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Erbitux

Generic name: cetuximab
Treatment for: Colorectal Cancer, Head and Neck Cancer

ImClone Submits Supplemental Biologics License Application for Erbitux in First-Line Head and Neck Cancer

NEW YORK--(BUSINESS WIRE)--Sep 3, 2008 - ImClone Systems Incorporated today announced that it has submitted an application to the U.S. Food and Drug Administration (FDA) to broaden the use of Erbitux (cetuximab) to include first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The application, submitted on August 29, 2008, was prepared in conjunction with Bristol-Myers Squibb Company, ImClone's partner for Erbitux in North America. ImClone has requested Priority Review of the application, which, if granted, means that the FDA would make a decision on the application within six months. The FDA will notify ImClone whether it has accepted the submission by the end of October.

Erbitux was approved by the FDA in March 2006 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. In that approval, the FDA noted that Erbitux was the first drug ever approved for head and neck cancer that showed a survival benefit in locally or regionally advanced SCCHN. If approved, the submitted label would extend the use of Erbitux for treatment of patients with recurrent and/or metastatic SCCHN in combination with platinum-based chemotherapy.

"As the first new therapy to be approved for head and neck cancer in the last 45 years, the additional approval of Erbitux in the first-line setting would represent a real breakthrough in the treatment of this disease," said Eric K. Rowinsky, M.D., Chief Medical Officer and Executive Vice President of ImClone. "This submission is an important milestone in ImClone's ongoing efforts to maximize the potential of Erbitux and provide cancer patients with new treatment options."

The submission is based on data from the EXTREME study(1) (Erbitux in first-line Treatment of REcurrent or MEtastatic head and neck cancer) investigating the efficacy of Erbitux in combination with platinum-based chemotherapy in the first-line setting in patients with recurrent and/or metastatic SCCHN. The EXTREME study, conducted by Merck KGaA, Darmstadt, Germany, ImClone's Erbitux partner outside of North America, showed that Erbitux, when added to current standard platinum-based chemotherapy, significantly increased the overall survival time for patients.

The Phase 3 randomized EXTREME study involved 442 patients with previously untreated recurrent and/or metastatic SCCHN who were treated with either Erbitux plus platinum-based chemotherapy (cisplatin or carboplatin plus infusional 5-fluorouracil (5-FU)) or platinum-based chemotherapy alone. The study met the primary endpoint of significantly increasing overall survival. The median overall survival for patients in the Erbitux plus platinum-based chemotherapy arm was 10.1 months, and 7.4 months for patients treated with platinum-based chemotherapy alone (Hazard Ratio (HR), 0.797 (p = 0.036)).(1) Erbitux plus platinum-based chemotherapy also conferred increased progression-free survival (PFS) and a higher response rate compared with chemotherapy alone. The median PFS values were 5.6 months and 3.3 months (HR = 0.538 (p less than 0.0001)) and the response rates were 35.6% and 19.5% (p = 0.0002) for patients treated with Erbitux plus chemotherapy and chemotherapy alone, respectively. Findings from the EXTREME study were 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.(1)

The toxicity profile of Erbitux in combination with platinum-based chemotherapy was manageable.

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.

About Head and Neck Cancer

According to the American Cancer Society, there will be an estimated 47,500 new cases of head and neck cancer in the U.S. in 2008, with 11,200 people dying from the disease.(2) Head and neck cancer is the sixth most frequently occurring cancer worldwide. About 40% of patients suffering from head and neck cancer are in the recurrent/metastatic state.(3) Head and neck cancer includes cancers of the tongue, mouth, salivary glands, pharynx, larynx, sinus, and other sites located in the head and neck area. About 90% of head and neck cancers are of the squamous cell variety(4) and nearly all express epidermal growth factor receptor, or EGFR, which is critical for tumor growth.(5) Although there have been significant improvements in chemotherapy and surgical techniques, the disease is particularly challenging to treat since most patients present with advanced disease, have secondary tumors and suffer from other co-morbidities.(6) The disease 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. Additionally, infection with certain strains of the Human Papilloma Virus (HPV) is known to increase risk of oropharyngeal cancers.(2)

References

1. Vermorken JB, et al. J Clin Oncol 2007;25(18S). Abstract 6091.

2. American Cancer Society.

3. www-dep.iarc.fr. April 2002.

4. Hunter KD, et al. Nat Rev Cancer. 2005 Feb; 5 (2): 127-35.

5. Bourhis J and Pinto H. Redefining 'State of the Art' in Head and Neck Cancer. Oral presentation, 6th International Conference on Head and Neck Cancer 7-11 August 2004.

6. Forastiere A, et al. N Engl J Med 2001:345(26), 1890-1900.

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

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 reactions (90%) 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 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.

Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (less than0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux where ILD is confirmed.

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.

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.

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.

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.

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.

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 (=> 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 => 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 gastrointestinal-other (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 global 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 projected. 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, including quarterly reports on Form 10-Q, current reports on Form 8-K and annual reports on Form 10-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.

Contact

ImClone Systems Incorporated
Tracy Henrikson, 908-243-9945
Corporate Communications
media@imclone.com

Posted: September 2008

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