Conclusion. The triplet-combination of encorafenib, binimetinib, and cetuximab as well as the doublet-regimen of encorafenib and cetuximab improved both PFS and OS in patients with metastatic, BRAF V600E–mutated colorectal cancer that has progressed after 1 or 2 lines of therapy.
Commentary
The current interim analysis of the BEACON CRC trial demonstrates improved response rates, PFS, and, importantly, OS with the triplet regimen of encorafenib, binimetinib, and cetuximab in patients with metastatic BRAF V600E–mutated colorectal cancer compared to standard irinotecan-based therapy. Similarly, a doublet-regimen of encorafenib and cetuximab also improved outcomes compared with irinotecan-based chemotherapy, resulting in significantly higher response rates, PFS, and OS.
BRAF mutations are seen in approximately 5% to 15% of colorectal cancers and are more commonly seen in right-sided disease. BRAF-mutated colorectal cancer has a poor prognosis, and the presence of a BRAF mutation is an independent prognostic factor for decreased survival.1 Previous work to improve outcomes in this subset of patients has been largely disappointing. For example, Kopetz and colleagues have previously shown that single-agent BRAF inhibition with vemurafenib in metastatic BRAF-mutated colorectal cancer did not show meaningful clinical activity.2 Preclinical studies have suggested that single-agent BRAF or MEK inhibition alone do not lead to sustained MAPK pathway inhibition. Mechanistically, inhibition of BRAF has been shown to lead to feedback activation of EGFR; thus, inhibition of BRAF alone does not lead to cessation of proliferation.3 In light of this, the combination of EGFR and BRAF inhibition has been an attractive therapeutic strategy. Yaeger and colleagues enrolled 15 patients in a pilot study looking at the efficacy and safety of the BRAF inhibitor vemurafenib and the EGFR antibody panitumumab in patients with BRAF-mutated metastatic colorectal cancer. In this cohort, combined BRAF and EGFR inhibition showed tumor regression in 10 of 12 patients.4 This finding was validated in other subsequent studies.5
The current study is the first phase 3 trial to validate the efficacy of BRAF, MEK, and EGFR inhibition in patients with BRAF-mutant metastatic colorectal cancer. The results of this study represent a very important step forward in treating this patient cohort that has historically had very poor clinical outcomes. The combination of encorafenib, binimetinib, and cetuximab improved OS by 48% compared with standard irinotecan-based chemotherapy. In light of this, we now have a chemotherapy-free targeted combination that improves survival and likely represents the new standard of care in patients with BRAF-mutated colorectal cancer after progression on 1 or 2 prior lines of therapy. Ongoing trials are being pursued to investigate the efficacy of these combinations in the upfront setting, and the results of these trials are eagerly awaited.
Applications for Clinical Practice
The combination of encorafenib, binimetinib, and cetuximab improved OS in patients with BRAF-mutated metastatic colorectal cancer after progression on 1 or 2 prior lines of therapy. This combination represents a potential new standard of care in this patient population.
–Daniel Isaac, DO, MS