Response to Anti-EGFR Therapy in Patients with BRAF non-V600–Mutant Metastatic Colorectal Cancer

Abstract

Purpose: While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy.Experimental Design: We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RASdependent (class 3).Results: Forty patients with oncogenic non-V600 BRAFmutant mCRC received anti-EGFR antibody treatment [n ¼ 12 (30%) class 2 and n ¼ 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P ¼ 0.02). Specifically, in firstor second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P ¼ 0.04). In third-or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P ¼ 0.14).Conclusions: Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment.See related commentary by Fontana and Valeri, p. 6896

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

“…Oncogenic RAS is required for kinase-dead BRAF to drive tumor progression [151]. Recently, the novel classification of BRAF mutations based on kinase activity was proposed, including class 1 (activating RAS-independent BRAF mutations signaling as monomers), class 2 (activating RAS-independent BRAF mutations signaling as dimers with CRAF), and class 3 (RAS-dependent BRAF mutations with impaired kinase activity or kinase-dead) [182][183][184]. This proposal was, to some extent, clinically accepted to reflect the sensitivity to anti-EGFR antibodies.…”

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

“…In an Italian study, three of four patients treated with upfront chemotherapy plus cetuximab provided partial response (PR) 18. Furthermore, our large cohort study including 118 patients with BRAF non-V600E mutated mCRC in Japan and the USA revealed that patients with class 2 BRAF mutated mCRC did not respond to anti-EGFR antibody treatment, while some of those with class 3 mutations did respond 19. Based on these results, we also added an exploratory anti-EGFR antibody refractory class 3 cohort to investigate the efficacy of triple combination therapy in those who are refractory to prior anti-EGFR antibody therapy.…”

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

“…Until now, based on the results from subgroup analysis of the TRIBE trial, there has been a consensus that the optimal front-line treatment for BRAF mutant patients might be intensive chemotherapeutic regimens (bevacizumab+5-fluorouracil, oxaliplatin and irinotecan; FOLFOXIRI) to mitigate the aggressive biology. 59 It would be worthwhile to evaluate if the targeted regimen (encorafenib and cetuximab with or without binimetinib) without cytotoxic agents could prove more effective than this intensive combination as a frontline treatment for BRAF V600-mutant mCRC.…”

“…64 65 Class 3 BRAF mutations, which comprise more than half of non-V600 BRAF mutants, frequently overlap with RAS mutations. However, in the case of class 3 BRAF mutants with wild-type RAS, inhibiting the RAS signal with anti-EGFR antibodies could be a reasonable option 59 ; moreover, anti-EGFR inhibitors when combined with MEK inhibitor can prevent feedback activation by BRAF inhibition and have been proposed as a more rational approach. 64 Class 2 BRAF mutants are difficult to target due to RAS-independent kinase activity, although treatment options such as combinations of anti-EGFR, MEK and/or ERK inhibitors would be worth further exploration.…”