BERLIN –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%).
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.
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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
Tracy Henrikson, 908-243-9945
John Elicker, 609-252-4611