Surprising Disease Progression With Cetuximab in Colorectal Cancer Study

The addition of cetuximab to chemotherapy containing oxaliplatin and fluorouracil resulted in a significantly shorter progression-free survival in patients with operable KRAS exon 2 wild-type colorectal cancer liver metastases. Based on these results, taken from an interim analysis of the New EPOC trial, the researchers could not recommend the use of cetuximab in this patient setting.

“The result is unexpected,” wrote John Primrose, MD, of the University of Southampton, Southampton, United Kingdom, and colleagues. “Possible explanations include interactions between cetuximab and the chemotherapy backbone, further mutations in the EGFR pathways conferring insensitivity to EGFR inhibition, and upregulation of alternative signaling pathways in combination with surgery.”

Prior research had shown that the addition of cetuximab to oxaliplatin and fluorouracil resulted in an overall survival advantage in patients with advanced KRAS wild-type colorectal disease. Based on this, Primrose and colleagues conducted a study to see if cetuximab also conferred a benefit in patients with operable colorectal liver metastasis.

The New EPOC trial randomly assigned 272 patients to chemotherapy alone (n = 128) or chemotherapy with cetuximab (n = 129) before and after metastasis resection between February 2007 and November 2012. Patients assigned chemotherapy received either 1) a backbone of oxaliplatin and fluorouracil followed by fluorouracil, 2) oxaliplatin and oral capecitabine, or 3) patients who had previously received oxaliplatin were allowed to receive irinotecan plus fluorouracil instead of oxaliplatin. The majority of patients treated with or without cetuximab received regimen one.

The trial was closed in November 2012 for having met protocol-defined futility criteria. Of the enrolled patients, 117 assigned chemotherapy alone and 119 assigned chemotherapy plus cetuximab are included in the primary analysis of progression-free survival. The results, published in the Lancet Oncology, are from the interim analysis.

With a median follow-up of 20.7 months, the median progression-free survival was 14.1 months for the cetuximab group compared with 20.5 months in patients assigned chemotherapy alone (HR = 1.48; 95% CI, 1.04-2.12; P = .03). Overall survival was 39.1 months in the chemotherapy plus cetuximab group and had not yet been reached in the chemotherapy alone group.

“The adverse effect of cetuximab was associated with characteristics normally deemed to be good prognostic features-ie, well or moderate differentiation in the primary tumor, three or fewer metastases, absence of N2 disease, and non-synchronous presentation,” the researchers wrote. “When only those patients treated with regimen one chemotherapy were considered, the difference in progression-free survival remained significant. For the regimen two and three chemotherapy backbones, the small numbers provided insufficient power to confidently detect or refute interactions.”

Three deaths occurred in the chemotherapy plus cetuximab group and one in the chemotherapy alone group that may have been treatment related, according to the researchers. The most common grade 3 or 4 adverse events were low neutrophil count, embolic events, peripheral neuropathy, nausea or vomiting, and skin rash.

“In summary, cetuximab in combination with chemotherapy cannot be recommended for patients with operable colorectal liver metastases,” the researchers wrote. “Neither failure to deliver systemic therapy, nor inadequate surgery, seems to be the cause of these findings. Further translational studies are needed to establish whether EGFR inhibition could have a role in this setting.”