
To be eligible or participation, patients
had to be 18 years old with histologically
conrmed mCRC, with disease progression
4 weeks prior to starting the study treat-
ment. Those with progressive disease diag-
nosed >3 months ater the last BEV adminis-
tration, rst-line PFS
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201227
line BEV were excluded.
Patients were stratied by rst-line che-
motherapy, PFS in rst-line setting [9 or
>9 months], time rom last BEV dose [42
or >42 days], and ECOG [Eastern Coopera-
tive Oncology Group] perormance status at
baseline [0/1 or 2], added Arnold.
Baseline characteristics
Baseline characteristics were well bal-
anced between the BEV/chemotherapy
(n=409) and chemotherapy-alone (n=411)
arms. In the rst-line setting, more than hal
o the patients in each arm had a PFS o
9 months (54 vs 56 percent) and received
irinotecan-based chemotherapy (59 vs 58
percent). The duration between the last BEV
dose and randomization was 42 days or
77 percent o patients in each arm.
Use o second-line chemotherapy was
well balanced during the study. The propor-
tions o patients receiving irinotecan- and
oxaliplatin-based chemotherapy were 42
and 58 percent, respectively, in the BEV/che-
motherapy arm, vs 43 and 57 percent in the
chemotherapy-alone arm.
Continuing BEV into second-line increases OS
The trial met its primary endpoint, with
OS signicantly increased in patients who
continued BEV beyond progression ater
rst-line BEV/chemotherapy. Ater a me-
dian ollow-up o 11.1 months or the BEV/
chemotherapy arm and 9.6 months or the
chemotherapy-alone arm, median OS was
11.2 vs 9.8 months. (Figure 1)
The OS benet was consistent in all pre-
specied subgroups, said Arnold. While
there appeared to be a dierence in treat-
ment eect according to gender, we ound
no real interaction between BEV benet and
gender as the treatment-gender interaction
test was not statistically signicant. (Figure 2)
In the study, 68.6 percent o patients in the
BEV/chemotherapy arm and 67.7 percent in
the chemotherapy-alone arm received 1
line o subsequent therapy, which included
BEV [11.5 vs 12.2 percent], anti-EGFR therapy
[39.2 vs 41.3 percent], and other therapies
[54.9 vs 50.4 percent]. The balance in urther
lines o treatment indicates the robustness o
the OS eect seen with continuing BEV into
the second-line setting ater rst progression,
suggested Arnold.
OSe
stimate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30 36 42 48
No. at risk
CT 410 293 162 51 24 7 3 2 0
BEV + CT 409 328 188 64 29 13 4 1 0
9.8 mo 11.2 mo
CT (n=410)
BEV + CT (n=409)
.
I .
.
.
.
.
.
.
.
.
.
.
I .
.
.
.
.
. .
.
.
.
.
.
.
Unstratifieda HR: 0.81p=0.0062
Stratifiedb HR: 0.83p=0.0211
: ..
: ..
Figure 1. OS: ITT population
a Primary analysis method; b stratied by rst-line CT, rst-line PFS, time rom last dose o BEV, ECOG perormance status at baseline;BEV = bevacizumab; CT = chemotherapy; ITT = intention-to-treat; OS = overall survival
Adapted rom Arnold D, et al. ASCO 2012; abstract CRA3503.
.
.
.
.
.
. .
Category Subgroup n HR
All All 819 0.81
Patient populationa AIO 260 0.86
ML18147 559 0.78
Gender Female 294 0.99
Male 525 0.73
Age 9 months 369 0.73
First-line CT Oxaliplatin-based 343 0.79
Irinotecan-based 476 0.82
Time from last BEV 42 days 630 0.82
>42 days 189 0.76
Liver metastasis only No 592 0.81
Yes 226 0.79
No. of organswith metastasis
1 307 0.83
>1 511 0.77
HR 0 1 2
.
.
.
.
.
: ..
: .
.
: .
.
: ..
Figure 2. Subgroup analysis o OS: IT T population
a Patient population reers to sequential enrolment o patients in ori ginal AIO and subsequent enrolment in ML18147 when study wastranserred to Roche, all patients listed under AIO were included in primary analysis; AIO = Working Group or Medical Oncology o theGerman Cancer Society; BEV = bevacizumab; CT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; ITT= intention-to-treat; OS = overall survival; PFS = progression-ree survival
Adapted rom Arnold D, et al. ASCO 2012; abstract CRA3503.
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ASCO 2012 Meet ing H igh l ightsJul-Aug 201228
Secondary endpoints
PFS was signicantly prolonged with BEV/
chemotherapy vs chemotherapy alone (5.7 vs
4.1 months). (Figure 3)
Overall response rates were similar in both
arms (5.4 percent or BEV/chemotherapy vs
3.9 percent or chemotherapy alone). How-
ever, disease control rate was signicantly
higher with BEV/chemotherapy (68 vs 54 per-
cent; p
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Case StudyJul-Aug 201229
Use of capecitabine in advanced metastatic
breast cancer
Dr. Foon-Yiu CheungClinical Oncologist
Presentation and treatmentA 47-year-old Chinese woman presented
in 2002 with a mass in her right breast. She
underwent modied radical mastectomy in
August 2002. Pathology revealed a 1.7-cm
invasive ductal carcinoma with grade 3 dis-ease. Nine out of 23 resected axillary lymph
nodes were involved by tumor. Resected mar-
gin was clear (5 mm). Estrogen receptor (ER)
and progesterone receptor (PR) were positive
while human epidermal growth factor recep-
tor 2 (HER2) was negative. Metastatic work-
up was negative.
The patient received adjuvant chemo-
therapy with the Milan scheme (four cyclesof 3-weekly adriamycin and eight cycles of
cyclophosphamide, methotrexate and 5-uo-
rouracil [5-FU]), followed by locoregional ra-
diotherapy (RT). She received tamoxifen from
June 2003 until June 2008.
In June 2009, she presented with an inci-
dental nding of lung masses on chest X-ray
(CXR). Transbronchial biopsy conrmed met-
astatic carcinoma. ER and PR were stronglypositive, while HER2 and thyroid transcrip-
tion factor-1 (TTF-1) were negative.
Paclitaxel and carboplatin were given for
six cycles, completed in October 2009. CXR
showed partial response. She underwent
ovarian ablation with irradiation in October
2009 and was started on letrozole in March
2010.
A few months later, the patient was found
to have a secondary brain tumor at the le
parieto-occipital region by CT scan while on
investigation for dizziness.
Palliative whole-brain irradiation was
given in June 2010 with 30 Gy in 10 fractions.
Follow-up CXR in November 2011 revealedinterval increase in size of the secondary lung
tumor.
A PET-CT in March 2012 revealed bilobar
liver metastases, multiple hypermetabolic
mediastinal lymph nodes and bilateral lung
metastases. The le parieto-occipital brain
metastasis remained hypermetabolic.
Palliative capecitabine (2500 mg/m2 daily
for 2 weeks in each 3-weekly cycle) was start-ed in March 2012. Treatment was well toler-
ated.
Repeat PET-CT in May 2012 aer the third
cycle revealed:
Metabolic remission of bilobar liver metas-
tases
Signicant metabolic improvement of
hypermetabolic media-stinal lymph nodes
Signicant metabolic improvement of
hypermetabolic intrapulmonary and le
Figure. PET-CT scans beore (top) and ater (bottom)
capecitabine treatment
(A) Brain metastasis (B) Liver metastasis (C) Right hilar metastasis
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Case StudyJul-Aug 201230
parieto-occipital brain metastases
No new hypermetabolic meta-static lesions
These ndings suggest a partial treatment
response.The patient plans to continue the present
treatment.
DiscussionBreast cancer is the most common cancer
among females in Hong Kong; in 2009, it was
the third cause of cancer mortality.1 This pa-
tient rst presented at a time when third-gen-
eration adjuvant chemotherapy with taxaneswas either unavailable or very expensive. Ad-
juvant chemotherapy using the Milan scheme
was the most potent option we could oer at
that time.
Aer relapse, she received subsequent
systemic therapy in line with the consensus,
using a taxane rst. The choice of paclitaxel
rather than docetaxel was solely a nancial
consideration, as paclitaxel is free. The subse-quent use of capecitabine aer progression is
also in line with international recommenda-
tions, such as the NICE guideline.2
Single-agent capecitabine has a response
rate of 14-28 percent in pretreated metastatic
breast cancer, and the median duration of
response is about 4.5-9 months. The most com-
monly reported side eects are hand-foot syn-
drome (2-21 percent); diarrhea (3-10 percent)and nausea (3-8 percent).3 Whether it should
be used in combination with other agents or
as monotherapy aer anthracyclin and tax-
ane failure remains inconclusive. Combina-
tion with IV or oral vinorelbine is common.
Although there is no phase III randomized tri-
al for this scheme, the response rate reported
in a phase II trial was 33-70 percent.4
This case illustrates that capcitabine is aneective agent for advanced breast cancer
patients aer anthracycline and taxane fail-
ure, which concurs with current published
evidence. The treatment is well tolerated and,
in this case, demonstrated activity against
brain metastasis as well.
References:1. Top 10 cancers in 2009. hp://www.ha.org.hk/cancereg. 2. NICEpathways: Advanced breast cancer, chemotherapy and biolog-ical therapy. hp://pathways.nice.org.uk/pathways/advanced-breast-cancer#path=view%3A/pathways/advanced-breast-cancer/advanced-breast-cancer-chemotherapy-and-biological-therapy.xml&content=close. 3. National Collaborating Center for Cancer.Advanced Breast Cancer: Diagnosis and treatment. EvidenceReview. NICE 2009. 4.Clinical Breast Cancer 2012;12:30-39.
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Case StudyJul-Aug 201231
Capecitabine in advanced gastric cancerFigure. PET scan
Dr. Wai-Tong Ng
Department of Clinical OncologyPamela Youde Nethersole EasternHospital Hong Kong
PresentationA 58-year-old Chinese man presented to
Pamela Youde Nethersole Eastern hospital,
Hong Kong, in February 2011 with a 2-month
history of dysphagia. Upon admission, he
could only tolerate uid diet.
Investigations and diagnosisEsophago-gastroduodenoscopy showed
a circumferential tumor growth at the lower
esophagus with extension to the gastric car-
dia. Biopsy revealed adenocarcinoma, HER2
immunohistochemistry (IHC) 3+. Computed
tomography (CT) showed an irregular growth
at the cardia extending to the gastroesopha-geal junction, and multiple slightly enlarged
lymph nodes over the gastroesophageal,
gastro-hepatic and upper para-aortic regions.
Positron emission tomography (PET) scan re-
vealed a primary tumor involving the distal
esophagus, gastric cardia and proximal lesser
curvature, and a hypermetabolic focus in the
liver, which was compatible with a liver me-
tastasis. (Figure A)
TreatmentThe patient was given palliative chemo-
therapy using cisplatin, 5-uorouracil (5-FU)
and trastuzumab. Aer 2 cycles of treatment,
there was a signicant improvement in symp-
toms and the patient could resume normal
solid diet. However, impaired renal function
was noted due to the use of cisplatin. He was
thus switched to oxaliplatin, capecitabine
The arrow indicates the site of liver metastasis.
(A) Beore chemotherapy
(B) Beore chemotherapy
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Case StudyJul-Aug 201232
and transtuzumab; 8 cycles of treatment were
given in total. A follow-up PET scan showed
good response and the liver metastasis be-
came hypometabolic. (Figure B)Total radical gastrectomy and distal esoph-
agectomy were performed in November 2011
with clear margins. The liver lesion was not
identiable during the operation. Repeat PET
scan aer the operation showed no gross
FDG-avid lesion.
In early February 2012, he was given
stereotactic body irradiation (55 Gy over
10 fractions) to the liver lesion (tumor lo-cation based on the pre-treatment PET
scan). Trastuzumab was continued for up
to 1 year and treatment was completed
in April 2012. He was stable and doing
well at the time of last follow-up, with no
deterioration in cardiac function.
Discussion
The combination of 5-FU and cisplatin is awidely accepted standard regimen for meta-
static gastric cancer (mGC). However, the
need for several days of hospital stay with
5-FU infusion and the potential renal toxicity
associated with cisplatin have prompted the
evaluation of alternative treatment regimens.
Two important studies ML17032 and
REAL-2 have evaluated the replacement of
these agents by capecitabine (an oral uoro-pyrimidine) and oxaliplatin (a platinum ana-
logue with less renal toxicity).1,2 Similar an-
titumor activity has been conrmed in these
studies.
In addition, a more interesting observa-
tion was noted in a recent combined analysis
of these two studies.3 In this meta-analysis,
a total of 1,318 patients who were random-
ized within REAL-2 (n=1,002) and ML17032
(n=316) were included. Overall survival (OS)
was compared for the 664 patients treated
with 5-FU combinations vs the 654 patients
treated with capecitabine combinations. The
median OS was 285 days for patients treatedwith 5-FU and 322 days for patients who re-
ceived capecitabine, with an unadjusted haz-
ard ratio (HR) of 0.87 in favor of capecitabine
(p=0.027). This meta-analysis is practice
changing as capecitabine is not only beer
than 5-FU in terms of survival, but also far
more convenient as patients can avoid unnec-
essary hospitalization or central line insertion
for the 5-FU infusion.Another important advance in the man-
agement of mGC is the integration of target-
ed agents into the chemotherapy backbone.
Trastuzumab is currently the most widely
used targeted therapy for patients with
HER2-positive tumors. In the ToGA trial,
median OS was 14 months among patients
assigned to trastuzumab plus chemotherapy
vs 11 months for those assigned to chemo-therapy alone (p=0.0046).4 A subgroup anal-
ysis indicated that trastuzumab was most
eective in prolonging survival in patients
with HER2 IHC 3+ or IHC 2+ and FISH
(uorescence in situ hybridization)-positive
tumors (HR=0.65). In these HER2-positive
patients, the median OS was 16.0 months in
the trastuzumab arm, compared with 11.8
months in the chemotherapy-alone arm.Currently, approximately 20 percent
of mGC patients are HER2-positive, and
trastuzumab plus chemotherapy repre-
sent the standard of care for this group of
patients.
References1.Ann Oncol 2009;20:666-673. 2.N Engl J Med 2008;358:36-46. 3.Ann
Oncol 2009;20:1529-1534. 4.Lancet 2010;376:687-697.
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NewsJul-Aug 201234
New evidence linking H. pylori with colon
cancer
Naomi Rodrig
While the association between Helico-bacter pylori (H. pylori) infection andan increased risk of gastric adenocar-
cinoma has been well established, evidence re-garding its role in the development of colorectalcancer (CRC) remains controversial.
Recently, a large epidemiological study re-ported at the 2012 Digestive Disease Week inSan Diego, USA has shown an increased risk ofcolon neoplasms in patients with H. pylori infec-tion.
The investigators reviewed the records ofnearly 157,000 patients who had undergone
both colonoscopy and esophago-gastroduoden-oscopy between 2008 and 2011.
Overall, 16,759 patients, or 11 percent, hadH. pylori infection conrmed by immunohisto-chemistry, reported lead author, Dr. AmnonSonnenberg of Oregon Health and Science Uni-versity and the Portland VA Medical Center,US. The prevalence of H. pylori gastritis was 9percent among patients without colonic polyps,11 percent in patients with hyperplastic polyps,12 percent in those with adenoma, 14 percent inpatients with advanced adenoma and 18 percent
in those with adenocarcinoma. The prevalencewas similar regardless of the site of the coloniclesion.
Furthermore, there was a trend of increasedprevalence of H. pylori infection with increasingnumber and size of adenomatous polyps.
The data suggest a link between the preva-lence of infection and lesion severity. H. pyloriconfers an increased risk for all types of colonic
neoplasms, and the risk appears to increase withadvancing stage of the neoplasm, from hyper-plastic and adenomatous polyps to tubulovil-
lous adenoma, adenoma with high-grade dys-plasia and adenocarcinoma, he concluded.
Another report published earlier this yearsuggested that H. pylori infection may be as-sociated with an increased risk of CRC in spe-cic colorectal sites. [Am J Epidemiol 2012. DOI:10.1093/aje/kwr331]
The authors assessed the association of H. py-
lori seroprevalence with risk of CRC in a largepopulation-based case-control study conductedin Germany between 2003 and 2007. Serum an-tibodies to H. pylori in general and the cytotox-in-associated gene A protein (CagA) were mea-sured in 1,712 incident CRC patients and 1,669controls. CagA-positive strains of H. pylori areconsidered more toxic or carcinogenic.
The association between H. pylori prevalenceand CRC risk was adjusted for potential con-founders and stratied by age group, gender,anatomic subsites, and cancer stage.
Overall, H. pylori seroprevalence was high-er in CRC patients than in controls (46.1 vs40.1 percent, respectively). Age- and gender-adjusted odds ratios (OR) were 1.3 and 1.14,respectively.
Stratied analyses showed that the risk eleva-tion was essentially conned to le-sided CRC,
with an OR of 1.22. H. pylori infection may beassociated with a small yet relevant risk increasein the le colorectum, the authors concluded.
The results of both recent studies are incontrast with previously published data. Forexample, a nested case-control study of menin the ATBC (Alpha-Tocopherol, Beta-Caro-tene) cancer prevention clinical trial in Finland,which analyzed data from nearly 30,000 sub-
jects, found no evidence of H. pylori being a riskfactor for CRC development. [Ann Epidemiol1994;4:1-10]
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Minimum Product InformationHerceptin (trastuzumab) Powder for Concentrate for infusion 150 mg single dose vial & 440 mg multidose vial (with solvent)Indications:HER2 positive patients with: (i) metastatic breast cancer (MBC), either as monotherapy following at least 2 chemotherapy (CT) regimens; or in combination with paclitaxel forpatients who have not received CT; or in combination with docetaxel for patients who have not received CT; or in combination with an aromatase inhibitor for the treatment ofpostmenopausal patients with hormone-receptor positive MBC, or (ii) early breast cancer (EBC) following surgery, CT (neo/adjuvant) and radiotherapy (if applicable); or followingadjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel; or in combination with adjuvant chemotherapy consisting of docetaxeland carboplatin, or (iii) metastatic gastric cancer (MGC) in combination with capecitabine or 5-FU and cisplatin. Dosage & administration:Please refer to Herceptin PI for full guidance.HER2 testing is mandatory prior ini tiation of therapy. EBC/MBC/MGC 3-weekly: loading dose - 8mg/kg; subsequent doses 6mg/kg repeated at 3-weekly intervals. BC weekly: loadingdose - 4mg/kg; subsequent doses: 2mg/kg weekly. Administer as IV infusions over approx. 90 min. Infusion time reduced to 30 min for subsequent doses if initial loading dose was welltolerated. Do not administer as an IV push or bolus. Observe for infusion-related symptoms. In MBC or MGC, treat until disease progression. Patients with EBC should be treated for 1 yearor until disease recurrence. Contraindications:Known hypersensitivity to trastuzumab or any product excipients. Warnings & Precautions:Discontinue Herceptin infusion in case of seriousadverse reactions. Patients experiencing dyspnoea at rest may be at risk of fatal infusion reactions or severe pulmonary reactions. Interstitial lung disease may occur as part of aninfusion-related reaction or with a delayed onset especially in patients with prior or concomitant therapy with other anti-neoplastic therapies, these patient should not be treated withHerceptin. Heart failure has been observed. Caution in patients with symptomatic heart failure, history of hypertension or documented coronary artery disease and in EBC, in thosepatients with an LVEF 10%): nasopharyngitis, anaemia, thrombocytopenia, weight changes, decreased appetite, insomnia, Nervous system disorders (including dizziness,headache, paraesthesia, hypoaesthesia), lacrimation increased, conjunctivitis, lymphoedema, Respiratory, thoracic and mediastinal disorders (including dyspnoea, epistaxis,oropharyngeal pain, cough, rhinorrhoea), Gastrointestinal disorders (including diarrhoea, vomiting nausea, abdominal pain, dyspepsia, constipation, stomatitis), erythema, rash,alopesia, arthralgia, myalgia, General disorders and administration site conditions (including asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion related reaction, pain,pyrexia, peripheral oedema, mucosal inflammation) & nail toxicity. Post Marketing refer to package insert.Date of preparation: December 2011Full prescribing information should be viewed prior to prescribing.
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NewsJul-Aug 201236
Overcoming treatment resistance in
pancreatic cancer
Christina Lau
Researchers in the US have discovered
how pancreatic cancer becomes resis-
tant to chemotherapy and identied
ways to improve treatment based on their nd-
ings.
The studies, presented recently at the Amer-
ican Association for Cancer Researchs (AACR)
rst-ever conference on pancreatic cancer, rep-
resent progress in a disease that is notoriously
dicult to treat, with 90 percent of patients
likely to die within 1 year from diagnosis.
Pancreatic cancer cells are largely resis-
tant to cell death induced by chemotherapy
and radiation. Fortunately, our data show that
this seemingly unconquerable disease has an
Achilles heel its toxin exhaust system, said
Professor Sanjay Awasthi of the City of Hope
Comprehensive Cancer Center in Duarte, USA.
The weak point Awasthi and colleagues
identied is the RLIP76 protein, which pumps
out toxic chemicals accumulating in pancreatic
cancer cells as a result of chemotherapy or ra-
diotherapy before they can cause cell death.
We found a higher level of RLIP76 inhuman pancreatic cancer cells than in normal
human pancreatic cells. Depletion of RLIP76
levels killed human pancreatic cancer cells
in culture and shrank established human
pancreatic tumors in mice, he reported.
Moreover, blocking or depleting levels of this
protein dramatically enhanced the ability of
radiation and doxorubicin to destroy human
pancreatic cancer cells in culture.An added benet to depleting RLIP76 levels
in mice with established tumors was a decrease
in blood glucose, cholesterol and triglycerides,
added Awasthi, who is founder of a company
that makes recombinant RLIP76 protein for
treatment of radiation poisoning.
Another approach already being tested in
the clinic is inhibition of the Hedgehog signal-
ing pathway, said Dr. Edward Kim of the Uni-
versity of Michigan Comprehensive Cancer
Center in Ann Arbor, USA. Early results look
promising.
The Hedgehog pathway is normally silent
in the adult pancreas but activated in patients
with pancreatic cancer, contributing to the
desmoplastic stroma that is characteristic of
the disease. This dense stroma is believed to
contribute to resistance to chemotherapy by
presenting a physical barrier to chemothera-
py delivery, said Kim. In addition, Hedge-
hog levels are increased in pancreatic can-
cer stem cells, which drive tumor growth by
generating bulk tumor cells and are par-
ticularly resistant to chemotherapy and
radiation.
Kim and colleagues have achieved some
success in a small number of patients withthe Hedgehog pathway inhibitor GDC-0449
(vismodegib), an oral agent approved for use
in basal cell carcinoma.
In 20 treatment-nave patients with
advanced pancreatic cancer, use of GDC-0449
(as monotherapy for 3 weeks and then in
combination with gemcitabine) led to a
partial response in ve patients and stable dis-
ease in ve patients. Progression-free survivalat 3 months was 50 percent.
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NewsJul-Aug 201239
Arthritis drug to be tested in lymphoma
Christina Lau
Singaporean researchers are planning to
test a Janus kinase 3 (JAK3) inhibitor
in patients with natural killer (NK)/T-
cell lymphoma a very aggressive form of
lymphoma frequently found to harbor JAK3
mutations.
NK/T-cell lymphoma is particularly
prevalent in Asia, accounting for almost half
of all T-cell lymphomas in some parts of theregion, said Professor Bin-Tean Teh of the
National Cancer Center SingaporeVan An-
del Research Institute Translational Research
Laboratory and DukeNational University of
Singapore Graduate Medical School.
Very lile was known about the genetic
and molecular defects causing the aggres-
sive disease before we started our study, he
continued. With no eective treatment, theprognosis of patients with NK/T-cell lympho-
ma is extremely poor.
In their study, Teh and colleagues con-
ducted whole-exome sequencing of NK/T-
cell lymphoma cells from four patients, and
identied JAK3 somatic-activating mutations
in two of them. Further validation was con-
ducted in another 61 patients with Sanger
sequencing and high-resolution melt (HRM)analysis. In total, 23 of 65 cases (35.4 percent)
harbored JAK3 mutations. [Cancer Discov
2012, e-pub 15 Jun]
The mutations enabled NK/T-cell lympho-
ma cell lines to grow in culture without the
normally essential growth factor, interleu-
kin-2 (IL-2). This means that JAK3 mutations
cause dysregulated activation of JAK3, sug-
gesting that JAK3 may be a good drug target.
There is a JAK3 inhibitor [CP-690550
(tofacitinib)] currently in phase III trials fortreatment of rheumatoid arthritis. In our
study, use of CP-690550 in the JAK3-mu-
tant NK/T-cell lymphoma cell lines led to
inhibition of STAT5 [signal transducer and
activator of transcription-5] phosphory-
lation, along with reduced cell viability,
reported Teh. We are in the process of plan-
ning a clinical trial to test the agent as a treat-
ment for NK/T-cell lymphoma with JAK3mutations.
It is tremendously rewarding to have
identied genetic mutations that appear to
have an important role in driving NK/T-cell
lymphoma in a considerable proportion of
cases, he continued. Although relatively
rare in the USA, this form of lymphoma is
responsible for the deaths of a large number
of people in Asia, especially in China and
Korea.
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Meet ing H igh l ightsJul-Aug 201241
Everolimus plus exemestane improves
PFS in advanced breast cancer
Pro.
Schfski
At a sponsored satellite symposium in conjunction with the Asian Oncology
Summit held recently in Singapore, Proessor Patrick Schski, Head o the
Department o General Medical Oncology and the Laboratory o Experimental
Oncology at the University Hospitals Leuven, Catholic University Leuven,
Belgium, reviewed the current treatment options or metastatic renal cell
carcinoma (mRCC). In particular, he highlighted the latest data ocusing on the
angiogenesis inhibitor pazopanib.
Unmet needs in mRCCThe treatment options or mRCC
have been revolutionized over a short
period o time. Since 2005, seven tar-
geted agents have been approved or
use in the treatment o mRCC, either as
rst- or second-line. This has resulted
in improved clinical outcomes or pa-tients with mRCC. However, the more
treatment options we have, the more
dicult and complicated it becomes to
make treatment decisions, said Schski.
The incidence o RCC worldwide con-
tinues to increase by 1 to 2 percent per
year, which may be partly attributed to
improved diagnosis. There is still an un-
met medical need in mRCC, Schski said.The drugs that we have today are not cur-
ing our patients. We are delaying tumor
growth and shrinking metastasis in a large
proportion o patients, but complete re-
sponses are rare.
Reractoriness to treatment develops in
the majority o cases. Other challenges in
targeted therapy or mRCC include iden-
tication o the most eective sequence
or combination o available targeted
agents to reduce adverse events and pre-
vent or overcome the development o
drug resistance.
Many patients suer rom adverse
events associated with some tyrosine ki-
nase inhibitors (TKIs). Mucositis, atigue,
hand-oot syndrome and gastrointestinalcomplaints such as diarrhea all require ad-
equate assessment and prompt manage-
ment.
In a retrospective study involving ap-
proximately 700 patients with mRCC, a va-
riety o adverse events were reported with
the targeted agents sunitinib, soraenib
or bevacizumab. In general, the adverse
event proles o these drugs varied con-siderably. [Levy A, et al. European Multidis-
ciplinary Cancer Congress 2011. Abstract
7.152]
For sunitinib, the main problem that
we all encounter, and Im seeing it daily
in my own patients as well, is atigue/as-
thenia, apart rom other side eects. For
soraenib, the dominant problem rom
my personal experience is hand-oot
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Meet ing H igh l ightsJul-Aug 201242
syndrome and also atigue/asthenia. For
bevacizumab, which is usually combined
with intereron-ala, the rate o atigue/
asthenia has reached 44.4 percent andthis has led to treatment discontinuation
in a considerable number o patients, he
reported.
Fatigue/asthenia is a repeating theme
among patients treated with these tar-
geted agents. In general, treatment-
related adverse events have a negative
impact on the well-being o patients,
and the actual dosing and scheduling odrugs. Drugs are used according to la-
beled instructions, but many patients do
not tolerate ull doses. Any variation to
the prescribed regimens has an eect on
treatment outcomes, Schski warned.
In the study, treatment modications
occurred quite oten. Between 12 to 25
percent o patients had to discontinue
treatment due to adverse events.
Pazopanib in mRCC: Ecacy andsaety
The treatment strategy or mRCC con-
tinues to evolve. Pazopanib a potent
inhibitor o VEGFR-2, the primary me-
diator o angiogenesis is a welcome
addition to the mRCC treatment port-
olio. The drug has a avorable overallrisk:beneit proile and works by inhib-
iting the intracellular tyrosine kinase
o vascular endothelial growth actor
receptor (VEGFR) and platelet-derived
growth actor receptor (PDGFR). In vitro
studies demonstrated that pazopanib
has >6 times greater ainity or VEGFR-2
and is overall more selective than suni-
tinib. Unlike sunitinib, pazopanib also
causes less inhibition o Fit-3, a mediator
o hematopoiesis. (Figure 1)
A phase III trial has demonstrated that
pazopanib improves progression-reesurvival (PFS) and response rates in both
treatment-nave and cytokine-pretreated
patients. In this study, patients were ran-
domized to either pazopanib (n=290) or
matching placebo (n=145). The study al-
lowed or early cross-over rom placebo to
active treatment with pazopanib, without
any impact on PFS.
In the overall study population, PFS wassignicantly longer with pazopanib than
with placebo (9.2 months vs 4.2 months,
p
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Meet ing H igh l ightsJul-Aug 201243
cidence and severity. Arterial hyperten-
sion is an uncommon event, but there are
clear guidelines on how to deal with it.
(Figure 4)Fatigue is also less prominent with
pazopanib than with other drugs Ive pre-
scribed beore or my patients. Fatigue can
be bothersome or patients and translates
into poorer outcomes, he remarked.
Schski noted that the ongoing COM-
PARZ (Pazopanib Versus Sunitinib in the
Treatment o Locally Advanced and/or Met-
astatic Renal Cell Carcinoma) trial, whichinvolves a head-to-head comparison o
the two TKIs, is expected to provide more
data to acilitate treatment selection or
individual patients.
Conclusions
Pazopanib is the third TKI and the sixthtargeted therapy approved or the treat-
ment o advanced or metastatic RCC.
Its saety prole is dierent rom other
agents. The drug is clearly manageable,
but it is important to assess and man-
age relevant adverse events such as
hypertension, liver enzyme elevation and
diarrhea. Guidelines are available to help
physicians make sound therapeutic deci-
This drug has
less hematologic toxicity
compared with other
targeted therapies
i
i i i
l
l
l
1.0
0.8
0.6
0.4
0.2
0Proportionprogression-free
Time (months)
60%reduction in
risk of
progressionor death withpazopanib vs
placebo
0 5 10 15 20
Number at riskPazopanib 155 84 39 11 1
Placebo 78 22 7 2
Median PFS
Pazopanib (n=155): 11.1 months
Placebo (n=78): 2.8 months
p
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Exper t Op in ionJul-Aug 201244
Cetuximab rechallenge: Extending
clinical benefits in mCRC
Dr. Hui
While the benets o rst-line chemotherapy plus cetuximab
top related