Near Doubling of Survival in Wild-Type or “Normal”
K-ras Patients Treated with ERBITUX
ImClone
Systems Incorporated (NASDAQ: IMCL) and Bristol-Myers
Squibb Company (NYSE: BMY) today announced the publication of study
results showing that metastatic colorectal cancer (mCRC) patients with
wild-type or “normal”
K-ras tumors who were treated with ERBITUX®
(cetuximab) plus best supportive care (BSC) had a statistically
significant increase in overall survival and progression-free survival
compared to those treated with BSC alone. Specifically, patients whose
tumors had the normal (mutant negative) K-ras gene achieved
a near two-fold improvement in overall survival and progression-free
survival over patients treated with BSC alone. In patients with mutated K-ras
tumors, there was no significant difference in overall or
progression-free survival between those treated with ERBITUX plus BSC
and those treated with BSC alone.
These analyses build on previously reported results of the study, which
demonstrated that treating patients with ERBITUX as a monotherapy plus
BSC significantly increased overall survival compared to BSC alone in
patients with unknown K-ras status.
The results of the K-ras analysis of the study were published in
the October 23, 2008 issue of the New England Journal of Medicine.
The data are from a retrospective analysis of the 394 available
archived tissue samples from the previously conducted pivotal Phase 3
study NCIC CTG CO.17. These results were announced in June 2008 at the 10th
World Congress on Gastrointestinal Cancer in Barcelona, Spain.
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In the 230 patients with normal, non-mutated, wild-type K-ras
tumors, median overall survival was 9.5 months for patients
treated with ERBITUX plus BSC, and 4.8 months with BSC alone
(Hazard Ratio [HR]=0.55;
95% Confidence Interval [CI]=0.41
to 0.74; p<0.001); median progression-free survival was 3.7 months
and 1.9 months, respectively (HR=0.40; 95% CI=0.30 to 0.54;
p<0.001).
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In the 164 patients with mutated K-ras tumors, median overall
survival was 4.5 months with ERBITUX plus BSC, and 4.6 months with
BSC alone (HR=0.98; 95% CI=0.70 to 1.37; p=0.89); median
progression-free survival was 1.8 months for both treatment groups
(HR=0.99; 95% CI=0.73 to 1.35; p=0.96).
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“These results provide critical insight as we
progress toward fully understanding the role of K-ras as a
predictive biomarker in the treatment of patients with advanced colon
cancer,” said Christos Karapetis, M.D., the
study’s lead investigator from Flinders
Medical Centre and Flinders University, Adelaide, Australia.
“These data provide us with important
information about which mCRC patients may benefit from ERBITUX,”
said Maurizio Voi, M.D., Executive Director, Oncology Global Medical
Affairs, Bristol-Myers Squibb. “We will
continue to study the role of K-ras so that we can understand how
best to utilize ERBITUX in treatment regimens for patients with
colorectal cancer.”
“We are encouraged by a near doubling of both
overall survival and progression-free survival times in mCRC
ERBITUX-treated patients with wild-type K-ras tumors, which is
consistent with the results demonstrated in other randomized studies of
ERBITUX in early mCRC treatment settings,”
said Eric K. Rowinsky, M.D., Chief Medical Officer and Executive Vice
President of ImClone. “These results add to
the growing body of ERBITUX data and further support the potential use
of ERBITUX as an important treatment option for the approximately 60
percent of colorectal cancer patients whose tumors are K-ras wild-type.”
About Study NCIC CTG CO.17
The Phase 3 study NCIC CTG CO.17 was designed to compare ERBITUX plus
BSC to BSC alone in patients with epidermal growth factor receptor
(EGFR)-expressing mCRC whose disease had progressed through treatment
with all approved chemotherapy, including irinotecan, oxaliplatin, and
fluoropyrimidines. The full analysis of the study results –
which demonstrated that treating patients with ERBITUX as a monotherapy
plus BSC significantly increased overall survival compared to BSC alone –
were previously published in the Nov. 15, 2007 edition of the New
England Journal of Medicine. BSC included palliative therapies
designed to alleviate pain and treat other effects caused by mCRC.
Of the 572 patients initially enrolled in the previously published
study, K-ras mutation status was ascertained in 394 patients
(wild-type K-ras: n=230; mutated K-ras: n=164). Baseline
characteristics for the 394 K-ras-evaluable patients were similar
to that of the overall population.
This independent, multicenter, open-label, randomized study was
conducted by the National Cancer Institute of Canada Clinical Trials
Group (NCIC CTG) in collaboration with the Australasian
Gastro-Intestinal Trials Group (AGITG).
About K-ras
K-ras is a gene that codes for a protein that plays an important
role downstream of the EGFR in the signaling pathway.1
There are two different types of the K-ras gene found in tumors,
either normal or non-mutated K-ras, known as wild-type K-ras,
or an abnormal, mutated gene known as mutant K-ras. In the mutant K-ras
tumors, the K-ras gene is constitutively activated resulting in
continuous signaling independent of EGFR activation. Approximately 60
percent of patients with colorectal cancer are classified as having “normal”
or wild-type K-ras status and approximately 40 percent of
patients with CRC have a mutated K-ras gene2.
About ERBITUX®
(Cetuximab)
ERBITUX (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to
inhibit the function of a molecular structure expressed on the surface
of normal and tumor cells called the epidermal growth factor receptor
(EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal
studies have shown that binding of ERBITUX to the EGFR blocks
phosphorylation and activation of receptor-associated kinases, resulting
in inhibition of cell growth, induction of apoptosis, and decreased
matrix metalloproteinase and vascular endothelial growth factor
production. In vitro, ERBITUX can mediate antibody-dependent
cellular cytotoxicity (ADCC) against certain human tumor types. In
vitro assays and in vivo animal studies have shown that
ERBITUX inhibits the growth and survival of tumor cells that express the
EGFR. No anti-tumor effects of ERBITUX were observed in human tumor
xenografts lacking EGFR expression.
Colorectal Cancer
ERBITUX, as a single agent, is indicated for the treatment of
EGFR-expressing metastatic colorectal cancer after failure of both
irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent,
is also indicated for the treatment of EGFR-expressing metastatic
colorectal cancer in patients who are intolerant to irinotecan-based
regimens.
ERBITUX, in combination with irinotecan, is indicated for the treatment
of EGFR-expressing metastatic colorectal carcinoma in patients who are
refractory to irinotecan-based chemotherapy. The effectiveness of
ERBITUX in combination with irinotecan is based on objective response
rates. Currently, no data are available that demonstrate an improvement
in disease-related symptoms or increased survival with ERBITUX in
combination with irinotecan for the treatment of EGFR-expressing
metastatic colorectal carcinoma.
For full prescribing information, including boxed WARNINGS regarding
infusion reactions and cardiopulmonary arrest, visit http://www.ERBITUX.com.
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IMPORTANT SAFETY INFORMATION
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Infusion Reactions
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Grade 3/4 infusion reactions occurred in approximately 3% of
patients receiving ERBITUX (cetuximab) in clinical trials, with
fatal outcome reported in less than 1 in 1000
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Serious infusion reactions, requiring medical intervention and
immediate, permanent discontinuation of ERBITUX, included rapid
onset of airway obstruction (bronchospasm, stridor, hoarseness),
hypotension, shock, loss of consciousness, myocardial infarction
and/or cardiac arrest
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Most (90%) of the severe infusion reactions were associated
with the first infusion of ERBITUX despite premedication with
antihistamines
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Caution must be exercised with every ERBITUX infusion, as there
were patients who experienced their first severe infusion reaction
during later infusions
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Monitor patients for 1 hour following ERBITUX infusions in a
setting with resuscitation equipment and other agents necessary to
treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous
antihistamines, bronchodilators, and oxygen). Longer observation
periods may be required in patients who require treatment for
infusion reactions
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Pulmonary Toxicity
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Interstitial lung disease (ILD), which was fatal in one case,
occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in
clinical trials. Interrupt ERBITUX for acute onset or worsening of
pulmonary symptoms. Permanently discontinue ERBITUX where ILD is
confirmed
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Dermatologic Toxicities
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In clinical studies of ERBITUX, dermatologic toxicities, including
acneform rash, skin drying and fissuring, paronychial
inflammation, infectious sequelae (eg, S. aureus sepsis,
abscess formation, cellulitis, blepharitis, conjunctivitis,
keratitis, cheilitis), and hypertrichosis, occurred in patients
receiving ERBITUX therapy. Acneform rash occurred in 76-88% of
1373 patients receiving ERBITUX in clinical trials. Severe
acneform rash occurred in 1-17% of patients
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Acneform rash usually developed within the first two weeks of
therapy and resolved in a majority of the patients after cessation
of treatment, although in nearly half, the event continued beyond 28
days
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Monitor patients receiving ERBITUX for dermatologic toxicities and
infectious sequelae
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Sun exposure may exacerbate these effects
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Electrolyte Depletion
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Hypomagnesemia occurred in 55% (199/365) of patients receiving
ERBITUX and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset
of hypomagnesemia and accompanying electrolyte abnormalities
occurred days to months after initiation of ERBITUX therapy
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Monitor patients periodically for hypomagnesemia, hypocalcemia and
hypokalemia, during, and for at least 8 weeks following the
completion of, ERBITUX therapy
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Replete electrolytes as necessary
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Pregnancy
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In women of childbearing potential, appropriate contraceptive
measures must be used during treatment with ERBITUX and for 6
months following the last dose of ERBITUX. ERBITUX should only be
used during pregnancy if the potential benefit justifies the
potential risk to the fetus
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Adverse Events
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The most serious adverse reactions associated with ERBITUX
across metastatic colorectal cancer studies were infusion
reactions, dermatologic toxicity, sepsis, renal failure,
interstitial lung disease, and pulmonary embolus
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The most common adverse reactions associated with ERBITUX
(incidence ≥25%) are cutaneous adverse
reactions (including rash, pruritus, and nail changes), headache,
diarrhea, and infection
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The most frequent adverse events seen in patients with metastatic
colorectal cancer (n=288) in the ERBITUX + best supportive care
arm (incidence ≥ 50%) were fatigue
(89%), rash/desquamation (89%), abdominal pain (59%), and
pain-other (51%). The most common grade 3/4 adverse events (≥10%)
included: fatigue (33%), pain-other (16%), dyspnea (16%),
abdominal pain (14%), infection without neutropenia (13%),
rash/desquamation (12%), and other-gastrointestinal (10%)
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The most frequent adverse events seen in patients with metastatic
colorectal cancer (n=354) treated with ERBITUX plus irinotecan in
clinical trials (incidence ≥ 50%) were
acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and
nausea (55%). The most common grade 3/4 adverse events (≥
10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise
(16%), and acneform rash (14%)
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About ImClone Systems
ImClone Systems Incorporated is a fully integrated biopharmaceutical
company committed to advancing oncology care by developing and
commercializing a portfolio of targeted biologic treatments designed to
address the medical needs of patients with a variety of cancers. The
Company’s research and development programs
include growth factor blockers and angiogenesis inhibitors. ImClone
Systems’ headquarters and research operations
are located in New York City, with additional administration and
manufacturing facilities in Branchburg, New Jersey. For more information
about ImClone Systems, please visit the Company’s
web site at http://www.imclone.com.
ERBITUX® is a
registered trademark of ImClone Systems Incorporated.
Certain matters discussed in this news release may constitute
forward-looking statements within the meaning of the Private Securities
Litigation Reform Act of 1995 and the Federal securities laws. Although
the company believes that the expectations reflected in such
forward-looking statements are based upon reasonable assumptions it can
give no assurance that its expectations will be achieved.
Forward-looking information is subject to certain risks, trends and
uncertainties that could cause actual results to differ materially from
those currently expected. Many of these factors are beyond the company's
ability to control or predict. Important factors that may cause actual
results to differ materially and could impact the company and the
statements contained in this news release can be found in the company's
filings with the Securities and Exchange Commission, particularly those
factors identified as “risk factors”
in the Company’s most recent annual report of
Form 10-K and in its quarterly reports on Form 10-Q and current reports
on Form 8-K. For forward-looking statements in this news release, the
company claims the protection of the safe harbor for forward-looking
statements contained in the Private Securities Litigation Reform Act of
1995. The company assumes no obligation to update or supplement any
forward-looking statements whether as a result of new information,
future events or otherwise.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to extend and enhance human life. For more information, visit www.bms.com.
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding product development. Such forward-looking statements are based
on current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Forward-looking statements in this press release should be evaluated
together with the many uncertainties that affect Bristol-Myers Squibb's
business, particularly those identified in the cautionary factors
discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the
year ended December 31, 2007, in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement, whether as
a result of new information, future events or otherwise.
1 Salomon DS, Brandt R, Ciardiello F, et al.
Epidermal growth factor-related peptides and their receptors in human
malignancies. Crit Rev Oncol Hematol 1995;19:183-232.
2 Bos JL, et al. Nature, 1987; 327:293-297.
Media and Investors:
ImClone Systems Incorporated
Tracy
Henrikson, 908-243-9945
Corporate Communications
Tracy.Henrikson@imclone.com
or
Rebecca
Gregory, 646-638-5058
Corporate Communications
Rebecca.Gregory@imclone.com
or
Bristol-Myers
Squibb
Media
Brian Henry, 609-252-3337
Brian.Henry@bms.com
or
Investors
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John.Elicker@bms.com
