New results from the BREAKWATER trial show that the targeted therapy combination of encorafenib and cetuximab with the chemotherapy FOLFIRI can reduce the size or number of tumours in BRAF V600E-mutant metastatic colorectal cancer (mCRC).

Adding the targeted therapies results in better responses than FOLFIRI alone without increasing the side effects.

The research will be presented at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, taking place January 8-10 in San Francisco.

“The recent FDA approval of encorafenib and cetuximab in combination with FOLFOX showcased the importance of using targeted therapy in this group of patients. But approximately 20% to 25% of patients with newly diagnosed BRAF V600E-mutant mCRC receive FOLFIRI as their chemotherapy. FOLFIRI may be chosen for various reasons, including its lower reported incidence of peripheral neuropathy,” said lead study author Scott Kopetz, MD, PhD, a medical oncologist at MD Anderson Cancer Center.

This cohort of the BREAKWATER trial was studied to see whether the targeted therapies encorafenib and cetuximab, given in combination with the chemotherapy FOLFIRI, could reduce tumours in people with BRAF V600E-mutant mCRC.

Encorafenib blocks the altered BRAF protein that results from the V600E genetic variant. Cetuximab blocks another protein called EGFR.

These two medicines work for a longer time when taken together. FOLFIRI is a chemotherapy regimen that combines several drugs, including folinic acid, fluorouracil, and irinotecan.

FOLFOX and FOLFIRI are comparably effective, but they tend to have different side effects. Encorafenib/cetuximab with FOLFIRI (the targeted treatment) was compared to FOLFIRI with or without bevacizumab (another cancer treatment sometimes given with chemotherapy).

This cohort of the trial included 147 participants with a median age of 62. Nearly half were men, and none had received treatment for their cancer. The participants had tumours that could be measured and had few or no limitations on their activity levels. 

The study participants were randomly assigned to one of two treatment groups: 

• 73 participants received encorafenib and cetuximab with FOLFIRI. 
• 74 participants received FOLFIRI with or without bevacizumab. 

After a median follow-up of about 10 months for both treatment groups, the study found that:

• 64% of participants who received encorafenib/cetuximab and FOLFIRI had a complete or partial response vs. 40% of participants who received FOLFIRI (with or without bevacizumab). 
• Both the targeted treatment and the chemotherapy treatment showed responses in about 7 weeks. After 6 months or longer, more than half of participants who received the targeted treatment and around a third of participants who received the chemotherapy regimen were still responding to treatment. 

The targeted therapies did not worsen the side effects of cancer treatment; 39% of participants in the targeted treatment group had severe side effects vs. 37% of participants not getting the targeted therapies. 

About 10% of participants in the targeted treatment group and about 9% of participants in the chemotherapy group quit their treatment early, indicating that the severity of the side effects was about the same between the groups. 

“This additional data from the BREAKWATER trial reveals that it is the targeted therapy backbone that provides the better disease control and response rate in BRAF V600E-mutant colorectal cancers. The addition of FOLFIRI chemotherapy in the frontline setting will give oncologists and patients more options when selecting a first-line regimen,” said Joel Saltzman, MD, an ASCO Expert in gastrointestinal cancers and Vice Chair of Regional Oncology at Taussig Cancer Center, Cleveland Clinic.

The BREAKWATER trial is ongoing. Researchers will continue to study this cohort to determine how long the responses last and how long people on the treatments survive.

Source: ASCO