Adding Cetuximab to FOLFIRI Best in RAS Wild-Type Colorectal Cancer

The phase III CRYSTAL trial demonstrated the adding cetuximab to fluorouracil, leucovorin and irinotecan (FOLFIRI) resulted in significant improvements in overall survival, progression-free survival, and objective response in patients with KRAS codon exon 2 wild-type metastatic colorectal cancer. Results of a post-hoc subgroup analysis published in the Journal of Clinical Oncology showed that there was no positive treatment effect of adding cetuximab to FOLFIRI in patients with tumors carrying other predefined mutations at the RAS loci.

“Reserving such first-line treatment for a RAS wild-type population allows the definition of a subgroup more likely to benefit from the addition of cetuximab to FOLFIRI,” wrote Eric Van Cutsem, MD, of University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium, and colleagues. “Molecular testing of tumors for all activating mutations in KRAS and NRAS before considering anti-EGFR therapy is therefore essential in selecting the most effective treatment for patients with metastatic colorectal cancer.”

According to the researchers, activating mutations of KRAS at codons other than 12 or 13 have been identified, and studies have shown that these mutations may affect outcomes in patients receiving certain targeted therapies.

For this investigation, Van Cutsem and colleagues used data from the CRYSTAL study to assess if adding cetuximab to FOLFIRI had any effect on patients with mutations at RAS loci other than KRAS codon 12 or 13.

Mutation status was evaluable in 64.6% of the 666 patients in CRYSTAL with KRAS exon 2 wild-type tumors. Of these patients, 14.7% had other RAS mutations.

A significant treatment benefit was seen with the addition of cetuximab in patients with RAS wild-type tumors; however, no cetuximab benefit was found for patients with RAS mutations.

“However, given the relatively small number of patients in this group, no definitive conclusions on the negative predictive value of other RAS mutations can be drawn,” the researchers wrote.

The researchers also pointed out that the absence of any negative effects of adding cetuximab to FOLFIRI in patients with RAS mutations conflict with data from the OPUS and PRIME studies, where worse outcomes were reported with the addition of cetuximab and panitumumab.

“However, our data are in line with findings in the second-line setting, which showed that there was no negative effect of combining panitumumab with FOLFIRI for patients with KRAS exon 2–mutant or other RAS-mutant tumors,” the researchers wrote. “Furthermore, on the basis of the findings from these studies, current clinical guidelines recommend that only patients with RAS wild-type tumors should be treated with cetuximab or panitumumab in combination with FOLFIRI or FOLFOX chemotherapy.”