Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

Abstract

BRAFV600-mutated colorectal cancer (CRC) accounts for 8% to 12% of all CRC diagnoses. These tumors are often associated with specific patient features, including right-sided primary tumor location, peritoneal and non-regional lymph node involvement, and poor prognosis. In approximately 30% of cases, a simultaneous mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype is identified. The prognostic impact of the BRAF mutation appears to be less marked in patients with MSI-H CRC than in patients with microsatellite stable (MSS) tumor. The treatment of BRAFV600-mutated CRC is still a challenge for the clinicians, mainly due to the poor survival outcomes obtained with traditional chemotherapy regimens. In recent years, two novel treatment strategies have offered remarkable changes in the treatment of this specific patient subgroup. The first approach has included targeted therapies directed against BRAF and MEK, with support from the epidermal growth factor receptor (EGFR) blockade. The second approach has included immunotherapeutic agents that have been shown to be particularly promising for patients with simultaneous dMMR/MSI-H phenotype. Here we review the clinical trials that specifically enrolled patients with BRAF-mutated CRC, from the phase I/II studies to the phase III trial BEACON CRC. We also examine the future directions towards a molecularly guided therapy for patients with BRAF-mutated CRC and the crucial role of a molecularly and clinically based algorithm in order to offer the best choice of treatment for these patients.

Figure 1

Mechanism of action of cetuximab, encorafenib and binimetinib. BRAF is a member of the RAF kinases group. RAF kinases generally promote the activation of the MAPK signaling pathway after the activating signal from RAS. In turn, RAF kinases activate by phosphorylation MEK 1 and MEK 2 (MEK kinases) that finally sustain ERK1 and ERK2 (ERK kinases) activation, resulting in phosphorylation of various cellular substrates with pivotal roles in cell survival and proliferation.