Healthcare Industry News:  Bristol-Myers Squibb 

Biopharmaceuticals Oncology

 News Release - October 22, 2008

Study Published in New England Journal of Medicine Shows K-ras Gene Mutation Status May Affect Response to ERBITUX(R) Treatment

Near Doubling of Survival in Wild-Type or "Normal" K-ras Patients Treated with ERBITUX

NEW YORK--(HSMN NewsFeed)--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.

-- 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).

--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).

“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.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

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

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

Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines

Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions

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

Pulmonary Toxicity

--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

Dermatologic Toxicities

--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

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

Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae

Sun exposure may exacerbate these effects

Electrolyte Depletion

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

Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy

Replete electrolytes as necessary

Pregnancy

--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

Adverse Events

--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

--The most common adverse reactions associated with ERBITUX (incidence =25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

--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%)

--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%)

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.


Source: Bristol-Myers Squibb

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