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Biopharmaceuticals Oncology

 News Release - September 16, 2008

ImClone Provides Update on Pivotal Phase 3 CRYSTAL Study in First-Line Metastatic Colorectal Cancer

Median Survival of 24.9 Months Demonstrated in Subset of Patients with K-Ras Wild-Type Oncogene

NEW YORK--(HSMN NewsFeed)--ImClone Systems Incorporated (NASDAQ: IMCL ) today announced an update from the previously reported positive Phase 3 CRYSTAL study of ERBITUX® (cetuximab) plus FOLFIRI, an irinotecan-based chemotherapy, in patients with previously untreated metastatic colorectal cancer (mCRC). These data were presented today at the 33rd European Society for Medical Oncology (ESMO) Congress in Stockholm.

As reported in 2007, the 1,198-patient CRYSTAL (Cetuximab combined with iRinotecan in first line therapY for metaSTatic colorectAL cancer) study, conducted by Merck KGaA, Darmstadt, Germany, met its primary endpoint of increasing progression-free survival (PFS). The study did not, however, demonstrate a statistically significant prolongation of overall survival, a secondary endpoint, compared to chemotherapy alone. In the recently completed analysis, the median overall survival of all ERBITUX-treated patients was 19.9 months compared to 18.6 months for FOLFIRI alone (Hazard Ratio [HR]=0.931, p=0.305). Notably, the median overall survival of ERBITUX-treated patients whose colon cancer had the non-mutated, or “wild-type,” form of the K-Ras oncogene, which is noted in about 65% of patients with mCRC, was 24.9 months, 4 months difference, compared to 21 months for FOLFIRI alone (HR=0.844, p=0.217). These survival times are among the longest seen in this indication.

As previously reported, the addition of ERBITUX to FOLFIRI in the CRYSTAL study decreased the risk of disease progression by 15% (8.9 months vs. 8.0 months, p=0.048) and demonstrated a 21% improvement in the response rate (46.9% vs. 38.7%, p=0.004). Additionally, as presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2008, a subsequent subset analysis of the CRYSTAL study demonstrated that patients whose tumors were K-Ras wild-type had the greatest benefit from ERBITUX treatment. In patients with K-Ras wild-type tumors, the addition of ERBITUX to FOLFIRI compared to FOLFIRI alone resulted in a 32% decrease in risk of progression (9.9 months vs. 8.7 months, HR=0.68, p=0.017) and a significant increase in response rate up to 59% (59.3% vs. 35%, p=0.003). Results of the K-Ras subset analysis in the CRYSTAL study are based on 540 patients with evaluable tumor samples; the K-Ras mutation was detected in 192 of those patients (36%).

A preliminary review of the data reveals that a greater proportion of patients randomized to the FOLFIRI-only arm went on to receive ERBITUX following the development of disease progression compared to patients randomized to FOLFIRI plus ERBITUX. This may explain why the CRYSTAL study met its primary endpoint of PFS but did not achieve a statistically-significant secondary endpoint of overall survival. Based on the results of the NCIC CTG CO.17 study, ERBITUX is known to improve overall survival following failure of irinotecan treatment.

“We believe healthcare professionals will find these results important, particularly those that pertain to ERBITUX as a treatment option for the approximately 65 percent of colorectal cancer patients whose tumors are K-Ras wild-type,” said Eric K. Rowinsky, M.D., Chief Medical Officer and Executive Vice President of ImClone. “ImClone is committed to developing ERBITUX and all of its pipeline agents in patients with the most appropriate molecular profile for each agent in order to achieve the best therapeutic outcomes.”

ImClone is planning to submit the results of the CRYSTAL study to the U.S. Food and Drug Administration (FDA) for registrational purposes.

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 (<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 =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 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 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.


Source: ImClone Systems

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