New EPOC Study: Use of Cetuximab in Patients with RAS Wild-Type Metastatic Colorectal Cancer
The phase 3 New EPOC study randomized patients with resectable or suboptimally resectable colorectal liver metastases (CRLM) and KRAS exon 2 wild-type disease status to receive chemotherapy with or without the anti–epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab (Bridgewater J, et al. EPOC study. ESMO 2014: Abstract 542P). The trial results showed that the addition of cetuximab to chemotherapy had an adverse impact on progression-free survival (PFS), lowering the median PFS from 20.5 to 14.1 months (hazard ratio [HR], 1.48; P = .03). It was notable that KRAS status was scored in the New EPOC study based on the analysis of only KRAS codons 12, 13, and 61. Given that benefit from EGFR inhibition in patients with advanced disease only extended to a population defined by all RAS wild-type status, tumor samples were analyzed retrospectively for KRAS (codons 12, 13, 61, 117, and 146), BRAF (V600E), NRAS (codons 12, 13, 61, 117, and 146), PIK3CA (codons 547 and 1047), and EGFR S492R using pyrosequencing.
Overall, RAS mutation status was analyzed in 132 primary tumor samples and in 113 CRLM samples, of which 76 samples were paired. KRAS mutations were found in samples from a total of 11 patients using more stringent selection. The entire population with RAS wild-type tumors included 53 patients who had received chemotherapy alone and 72 patients who received cetuximab plus chemotherapy. In the entire population with RAS wild-type disease, cetuximab plus chemotherapy was still associated with an inferior PFS compared with chemotherapy alone (14.3 vs 24.5 months; HR, 1.54; P = .011).
These findings confirmed the previously reported results that the addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients had an adverse effect on survival; more stringent selection of an all-RAS wild-type cohort did not alter the detriment observed. Bridgewater and colleagues concluded that the treatment effect of EGFR inhibition in colorectal cancer is contextual and is highly dependent on the disease setting in which it is used.