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FDA Approves Cetuximab Plus FOLFIRI for Metastatic Colorectal Cancer

Ben Leach
Published: Tuesday, Jul 10, 2012

Erbitux (Cetuximab) The FDA has approved cetuximab (Erbitux, Bristol Myers-Squibb and Eli Lilly) in combination with the irinotecan, 5-fluorouracil, leucovorin (FOLFIRI) regimen as a first-line treatment for patients with metastatic colorectal cancer (mCRC) who express the epidermal growth factor receptor (EGFR) and who are also KRAS wild-type, meaning they test negative for the KRAS mutation.

Approved concurrently was a diagnostic test designed to help identify patients who will benefit from the combined therapies.

Cetuximab, a chimeric monoclonal antibody and EGFR inhibitor, has been approved to treat mCRC since 2004, but the previous approval was only for patients who were refractory or intolerant to irinotecan-based therapy. It is estimated that between 30% and 50% of patients with colorectal cancer have the KRAS mutation. While not every patient without the KRAS mutation will respond to an anti-EGFR therapy, this newly approved combination could still potentially increase survival in thousands of colorectal cancer patients.

“Cancer is a heterogeneous disease and we have learned that not all patients with mCRC should be viewed as the same,” said Brian Daniels, senior vice president of Global Development and Medical Affairs for Bristol-Myers Squibb, in a statement released July 6. “Today’s approval demonstrates our ability to bring diverse cancer therapies to market that address the needs of patients with KRAS mutation-negative (wild-type) mCRC.”

Positive data from the CRYSTAL, CA225025, and EMR 62 202-047 (OPUS) trials suggested a statistically significant benefit to mCRC patients. In 2011, an updated analysis of overall survival among participants in the CRYSTAL trial was published in the Journal of Clinical Oncology. In that analysis, 1,198 patients in the intent-to-treat (ITT) population were randomly assigned to receive either cetuximab plus FOLFIRI (n=599) or FOLFIRI alone (n=599). Wild-type KRAS patients receiving cetuximab plus FOLFIRI had a significantly improved period of progression-free survival (PFS) with a median PFS of 9.9 months compared to 8.4 months in patients who received FOLFIRI alone (HR=0.696, P = .0012). Wild-type KRAS patients in the cetuximab plus FOLFIRI arm of the study also experienced significantly improved overall survival (OS), with a median OS of 23.5 months compared to 20.0 months in the FOLFIRI alone arm (HR=0.796, P = .0093).

However, the same improvements were not observed in patients with the KRAS mutation. For example, the same study found that in patients with mutated KRAS who received the cetuximab plus FOLFIRI combination, the median overall survival was 16.2 months (95% CI, 14.9-17.9), which was lower than the median overall survival of 19.9 months observed in the entire study population that received the combination therapy (95% CI, 18.5-21.3).

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Because the benefit of the combination therapy applies only to those with this specific set of genetic characteristics, the FDA concurrently approved the therascreen KRAS RGQ PCR Kit (Quiagen), a polymerase chain reaction (PCR) companion diagnostic that can provide information about the KRAS gene mutation in patients whose CRC has metastasized. and the first genetic test designed to help determine whether the combination of cetuximab and FOLFIRI could potentially benefit these patients.

“The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a statement released July 6. “Clinical trial data leading to the approval of this new indication supports the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations.”


Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.



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