Study Published In New England Journal Of Medicine Shows ERBITUX® Improved Survival In First-Line Recurrent And/Or Metastatic Head And Neck Cancer

Main Category: Ear, Nose and Throat
Also Included In: Cancer / Oncology;  Clinical Trials / Drug Trials;  Pharma Industry / Biotech Industry
Article Date: 12 Sep 2008 - 4:00 PDT

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ImClone Systems Incorporated (NASDAQ: IMCL) and Bristol-Myers Squibb Company (NYSE: BMY) announced the publication of results from a Phase 3 trial in the New England Journal of Medicine of ERBITUX® (cetuximab) plus platinum-based chemotherapy in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Results of the study, known as EXTREME (ErbituX in first-line Treatment of REcurrent or MEtastatic head & neck cancer) and conducted by Merck KGaA, Darmstadt, Germany, show that adding ERBITUX to a platinum-based chemotherapy in the first-line treatment of SCCHN resulted in statistically significant improvement in the primary endpoint of overall survival, as well as secondary endpoints of progression-free survival and overall response rate.

The open-label, multicenter, randomized study enrolled a total of 442 patients with previously untreated recurrent and/or metastatic SCCHN randomized to receive either ERBITUX along with a platinum-based chemotherapy (cisplatin or carboplatin) plus 5-fluorouracil (5-FU), or chemotherapy alone. Platinum-based chemotherapy is currently the standard treatment for recurrent or metastatic SCCHN. Results show that patients who received ERBITUX plus platinum-based chemotherapy experienced a statistically significant increase in median overall survival of 2.7 months, compared to patients who received chemotherapy alone (10.1 months vs. 7.4 months, respectively) [HR: 0.80; 95% CI: 0.64-0.99; p=0.036]. Patients who received ERBITUX plus platinum-based chemotherapy also experienced a significant increase in median progression-free survival of 2.3 months (5.6 vs. 3.3 months, respectively) [HR: 0.54; 95% CI: 0.43-0.67; p<0.001] and an 80 percent relative increase in tumor response rate compared to chemotherapy alone (36% vs. 20%, respectively; p<0.001).

"With the results of EXTREME, ERBITUX is now the first biologic to demonstrate a significant survival improvement for patients with recurrent or metastatic head and neck cancer," said Eric K. Rowinsky, M.D., Chief Medical Officer and Executive Vice President, ImClone. "We are committed to exploring the utility and developing ERBITUX in a much wider range of cancers."

"These results add to the growing body of ERBITUX data for the treatment of head and neck cancer," said Maurizio Voi, M.D., Executive Director, Oncology Global Medical Affairs, Bristol-Myers Squibb. "Through our comprehensive research program, we continue to explore and answer important questions for patients and health care professionals about the potential use of ERBITUX to treat a variety of cancers particularly those with the highest unmet treatment needs."

In EXTREME, the most common grade 3 or 4 adverse events in the chemotherapy-alone and ERBITUX groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%, respectively), and thrombocytopenia (11% in both groups). Sepsis occurred in nine patients in the ERBITUX group and in one patient in the chemotherapy-alone group (p=0.02). Of 219 patients receiving ERBITUX, nine percent had grade 3 skin reactions (vs. 0% in chemotherapy-alone group; p<0.001) and six patients experienced grade 3 or 4 infusion-related reactions. There were no ERBITUX-related deaths.

ERBITUX is currently approved in the United States for use in combination with radiation therapy for the treatment of locally or regionally advanced SCCHN, and as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.

This study is the basis for the recent supplemental biologics license application (sBLA) submitted by ImClone to the U.S. Food and Drug Administration (FDA) on August 29, 2008. These data were previously presented at the American Society of Clinical Oncology (ASCO) meeting in June 2007 and at the European Congress of Clinical Oncology (ECCO) in September 2007.

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.1 In addition, it is estimated that more than 13,090 Americans will die from this disease this year.2 Head and neck cancer most often affects people over the age of 50, and men are twice as likely to be diagnosed as women.3 The most common risk factors are tobacco and excessive alcohol use.4

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.

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, loss of consciousness, 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 (less than 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, 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/m2) 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 greater than or equal to 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 greater than or equal to 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 (greater than or equal to 10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%)

-- The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence greater than or equal to 50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (greater than or equal to 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 greater than or equal to 50%) were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (greater than or equal to 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 and related health care products company whose mission is to extend and enhance human life.

References

1 American Cancer Society: Cancer Fact and Figures 2008.

2 American Cancer Society: Cancer Fact and Figures 2008.

3 National Cancer Institute (3/9/2005). "Head and Neck Cancers: Questions and Answers." http://www.cancer.gov/cancertopics/factsheet/sites-types/head-and-neck Accessed September 9, 2008.

4 American Cancer Society: Cancer Facts and Figures 2007.