Colorectal cancer is the third most common cancer globally, with 294,500 cases in 2024, and the second leading cause of cancer deaths. In the US, 156,000 cases are expected in 2025, with 20% metastatic at diagnosis and up to 50% of localized cases eventually progressing. BRAF mutations occur in 8–12% of mCRC cases and are linked to poor outcomes, especially the BRAF V600E variant, which doubles mortality risk.

BRAFTOVI (encorafenib), a BRAF V600E inhibitor, is approved with cetuximab and mFOLFOX6 for first-line treatment of BRAF V600E-mutant mCRC based on response rate. The Phase III BREAKWATER trial, presented at ASCO 2025, met its primary endpoint and demonstrated significant clinical benefit, supporting its role as a new standard of care in this high-risk population. Data presented at ASCO 2025 included progression-free survival (PFS) and updated overall survival (OS) data. 

In this trial, 637 patients were randomized to BRAFTOVI plus cetuximab, BRAFTOVI plus cetuximab plus mFOLFOX6, or standard of care (SoC). At data cutoff (January 6, 2025), BRAFTOVI plus cetuximab plus mFOLFOX6 demonstrated a clinically meaningful and statistically significant PFS improvement vs SoC, meeting the other dual primary endpoints; median PFS 12.8 vs 7.1 months. OS was clinically meaningful and statistically significant vs SoC; median OS 30.3 vs 15.1 months. Median PFS and OS in the BRAFTOVI plus cetuximab arm were 6.8 and 19.5 months. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of patients in the safety analysis set. Safety was consistent with that known for each agent. Safety was manageable but Grade ≥3 AEs were higher in the BRAFTOVI plus cetuximab +  mFOLFOX6 group [46% vs 39% (SoC)].

Therefore, BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with BRAFTOVI plus cetuximab plus mFOLFOX6 vs SoC and manageable toxicities. BRAFTOVI plus cetuximab +  mFOLFOX6  is potentially practice changing as the new SoC.

KOL insights

“I am looking forward to seeing the updated survival data coming out of the phase III BREAKWATER trial of first-line BRAFTOVI plus cetuximab and mFOLFOX6 [fluorouracil, leucovorin, and oxaliplatin] in patients with BRAF V600E mutated mCRC. This study previously met one of its primary endpoints with an improvement in ORR vs chemotherapy with or without bevacizumab, resulting in accelerated approval from the FDA of the regimen in the front-line setting for this very aggressive subpopulation of patients with metastatic CRC. Further survival data will hopefully solidify the consistent use of this regimen in patients with treatment-naive disease.” – Expert Opinion

“This regimen was recently approved by the FDA through its accelerated mechanism based on the ORR benefit. Data to be presented at ASCO will include progression-free survival and updated OS data which may allow for a full approval if meaningfully positive. We also await the results of the FOLFIRI [5-fluorouracil, leucovorin, and irinotecan]-based combination in the near future” – Expert Opinion

“BREAKWATER OS results are in—and they should reshape the first-line standard for BRAF V600E-mutant mCRC. Encorafenib + cetuximab + mFOLFOX6 vs standard chemo ± bevacizumab: PFS: 12.8 vs 7.1 months (HR 0.53, p < 0.0001)” – Expert Opinion

Conclusion

BRAFTOVI + cetuximab + mFOLFOX6 regimen has emerged as a potential new standard of care for treatment-naïve patients with BRAF V600E-mutant mCRC, demonstrating unprecedented survival benefits—51% reduction in death risk and 47% reduction in disease progression vs SoC—in the Phase III BREAKWATER trial. With accelerated FDA approval already granted based on ORR, these updated PFS and OS data strongly support full approval and mark a pivotal shift in first-line treatment for this high-risk population. There is no doubt that BRAFTOVI plus cetuximab + mFOLFOX6 has demonstrated an unprecedented OS benefit in BRAF mCRC, but is it suitable for all or just a select group? This could be a new standard of care, yet careful consideration is necessary. Despite promising results, several key concerns remain: the open-label design introduces potential bias, the early closure of the BRAFTOVI plus cetuximab arm limits comparisons (abandoned after a protocol amendment), and the SoC arm (chemo ± Bev) lacks global standardization. Toxicity is increased with FOLFOX6 (leading to neuropathy and myelosuppression), and QoL (quality of life) data is missing. Applicability is also a question, BRAFTOVI plus cetuximab with an OS of 19.5 months is sufficient for frail patients?