Encorafenib, cetuximab and chemotherapy in metastatic colorectal cancer

The phase 3 BREAKWATER study, recently published on Nature Medicine, showed an improved response rate and a durable response with encorafenib, cetuximab and chemotherapy in previously untreated BRAF-mutant metastatic colorectal cancer.

BRAF V600E mutations occur in 8–12% of metastatic colorectal cancers and the presence of these mutations is linked to poor prognosis and resistance to standard chemotherapy regimens compared with wild-type disease; the association of encorafenib, a highly selective BRAF inhibitor, and cetuximab, ans anti-EGFR monoclonal antibody, (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer. The BREAKWATER trial investigated EC +mFOLFOX6 versus standard of care in patients with previously untreated BRAF V600E  metastatic colorectal cancer. 236 patients were randomized to the EC+mFOLFOX6 arm and 243 were randomized to the standard of care arm; the median duration of treatment was 28.1 weeks and 20.4 weeks respectively. At data cutoff data were not mature for the primary endpoint of progression-free survival. However a significant and clinically relevant improvement in objective response rate was demonstrated, with 60.9% in the EC+mFOLFOX6 arm versus 40% in the standard of care arm; median duration of response was 13.9 versus 11.1 months, with safety profiles consistent with those known for each agent. As authors conclude, «BREAKWATER showed substantially improved clinical benefit with EC+mFOLFOX6 as a first-line treatment for patients with BRAF V600E-mutant metastatic colorectal cancer. These encouraging data support this regimen to potentially become the new standard of care in BRAF V600E-mutant metastatic colorectal cancer; prespecified analyses of mature progression-free survival and overall survival data are planned».