BREAKWATER study: additional analyses

Prof Dr Marc Van den Eynde, a gastrointestinal oncologist at Cliniques Universitaires Saint-Luc in Brussels, discussed updated results from the BREAKWATER study, evaluating the efficacy of encorafenib plus cetuximab (EC), with or without FOLFOX, as first-line therapy for patients with BRAF V600E–mutated mCRC. The study included three arms: EC, EC combined with FOLFOX, and a control arm consisting primarily of FOLFOX, FOLFIRI, or FOLFOXIRI with or without bevacizumab. The co-primary endpoints were ORR and PFS, with OS as a key secondary endpoint. All primary and secondary objectives were met. Among all regimens, EC plus FOLFOX achieved the best OS outcomes, followed by EC alone; the control arm showed the poorest survival.

Additional analyses presented at the meeting focused on safety and on subsequent lines of therapy. The combination of EC with FOLFOX did not reveal any new or unexpected safety concerns, and toxicity was manageable. Importantly, the addition of EC did not compromise chemotherapy delivery, as FOLFOX dose intensity and exposure were maintained. 

A complementary analysis examined post-protocol treatments. At the time of the BREAKWATER trial, EC was already approved as standard care in later-line settings in many countries, and most patients in the control arm subsequently received EC. Despite this crossover, outcomes continued to favour EC plus FOLFOX in the first-line setting, indicating that treatment sequencing matters. Progression-free survival after second-line therapy (PFS2) also supported the superiority of initiating treatment with EC plus FOLFOX rather than delaying EC to later lines.

Given the poor prognosis associated with BRAF-mutated mCRC, these updated results reinforce the importance of using the most active available regimen upfront. The combination of EC with FOLFOX in first line provides a clinically meaningful survival advantage, further confirmed by the extended safety and sequencing data presented.