The addition of the BRAF inhibitor encorafenib and the EGFR antibody cetuximab to chemotherapy with FOLFIRI (leucovorin, fluorouracil, and irinotecan) in the first-line treatment of BRAF V600E–mutated metastatic colorectal cancer led to a significant improvement in overall response rate—compared with chemotherapy with or without bevacizumab—in the phase III BREAKWATER trial.1 Findings for this subset, Cohort 3, were presented at the 2026 ASCO Gastrointestinal (GI) Cancers Symposium.
“Encorafenib/cetuximab plus FOLFIRI is an additional standard of care for patients needing FOLFIRI in the first-line setting,” said Scott Kopetz, MD, PhD, FACP, FASCO, of The University of Texas MD Anderson Cancer Center in Houston. “A significantly greater proportion of [patients with] BRAF-mutant metastatic colorectal cancer receiving the targeted combination regimen had their tumors shrink than those who received FOLFIRI with or without bevacizumab. The responses observed with encorafenib [and cetuximab] plus FOLFIRI were rapid and durable.”
The combination of the targeted therapy duo with FOLFIRI led to objective responses in 64.4% of patients vs 39.2% for FOLFIRI with or without bevacizumab (odds ratio [OR] = 2.76; P = .001); complete responses were seen in 4.1% and 1.4% of patients, respectively. This benefit was found to be associated with an improved duration of response. Dr. Kopetz reported that 57.4% of patients in the experimental arm had responses lasting 6 months or more, compared with 34.5% in the control arm; responses lasting 12 months or longer were observed in 4.3% and 0% of patients, respectively.
Overall survival data were immature, but a trend favoring encorafenib and cetuximab plus FOLFIRI was emerging, he added.
Building Upon Previous Findings with FOLFOX
BREAKWATER is a global, open-label phase III study in 147 previously untreated patients with BRAF V600E-mutated metastatic colorectal cancer. Patients received standard-of-care chemotherapy with or without bevacizumab, or encorafenib plus cetuximab in combination with the same chemotherapy backbone. The primary endpoint was objective response rate by blinded central review. Progression-free survival was the key secondary endpoint.
Investigators previously reported an improvement in objective response rate in this setting when encorafenib and cetuximab were paired with another standard chemotherapy backbone, modified FOLFOX6 (oxaliplatin, leucovorin, and fluorouracil): The rate was 60.9% with encorafenib and cetuximab plus modified FOLFOX6 vs 40.0% with standard care (OR = 2.443; one-sided P = .0008).2 Those results led to accelerated approval of the targeted combination regimen.
In a subsequent report, the median progression-free survival was 12.8 months with encorafenib and cetuximab plus modified FOLFOX6 vs 7.1 months with standard care (hazard ratio [HR] = 0.53; P < .001), and interim overall survival was 30.3 vs 15.1 months (HR = 0.49; P < .001), respectively.3
Dr. Kopetz stated that the investigators were “encouraged by the magnitude of benefit and the clinical synergy we see with this cytotoxic chemotherapy and targeted therapies in this setting with FOLFOX.” He therefore posed the question, “Was this a FOLFOX-specific phenomenon, or [was it] something that might be relevant with cytotoxic therapies in general?...The data are still early but suggest that it is a broader effect. And the great thing is that it’s going to give providers and patients more options and flexibility.”
“Many patients with metastatic colorectal cancer receive FOLFIRI—not FOLFOX—in the first-line setting. Therefore, it is important to test the efficacy and safety of encorafenib/cetuximab and FOLFIRI [compared with] FOLFIRI with and without bevacizumab,” he pointed out.
Safety Profile
In Cohort 3, no new safety signals were observed, and adverse events appeared consistent with those expected with each of the study drugs. The addition of encorafenib and cetuximab to FOLFIRI was associated with numeric increases in the adverse events (any grade) of anemia (25.4% vs 19.1%), dry skin (21.2% vs 5.9%), rash (16.9% vs 0%), and arthralgias (16.9% vs 0%), he said, noting that aside from these events, the toxicity profile was similar between the arms.
Serious treatment-emergent adverse events were reported in 39.4% of patients in the intervention arm vs 36.8% in the control arm. Discontinuation rates were found to be similar between the two arms, at 9.9% and 8.8%, respectively.
Eye to the Future
During the discussion period, Dr. Kopetz was asked about the concept of switching between modified FOLFOX6 and FOLFIRI backbones when combining with encorafenib and cetuximab. He answered, “While we are really encouraged by the data we see in the first-line [setting], we recognize that these are patients who have a substantial unmet need in later lines, so there are a lot of questions about some of the creative approaches we could take to treat them as drug development tries to catch up with this need in the BRAF-refractory setting. At the moment, there are no data to support switching, but keep an eye on some of the treatment rechallenge studies.”
Expert Points of View
ASCO Expert Joel Saltzman, MD, FASCO, of the Cleveland Clinic, commented at a press briefing, “When we see patients [with colorectal cancer] in clinic with this relatively uncommon mutation [BRAF V600E], but awfully difficult to treat, having as many options as possible is certainly something we all hope for.”
Before the release of the BREAKWATER data a year ago, he noted that the standard approach was to treat patients with BRAF-mutated disease “exactly the same as we would treat someone else, knowing they had a poor prognosis,” Dr. Saltzman said. However, he noted that although modified FOLFOX6 (oxaliplatin, leucovorin, and fluorouracil) provided an option that improved survival, intolerance to oxaliplatin (largely because of neuropathy) makes it a poor option for many. BREAKWATER now provides evidence that FOLFIRI (leucovorin, fluorouracil, and irinotecan) as the backbone for the BRAF inhibitor encorafenib and the EGFR antibody cetuximab combination “is certainly going to be powerful” for these patients, he said.1
Invited discussant of BREAKWATER, Eric Scott Christenson, MD, Assistant Professor of Oncology at Johns Hopkins University School of Medicine, Baltimore, stated that he was excited to see the positive results in the study’s Cohort 3, which point to encorafenib plus cetuximab and FOLFIRI as an effective alternative to this targeted duo plus modified FOLFOX6, which were reported to be effective over standard treatment.2,3
“Is encorafenib/cetuximab plus FOLFIRI likely better than FOLFIRI plus bevacizumab? I would say the answer is almost certainly yes,” Dr. Christenson said. “Is it a viable alternative to encorafenib/cetuximab plus FOLFOX as front-line treatment for BRAF V600E–mutant colorectal cancer? Maybe.”
He noted the doubling in response rate, the response durability of at least 6 months in nearly 60% of patients, and the nonsignificant improvement in median overall survival “heading in that direction.” He added, “Serious treatment-related adverse events were also similar between the arms, so the addition of encorafenib/cetuximab didn’t add much toxicity to FOLFIRI.”
In terms of a comparison between FOLFIRI and modified FOLFOX6—the two backbones evaluated in BREAKWATER—he noted the control arms in both comparisons performed similarly, the response rates for the two experimental arms were also similar, and the hazard ratios for overall survival were identical at 0.49; the narrower confidence interval for modified FOLFOX6 was likely due to that arm’s larger patient population and longer follow-up, he maintained.
Dr. Christenson called the previously reported results with the modified FOLFOX6 backbone “groundbreaking,” with the near-doubling in progression-free survival and the doubling in overall survival (from 15 to 30 months) over standard care.3 “However, a big limitation to that approach is that with the long-term use of oxaliplatin, neuropathy does become a dose-limiting toxicity,” he said. With the targeted combination in BREAKWATER, grade 3 or 4 neuropathy rates doubled, and grade 3 or 4 anemia rates more than tripled, he noted.
He stated that the data for the targeted therapy with these backbones look “strikingly similar,” though with FOLFIRI the data overall are less mature and the survival data remain immature. Because of the “major downside” of combining encorafenib and cetuximab with modified FOLFOX6—peripheral neuropathy, particularly with prolonged use—he commented, “I would say that encorafenib and cetuximab plus FOLFIRI deserves immediate consideration in patients with absolute or relative contraindications to oxaliplatin. And I think that FOLFIRI may ultimately prove to be a better first-line partner for encorafenib and cetuximab in most patients, but we need more mature survival data before its full adoption.”
DISCLOSURE: Dr. Kopetz reported relationships with Frontier Medicines, Lutris, Navire, Alentis Therapeutics, AmMax Bio, Arcus Biosciences, AstraZeneca, Aveo, BeOne Medicines (formerly BeiGene), BioNTech SE, Boehringer Ingelheim, Bristol Myers Squibb/Medarex, Carina Biotech, Clasp Therapeutics, Cytovation, Dewpoint Therapeutics, EMD Serono, Erasca, Flame Biosciences (now Leap Therapeutics), Genentech, Harbinger, Ikena Oncology (merged with ImageneBio), Iterion Therapeutics, Kivu Bioscience, Marengo Therapeutics, Pfizer, Regeneron, Roche, SageMedic, Servier, Shionogi, T-CypherBio, Tachyon Therapeutics, TransCode Therapeutics, Xaira Therapeutics, and Zentalis. Dr. Saltzman reported relationships with Eli Lilly, GoodRx, Sana Biotechnology, and Primum. Dr. Christenson reported relationships with Boston Scientific, Parabilis, Roche, Seres Therapeutics, Sirtex, TATUM Bioscience, UroGen, and NextCure.
REFERENCES
1. Kopetz S, Wasan HS, Yoshino T, et al: BREAKWATER: Primary analysis of first-line encorafenib + cetuximab + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer. 2026 ASCO GI Cancers Symposium. Abstract 13. Presented January 10, 2026.
2. Kopetz S, Yoshino T, Cutsem EV, et al: Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: A randomized phase 3 trial. Nat Med 31:901-908, 2025.
3. Elez E, Yoshino T, Shen L, et al: Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med 392:2425-2437, 2025.
