BREAKWATER: New Treatment Option for Metastatic Colorectal Cancer With BRAF V600E Mutation

Scott Kopetz, MD, PhD MD Anderson Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• The BREAKWATER trial showed encorafenib, cetuximab, and chemotherapy doubled median overall survival (OS) compared with standard of care in BRAF V600E–mutated metastatic colorectal cancer.

• Genetic and biomarker testing for BRAF V600E and other biomarkers is crucial for guiding the first treatment decision in newly diagnosed patients.

• Perioperative targeted therapy may allow more patients with oligometastatic disease to proceed to potentially curative surgery.

• There is a substantial unmet need for subsequent treatment options for patients with metastatic colorectal cancer who progress on the BREAKWATER regimen.

Treatment Options for Metastatic Colorectal Cancer With BRAF V600E Mutation

As part of a three-part series on the Oncology Brothers podcast covering colorectal cancer across treatment settings, cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with the lead author on the BREAKWATER trial, Scott Kopetz, MD, PhD, of MD Anderson Cancer Center. 

The BREAKWATER trial established encorafenib and cetuximab plus fluorouracil–based chemotherapy as a new standard of care for patients with metastatic colorectal cancer with BRAF V600E mutation. Dr. Kopetz discussed the trial’s findings and how the regimen fits amongst treatment options for metastatic colorectal cancer with BRAF V600E mutation. 

To start, the doctors emphasized the need to perform mutation and biomarker profiling immediately upon seeing a new patient, as BRAF and microsatellite instability (MSI) status are critical for the first treatment decision. In patients with both BRAF V600E mutation and high MSI, PD-(L)1–directed treatment should be prioritized over the BREAKWATER regimen unless there is an absolute contraindication for immunotherapy, said Dr. Kopetz. If patients progress while on upfront immunotherapy, they can switch to the BREAKWATER regimen in the second line.

BREAKWATER Trial Findings

The phase 3 BREAKWATER trial initially enrolled patients to one of three treatment arms: arm A received encorafenib and cetuximab; arm B received encorafenib, cetuximab, and mFOLFOX6 (modified leucovorin [folinic acid], fluorouracil, and oxaliplatin); and arm C received either mFOLFOX6, FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, and irinotecan), or CAPOX (capecitabine and oxaliplatin), each with or without bevacizumab. The trial was amended to cease randomization to arm A, and a new cohort was added with randomization between two treatment arms: arm D received encorafenib and cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan), and arm E received FOLFIRI with or without bevacizumab. 

The median progression-free survival was 12.8 months (95% CI, 11.2-15.9) in arm B compared with 7.1 months (95% CI, 6.8-8.5) in arm C (HR, 0.53; 95% CI, 0.41-0.68; P < .0001). The median OS was 30.3 months (95% CI, 21.7-not estimable) in arm B and 15.1 months (95% CI, 13.7-17.7) in arm C (HR, 0.49; 95% CI, 0.38-0.63; P < .0001). The objective response rate (ORR) was 61% (95% CI, 52-70) in arm B and 40% (95% CI, 31-49) in arm C (P = .0008). In the additional cohort, the investigational regimen in arm D also demonstrated an ORR benefit and a trend toward improved OS compared with the control in arm E.

Perioperative BREAKWATER and Later Lines of Therapy

Perioperative therapy with the BREAKWATER regimen is a routine part of practice at Dr. Kopetz’s center. Compared with historical treatments, novel targeted therapies have made more patients with BRAF–mutated oligometastatic disease eligible for curative-intent surgery, said Dr. Kopetz. There are no data on potential treatment modifications after surgery, and Dr. Kopetz generally completes the entire preplanned treatment duration regardless of the timing of surgery.

Ending the discussion, the doctors considered subsequent treatment options for BRAF V600E–mutated metastatic colorectal cancer if patients progress while on the BREAKWATER regimen. Unfortunately, this is a huge unmet need, and there are no available data to guide subsequent lines of therapy, said Dr. Kopetz. Outside of referring patients to experimental clinical trials, Dr. Kopetz’s current practice is to switch from oxaliplatin-based chemotherapy combinations to irinotecan-based combinations, or vice versa, while continuing encorafenib and cetuximab.