New results from the BREAKWATER trial show that the targeted therapy combination of encorafenib and cetuximab with the chemotherapy fluorouracil, folinic acid, and irinotecan (FOLFIRI) can reduce the size or number of tumors in patients with BRAF V600E–mutant metastatic colorectal cancer. Adding the targeted therapies results in better responses than FOLFIRI alone without increasing the effects. This research will be presented by Scott Kopetz, MD, PhD, FASCO, and colleagues at the upcoming 2026 ASCO Gastrointestinal Cancers Symposium, taking place January 8–10 in San Francisco (Abstract 13).
Scott Kopetz, MD, PhD, FASCO
BREAKWATER
“The recent [U.S. Food and Drug Administration] approval of encorafenib and cetuximab in combination with [leucovorin, fluorouracil, and oxaliplatin (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 metastatic colorectal cancer receive FOLFIRI as their chemotherapy. FOLFIRI may be chosen for various reasons, including its lower reported incidence of peripheral neuropathy,” explained Dr. Kopetz, of The University of Texas 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 tumors in people with BRAF V600E–mutant metastatic colorectal cancer. Encorafenib blocks the altered BRAF protein that results from the V600E genetic variant, while cetuximab is an EGFR inhibitor. FOLFOX and FOLFIRI are comparably effective, but they tend to have different side effects. Encorafenib/cetuximab with FOLFIRI was compared to FOLFIRI with or without bevacizumab.
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 tumors 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, and 74 participants received FOLFIRI with or without bevacizumab.
Key Findings
After a median follow-up of about 10 months for both treatment groups, 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 discontinued treatment, indicating that the severity of the side effects was about the same between the groups.
The study authors concluded, “These data support [encorafenib and cetuximab plus] FOLFIRI as a potential new standard of care in BRAF V600E–mutant metastatic colorectal cancer.”
Next Steps
The BREAKWATER trial is ongoing. Researchers will continue to study this cohort to determine duration of response and survival.
ASCO Perspective
“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.
Disclosure: The BREAKWATER trial was funded by Pfizer. For full disclosures of the study authors, visit coi.asco.org.
