New First-Line Treatment Option for BRAF V600E–Mutant Metastatic Colorectal Cancer
January 2026
Some individuals with metastatic colorectal cancer have a specific genetic change called BRAF V600E. This mutation is linked to faster-growing cancer and has traditionally been harder to treat. Researchers are working to find better first-line (initial) treatment options for this group of patients.
The study
New findings from the BREAKWATER trial presented at the ASCO GI 2026 Symposium showed whether adding two targeted therapies – encorafenib and cetuximab – to a standard chemotherapy regimen called FOLFIRI could improve outcomes compared with chemotherapy alone.
- Encorafenib targets the abnormal BRAF protein caused by the V600E mutation.
- Cetuximab blocks EGFR, a signal cancer cells use to grow.
- FOLFIRI is a commonly used chemotherapy option, sometimes chosen because it causes less nerve damage than another regimen (FOLFOX).
- 147 people with previously untreated BRAF V600E–mutant metastatic colorectal cancer, median age: 62
- All participants were well enough to receive combination treatment
- Patients were randomly assigned to:
- Targeted therapy + FOLFIRI, or
- FOLFIRI alone (with or without bevacizumab)
Findings
- 64% of patients who received encorafenib + cetuximab + FOLFIRI had their tumors shrink (partial or complete response)
- 40% of patients who received FOLFIRI alone had a tumor response
- Tumor responses happened quickly, in about 7 weeks in both groups
- After 6 months or longer, more than half of patients on the targeted therapy combination were still responding, compared with about one-third of patients on chemotherapy alone
Side effects
- Serious side effects were similar in both groups
- 39% with targeted therapy + chemotherapy
- 37% with chemotherapy alone
- About 10% of patients in both groups stopped treatment because of side effects
- This means adding the targeted therapies did not make treatment harder to tolerate
Conclusion
- This study suggests that adding encorafenib and cetuximab to FOLFIRI can lead to better tumor control without more side effects
- Researchers believe this combination could become a new standard first-line treatment option for people with BRAF V600E–mutant metastatic colorectal cancer
- It also gives patients and doctors more flexibility when choosing a treatment plan
The BREAKWATER trial is still ongoing. Researchers will continue to follow patients to learn how long the responses last and whether the treatment helps people live longer (improve overall survival).
For people with BRAF V600E–mutant metastatic colorectal cancer, combining targeted therapy with chemotherapy as a first treatment leads to higher response rates without added toxicity. This is an encouraging step toward more effective, personalized treatment options.
