Expert Perspectives on the BREAKWATER Trial in Metastatic Colorectal Cancer
Key Points
- The BREAKWATER trial established FOLFIRI (folinic acid, fluorouracil, irinotecan) plus encorafenib and cetuximab as the first-line standard of care for patients with BRAF V600E–mutated metastatic colorectal cancer.
- Increased peripheral neuropathy has been seen in patients who receive encorafenib plus cetuximab–based chemotherapy compared with chemotherapy alone.
- Maintenance approaches that eliminate oxaliplatin while continuing targeted therapy may help mitigate cumulative neuropathy without compromising disease control.
In an interview surrounding new data from the 2026 ASCO Gastrointestinal Cancers Symposium, Daniel Tuerff, MD, of the University of Miami, spoke with Nicholas Hornstein, MD, PhD, of Northwell Health, about the evolving role of the BREAKWATER trial in BRAF V600E–mutated metastatic colorectal cancer.
Dr. Hornstein explained that although BREAKWATER included several study arms, the most clinically impactful regimen remains FOLFIRI combined with encorafenib and cetuximab. This combination has become the accepted first-line standard of care for patients with the disease.
The conversation then explored adverse events, particularly peripheral neuropathy. Increased rates of neuropathy observed in the BREAKWATER experimental arm are largely attributable to longer treatment duration and greater cumulative oxaliplatin exposure among responding patients, Dr. Hornstein said.
In clinical practice, Dr. Hornstein is transitioning patients to maintenance therapy with 5-fluorouracil, encorafenib, and cetuximab while discontinuing oxaliplatin, an approach that appears to preserve efficacy while reducing neuropathy.