ErbituxTreatment for Colorectal Cancer, Head and Neck Cancer
Erbitux Supplemental Biologics License Application for First-Line Recurrent or Metastatic Head and Neck Cancer Accepted for Priority Review by U.S. Food and Drug Administration
NEW YORK--(BUSINESS WIRE)--Oct 30, 2008 - ImClone Systems Incorporated (NASDAQ: IMCL) and Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing and review the companies' supplemental Biologics License Application (sBLA) to broaden the indication for Erbitux (cetuximab) to include use in combination with platinum-based chemotherapy for the first-line treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The companies also announced today that, as requested, the application has been granted a priority review designation by the FDA. Priority review status indicates that the FDA will aim to complete its review of the sBLA within six months.
The sBLA submission is based on data from the randomized Phase 3 EXTREME (Erbitux in first-line Treatment of REcurrent or MEtastatic head and neck cancer) study(1) investigating the efficacy of Erbitux in combination with platinum-based chemotherapy in the first-line treatment of patients with recurrent or metastatic SCCHN. The study was conducted by Merck KGaA, Darmstadt, Germany, the partner of ImClone for Erbitux outside of North America, and showed that Erbitux, in combination with platinum-based chemotherapy, resulted in a statistically significant improvement in median overall survival time compared with chemotherapy alone.
If approved, this will be the third U.S. indication for Erbitux in head and neck cancer. Erbitux was initially approved to treat locally or regionally advanced SCCHN in combination with radiation therapy, and as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed, in March 2006. At that time, the FDA noted that Erbitux was the first drug approved for head and neck cancer since the 1950's, and that the data showed a survival benefit for Erbitux in combination with radiation compared with radiation alone in locally or regionally advanced SCCHN.(1) Erbitux remains the first and only monoclonal antibody to be approved by the FDA for this type of cancer.
"There is a significant need for new therapeutic options in the first-line treatment of patients with head and neck cancer," said Eric K. Rowinsky, M.D., Chief Medical Officer and Executive Vice President of ImClone. "The granting of a priority review for this sBLA by the FDA underscores this unmet need and is a designation given to drugs that potentially offer a significant therapeutic advance over currently available treatments for serious diseases."
The EXTREME study randomized 442 patients with previously untreated recurrent or metastatic SCCHN to receive treatment with either Erbitux plus platinum-based chemotherapy (cisplatin or carboplatin plus infusional 5-fluorouracil (5-FU)) or platinum-based chemotherapy alone, for a maximum of 6 cycles.(2) Erbitux was administered at a 400 mg/m(2) initial dose, followed by a 250 mg/m(2) weekly dose in combination with chemotherapy. After completing chemotherapy plus Erbitux, patients were able to continue on a 250 mg/m(2) weekly dose of Erbitux. Results showed that patients who received Erbitux plus platinum-based chemotherapy experienced a statistically significant increase in the primary endpoint of median overall survival compared to patients who received chemotherapy alone (10.1 months vs. 7.4 months, respectively; Hazard Ratio (HR)=0.80; 95% Confidence Interval (CI)=0.64-0.99; p = 0.04).(1) Patients who received Erbitux plus platinum-based chemotherapy also showed a significant increase in median progression-free survival (5.6 months vs. 3.3 months, respectively; HR=0.54; 95% CI=0.43-0.67; p<0.001) and a significantly higher tumor response rate (36% vs. 20%, respectively; p<0.001) compared to those that received chemotherapy alone. Both were secondary endpoints of the study. Grade 3 or 4 adverse events occurring in >5% of patients in either treatment group included: neutropenia, anemia, thrombocytopenia, leukopenia, skin reactions, hypokalemia, cardiac events, asthenia, and dyspnea.
Findings from the EXTREME study were recently published in the September 11, 2008 issue of the New England Journal of Medicine.
Also, as previously announced, Merck KGaA submitted an application to the European Medicines Agency (EMEA) in June 2008 to broaden the use of Erbitux to include first-line treatment of patients with recurrent and/or metastatic SCCHN.(3)
About Head and Neck Cancer
According to the American Cancer Society, 87,290 Americans will be diagnosed with head and neck cancer in 2008, including cancers of the tongue, the rest of the mouth, the salivary glands and inside the throat, the voice box, eye and orbit, thyroid and the lymph nodes in the upper neck. In addition, it is estimated that more than 13,090 Americans will die from this disease this year. Head and neck cancer most often affects people over the age of 50, and men are twice as likely to be diagnosed as women. The most common risk factors are tobacco and excessive alcohol use.
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.
Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Erbitux, in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck.
Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed.
IMPORTANT SAFETY INFORMATION
Infusion Reactions -0-
-- 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 Cardiopulmonary Arrest -- Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last Erbitux treatment -- Carefully consider the use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks -- Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after Erbitux therapy 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 Erbitux Plus Radiation Therapy and Cisplatin -- The safety of Erbitux in combination with radiation therapy and cisplatin has not been established -- Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m(2)) in patients with locally advanced squamous cell carcinoma of the head and neck -- Two of 21 patients died, one as a result of pneumonia and one of an unknown cause -- Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events 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 Late Radiation Toxicities -- The overall incidence of late radiation toxicities (any grade) was higher with Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the Erbitux and radiation versus radiation alone arms, respectively -- The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the Erbitux plus radiation therapy arms 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 all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, 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 carcinomas of the head and neck receiving Erbitux in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence >=50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for Erbitux in combination with radiation therapy ((>=)10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%)
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. Among other risks, there can be no guarantee that the supplemental application will be approved. 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. -0-
(1) FDA News, FDA Approves First Head & Neck Cancer Treatment in 45 Years; Data Shows Treatment with Erbitux Extends Survival. http://www.fda.gov/bbs/topics/news/2006/new01329.html. Accessed October 14, 2008. (2) Vermoken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 358:116- 1127. (3) News Release. Merck Applies to Extend Use of Erbitux for First- Line Head and Neck Cancer in Europe. http://news.merck.de/emd/cc/newsrelease.nsf/d6db9bdc0c08af7ec 1257243005130ee/13d501339b5c59f7c125746d00358437?OpenDocument. Accessed October 14, 2008. (Due to its length, this URL may need to be copied/pasted into your Internet browser's address field. Remove the extra space if one exists.)
Media and Investor:
ImClone Systems Incorporated
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ImClone Systems Incorporated
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Posted: October 2008
- FDA Approves Erbitux to Treat Late-stage Head and Neck Cancer - November 7, 2011
- Erbitux Supplemental Biologics License Application for Advanced Non-Small Cell Lung Cancer Submitted to U.S. Food and Drug Administration - December 8, 2008
- ImClone Submits Supplemental Biologics License Application for Erbitux in First-Line Head and Neck Cancer - September 3, 2008
- Merck Applies to Extend Use of Erbitux for 1st-Line Colorectal Cancer - September 4, 2007
- FDA Accepts and Grants Priority Review of Erbitux (Cetuximab) sBLA for Overall Survival in Patients With Advanced Colorectal Cancer - June 11, 2007
- ImClone Systems Incorporated and Bristol-Myers Squibb File Supplemental Biologics License Application for Erbitux for Treatment of Head and Neck Cancer - August 30, 2005
- Erbitux ImClone - Treatment for Advanced Colorectal Cancer - February 12, 2004