KRAS mutations linked to ineffectiveness of cetuximab in colorectal cancer

CHICAGO — Patients with metastatic colorectal cancer who have mutations to the KRAS gene do not appear to benefit from the addition of cetuximab to FOLFIRI chemotherapy.

Those with wild-type KRAS genes, however, have a longer progression-free survival when they receive cetuximab (Erbitux, ImClone) with chemotherapy as first-line treatment, according to Eric Van Cutsem, MD, PhD, a professor at the University Hospital Gasthuisberg, Leuven in Belgium. Van Cutsem presented data from a retrospective analysis of the CRYSTAL trial at an ASCO 2008 Annual Meeting Plenary Session.

“Because of the rapidly evolving science on KRAS and because it was clear from the CRYSTAL study data that there was a group a patients who benefitted from the combination treatment while others did not, we decided to perform an analysis on the KRAS status of the tumors,” Van Cutsem said. “Our data show that the benefit of cetuximab is confined to the KRAS wild-type patients.”

In this retrospective analysis, they investigated the role of KRAS mutation status on progression-free survival and response rate. From the 1,198 patients in the CRYSTAL trial, 540 were evaluable for KRAS status: 348 (65%) were KRAS wild-type and 192 (35%) were KRAS mutant.

In the KRAS wild-type population, the one year progression-free survival rate for those who received cetuximab and FOLFIRI was 43% vs. 25% for those who received FOLFIRI alone and the risk of progression was decreased by 32% in the combination treatment arm. In the KRAS mutant population, however, there was no difference in progression-free survival between the two arms.

The response rate in the KRAS wild-type population was 59% for cetuximab and FOLFIRI vs. 43% for FOLFIRI alone. In the KRAS mutant population, the response rate was 36% for cetuximab and FOLFIRI vs. 40% for FOLFIRI alone.

Van Cutsem E, Lang I, D’haens G, et al. #2. Presented at: 2008 ASCO Annual Meeting; May 30 - June 2; Chicago.

With 1,200 patients worth of progression-free survival data using cetuximab with chemotherapy or panitumumab as a single agent, it is warranted to test all patients being considered for these agents for KRAS mutations.

In September 2007, the European Medicines Agency granted conditional marketing approval of panitumumab to patients who have non-mutated KRAS genes. This has recently been updated to include the use of cetuximab with chemotherapy. As physicians, it will be important to convey to our patients with KRAS mutations that the current regimens are effective, and that these decisions are intended to improve the risk-benefit ratio for them.

Clearly these results will affect ongoing and future randomized trials both in the metastatic and adjuvant settings for colorectal cancer. Groups representing the industry, the NCI, academic institutions, the FDA, the EMEA will need to work together to develop validated assays for KRAS testing. Fortunately, this is already underway.

These results also raise a number of questions for future research. We need to develop alternative biological “potentiators” of chemotherapy for patients with KRAS mutant tumors. We need to better understand the relationship between baseline predictive markers and pharmacodynamic markers to further enhance patient selection. We should continue to assess biomarkers that predict chemotherapy regimens use and how they interact with EGFR based predictive markers.

These results, in conjunction with other data, comprise a consistent body of data supporting the selection of patients for EGFR-targeted antibodies, thus enhancing their benefit. These results, although robust, were obtained retrospectively. In the future, we should expend greater efforts to develop biomarkers in concert with early clinical trials so that biomarker validation becomes the norm in large randomized phase-3 studies. Hopefully, what we have observed here is only the beginning of individualized therapy for patients with colorectal cancer.

– S. Gail Eckhardt, MD

Professor of Medicine, Director Gastrointestinal Malignancies Program
University of Colorado Health Science Center