Results from Extended Follow-Up of Pivotal CRYSTAL Study
Medical Research Council's COIN Trial Presented at Presidential Session III

BERLIN--(BUSINESS WIRE)--Sep. 23, 2009-- According to a recent retrospective analysis of the pivotal Phase 3 CRYSTAL study, ERBITUX® (cetuximab), when added to FOLFIRI, was shown to increase median overall survival to 19.9 months in an intent-to-treat (ITT) population of first-line metastatic colorectal cancer (mCRC) patients compared to 18.6 months in those receiving FOLFIRI alone (hazard ratio [HR] 0.878; 95% CI 0.774 - 0.995; p=0.042). In a subset of mCRC patients with wild-type K-ras tumors, median overall survival was increased to 23.5 months in patients who received ERBITUX plus FOLFIRI compared to 20 months for those taking FOLFIRI alone (HR 0. 796; 95% CI 0.670 - 0.946; p=0.0094).

The retrospective CRYSTAL analysis was conducted as a result of an effort to increase the tissue ascertainment rate to determine the K-ras status of patients' tumors. The analysis included extended patient follow up of nearly 1.5 years and doubled the tissue ascertainment rate from 45% to 89%. These data are an update from the overall survival results from CRYSTAL that were published in the April 2009 issue of the New England Journal of Medicine.

The recently completed retrospective analysis from CRYSTAL, a multi-national study conducted by Merck KGaA, Darmstadt, Germany, marks the first time an overall survival benefit has been demonstrated with an epidermal growth factor (EGFR)-inhibitor in the first-line treatment of mCRC in an ITT patient population and in a K-ras wild-type subset of patients. An ITT analysis considers all randomized patients in a clinical trial.

In the CRYSTAL trial, the following Grade 3 or 4 adverse events were reported in the April 2009 New England Journal of Medicine as being more frequent with ERBITUX plus FOLFIRI than FOLFIRI alone in the overall patient population: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, p<0.001), infusion-related reactions (in 2.5% vs. 0%, p<0.001), and diarrhea (in 15.7% vs. 10.5%, p=0.008).

A second Phase 3 study of ERBITUX plus chemotherapy (primarily capecitabine plus oxaliplatin) in first-line mCRC, known as COIN, was conducted in the UK by the Medical Research Council, a UK-based publicly funded organization. The COIN study did not meet its primary endpoint of overall survival in K-ras wild type patients receiving ERBITUX plus chemotherapy vs. chemotherapy alone (17 months vs. 17.9 months) (HR 1.038; 95% CI 0.90 - 1.20; p=0.68). Patients with K-ras wild type tumors receiving ERBITUX plus chemotherapy experienced an increase in the following Grade 3 or 4 adverse events vs. those taking chemotherapy alone: non-hematological events (77% vs. 62%), diarrhea (24% vs. 14%), hypomagnes-aemia (4% vs. 0%), hand foot syndrome (11% vs. 4%) and skin rash (20% vs. <1%).

About ERBITUX^® (cetuximab)

In mCRC, ERBITUX is approved by the U.S. Food and Drug Administration as: a single agent for the treatment of EGFR-expressing MCRC after failure of both irinotecan- and oxaliplatin-based regimens; a single agent for the treatment of EGFR-expressing mCRC in patients who are intolerant to irinotecan-based regimens; and in combination with irinotecan for the treatment of EGFR-expressing mCRC 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. Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations.

For Full Prescribing Information, including BOXED WARNINGS, visit http://www.ERBITUX.com.

Important Safety Information Including BOXED WARNINGS

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
  • Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions
• 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 may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. 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

Additional information about ImClone, a wholly-owned subsidiary of Eli Lilly and Company, is available at www.imclone.com.

About Eli Lilly and Company

Additional information about Lilly is available at www.lilly.com.

About Bristol-Myers Squibb

Additional information about Bristol-Myers Squibb is available at www.bms.com.

ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company (NYSE: LLY), licensed to Bristol-Myers Squibb Company (NYSE: BMY) for commercialization in the U.S. and Canada and to Merck KGaA, Darmstadt, Germany, for commercialization outside the US and Canada. In Japan, ImClone Systems, Bristol-Myers Squibb and Merck KGaA jointly develop and commercialize ERBITUX.

Eli Lilly and Company
Marni Lemons
Tel: 317-433-8990
Cell: 317-532-7826
mlemons@lilly.com
or
ImClone Systems
Tracy Henrikson, 908-243-9945
Tracy.Henrikson@imclone.com
or
Bristol-Myers Squibb
Media
Sarah Koenig
Tel: 609-252-4145
Cell: 908-397-5379
Sarah.Koenig@bms.com
or
Investors
John Elicker, 609-252-4611
John.Elicker@bms.com