Encorafenib Plus Cetuximab and mFOLFOX6 for Patients With BRAF V600E-Mutated Metastatic Colorectal Cancer

Scott Kopetz, MD, PhD, discusses results from the BREAKWATER study which demonstrated that encorafenib plus cetuximab and mFOLFOX6 improved survival compared to standard of care among previously untreated patients with BRAF V600E-mutated metastatic colorectal cancer. 

Key Clinical Takeaways: 

• Study Design & Arms

·       Phase 3, open-label, multicenter trial.

·       Control: FOLFOX, CAPOX, or FOLFOXIRI ± bevacizumab.

·       Experimental:

·       EC + FOLFOX (encorafenib + cetuximab + FOLFOX).

·       EC alone

·       Dual primary endpoints: Progression-Free Survival (PFS) and Overall Survival (OS).

• Accelerated Approval (FDA’s Project FrontRunner)
  • Response rate: 66% with EC + FOLFOX vs 37% with SOC.
  • Supported accelerated approval of EC + FOLFOX as first-line therapy.
• Final Analysis Outcomes
  • Progression-Free Survival: 12.8 months (EC + FOLFOX) vs 7.1 months (SOC).
  • Overall Survival: 30.3 months (EC + FOLFOX) vs 15.1 months (SOC).
  • Hazard Ratio: 0.49; statistically significant.
  • Demonstrated benefit even against triplet cytotoxic regimens.
• Safety & Tolerability
  • Generally well tolerated.
  • Notable adverse events: anemia, arthralgia, rash.
  • Low discontinuation rates.
• Clinical Implications
  • Establishes new standard of care: EC + FOLFOX in first-line treatment of BRAF V600E-mutated metastatic colorectal cancer.
  • Highlights importance of early introduction of targeted therapy in aggressive BRAF V600E disease.
• Future Directions
  • Mechanisms of resistance
  • Role of FOLFIRI + EC combinations
  • Anticipated full regulatory approval in US and internationally

Transcript: 

Hi, my name is Scott Kopetz, Professor of GI Medical Oncology at MD Anderson Cancer Center, delighted to share some updates on the BREAKWATER study. 

The BREAKWATER study was an open-label, multicenter, phase 3 study enrolling patients to standard of care with FOLFOX, CAPOX, or FOLFOXIRI with or without bevacizumab, and the experimental arm was EC [encorafenib and cetuximab] and FOLFOX, there was also an EC alone arm as well. Dual primary end points were progression-free survival and overall survival. This was the first study to use the FDA's Project FrontRunner, which allowed response rate to be used for an accelerated approval, and this demonstrated indeed approximately 66% response rate with EC and FOLFOX compared with a 37% [response rate] for standard-of-care therapy alone. As a result of that, it then went on to receive accelerated approval for EC and FOLFOX in first-line therapy. 

The latest update with the final analysis of overall survival and progression-free survival was reported in the New England Journal [of Medicine]. This demonstrated a progression-free survival of 12.8 months compared to 7.1 months in the standard of care, and impressively, an improvement in overall survival from 15.1 months in standard of care to 30.3 [months], doubling of overall survival, hazard ratio of 0.49, all of which was statistically significant. It's anticipated that this agent will receive full approval both in the US, as part of Project FrontRunner, as well as internationally. 

Now of interest, the patients were allowed to receive a triplet cytotoxic regimen, and a number of those patients did in the control arm, and so this shows superiority even in the setting of a triplet cytotoxic standard therapy. The patients were allowed to receive, on the control arm, BRAF-directed therapy on subsequent therapies, and a majority of patients that went on to receive treatment did indeed get a BRAF-targeted therapy, in combination with an EGFR [inhibitor] most commonly, so the current standards of care were available to them. 

The safety suggested good tolerance with some anemia and some arthralgias that are class associated with this regimen with rash also being appreciated there, but overall, well tolerated with low rates of dose continuations. 

This really suggests that there's a new standard of care for first line treatment of BRAF V600E-mutated metastatic colorectal cancer, that FOLFOX combined with EC is demonstrating higher response rates, progression-free survival, and a doubling of overall survival despite having availability of subsequent EC in the control arm, really suggesting that early first treatment with targeted therapies here are critical in this aggressive disease. We look forward to more data on mechanisms of resistance, the role of FOLFIRI in combination as well, and there's still much to be learned. Thank you.

Source: 

Elez E, Yoshino T, Shen L, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med. Published online: May 30, 2025. doi: 10.1056/NEJMoa2501912