New results from the BREAKWATER trial (NCT04607421), funded by Pfizer, show that the targeted therapy combination of encorafenib (Braftovi®; Pfizer) and cetuximab (Erbitux®, Eli Lilly & Co.) with FOLFIRI*can reduce tumor size or number in BRAFV600E-mutant metastatic colorectal cancer (mCRC).
The outcomes showed that adding targeted therapies led to better responses than FOLFIRI alone, without increasing side effects. The research was presented at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held January 8-10, 2026, in San Francisco, California.
About 8% to 12% of people with mCRC have a BRAF V600E genetic variant. Cancers with this variant don’t respond well to chemotherapy.
Study design
“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 BRAFV600E-mutant mCRC receive FOLFIRI as their chemotherapy,” explained lead study author Scott Kopetz, MD, PhD, a medical oncologist at MD Anderson Cancer Center.
“FOLFIRI may be chosen for various reasons, including its lower reported incidence of peripheral neuropathy,” Kopetz added.
Tumor burden
This cohort of the BREAKWATER trial was studied to determine whether the targeted therapies encorafenib and cetuximab, when combined with the chemotherapy FOLFIRI, could reduce tumor burden in people with BRAFV600E-mutant mCRC.
Encorafenib blocks the altered BRAF protein caused by the V600E genetic variant. In addition, cetuximab blocks another protein called EGFR. These two medicines work longer when taken together. FOLFIRI is a chemotherapy regimen that combines folinic acid, fluorouracil, and irinotecan.
FOLFOX and FOLFIRI are comparably effective but have different side effects. Encorafenib/cetuximab with FOLFIRI was compared to FOLFIRI with or without bevacizumab (Avastin®; Genentech/Roche).
This cohort of the trial included 147 participating patients with a median age of 62. Nearly half were men, and none had received treatment for their cancer. The patients included had measurable tumors and 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.
Study Findings
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 achieved a complete or partial response, compared with 40% of participants who received FOLFIRI (with or without bevacizumab).
- Both targeted and chemotherapy treatments showed responses within about 7 weeks. After 6 months or longer, more than half of the participants who received the targeted treatment and around a third of those who received the chemotherapy regimen were still responding to treatment.
The study found that targeted therapies did not worsen the side effects of cancer treatment. Overall, 39% of patients in the targeted treatment group experienced severe side effects, compared with 37% of participants not receiving targeted therapies. About 10% of participants in the targeted treatment group and about 9% of participants in the chemotherapy group discontinued treatment early, indicating that the severity of side effects was similar between the groups.
Next Steps
Although 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.
The 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,” explained Joel Saltzman, MD, an ASCO Expert in gastrointestinal cancers and Vice Chair of Regional Oncology at Taussig Cancer Center, Cleveland Clinic.
“The addition of FOLFIRI chemotherapy in the frontline setting will give oncologists and patients more options when selecting a first-line regimen,” he concluded
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Note:* FOLFERI is a chemotherapy regimen using leucovorin (folinic acid), fluorouracil (5-FU), and irinotecan to treat advanced colorectal cancer and other cancers, designed to shrink tumors and slow their growth by different mechanisms, including DNA interference and inhibition of cell growth.
** FOLFOX is a combination chemotherapy regimen used to treat colorectal cancer and other GI cancers, consisting of leucovorin (folinic acid), fluorouracil (5FU), and oxaliplatin. The regimen is a standard, effective treatment for both advanced and early-stage colorectal cancer, often used as a backbone therapy to which other drugs can be added.
Clinical trial
[1] A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer – ClinicalTrials.gov ID – NCT04607421
Highlights of prescribing information
Encorafenib (Braftovi®; Pfizer)[Prescribing information]
Cetuximab (Erbitux®, Eli Lilly & Co)[Prescribing Information]
Bevacizumab (Avastin®; Genentech/Roche)[Prescribing Information]
Reference
[1] Kopetz S, Wasan HS, Yoshino T, Kim TW, Eng C, Van Cutsem E, Ciardiello F, Desai J, Maughan T, Yaeger R, Zhang X, Beyzarov E, Mori A, Zhang X, Tabernero J. BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). (Oral Abstract Session during the2 026 ASCO Gastrointestinal Cancers Symposium) J Clin Oncol 44, 2026 (suppl 2; abstr 13) | 10.1200/JCO.2026.44.2_suppl.13
Featured image courtesy: © 2023 -2025 ASCO/Scott Morgan. Used with permission.
DOI
, funded by Pfizer, show that the targeted therapy combination of encorafenib (Braftovi®; Pfizer) and cetuximab (Erbitux®, Eli Lilly & Co.) with FOLFIRI*can reduce tumor size or number in BRAFV600E-mutant metastatic colorectal cancer (mCRC).){kind=link}