First-Line Encorafenib/Cetuximib Plus Chemo Best SOC in BRAF V600E+ mCRC

Frontline encorafenib (Braftovi) plus cetuximab (Erbitux; EC) and FOLFIRI (folinic acid, fluorouracil, and irinotecan) yielded significant improvement in objective response rate (ORR) compared with a control regimen of FOLFIRI with or without bevacizumab (Avastin) as well as a positive trend toward overall survival (OS) and tolerable safety in patients with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations.¹

Data from the primary analysis of ORR by blinded independent central review (BICR) in cohort 3 of the phase 3 BREAKWATER study (NCT04607421) were presented during the 2026 Gastrointestinal Cancers Symposium (ASCO GI). The confirmed ORR with EC plus FOLFIRI in evaluable patients (n = 73) was 64.4% (95% CI, 52.9%-74.4%) vs 39.2% (95% CI, 28.9%-50.6%) with the control regimen (n = 74; odds ratio, 2.756 (95% CI, 1.420-5.348; 1-sided P = .0011), meeting the primary end point of the study. Among those who responded to EC plus FOLFIRI, 4.1% achieved a complete response, 60.3% experienced a partial response, and 20.5% had stable disease; 1 patient each experienced non-CR/non–progressive disease (PD) and PD. Nine patients were not evaluable for response.

The clinical benefit observed with EC plus FOLFIRI was noted across key prespecified subgroups, including age, sex, baseline ECOG performance status, number of organs involved at baseline, side of tumor, and baseline liver metastases.

Moreover, the median time to response (TTR) with EC plus FOLFIRI was 6.9 months (95% CI, 5.4-36.1) vs 7.1 months (95% CI, 5.9-25.3) with the control regimen, and the estimated duration of response (DOR) in both arms was not estimable. In the EC/FOLFIRI arm, 57.4% of patients experienced a DOR of at least 6 months, and 4.3% had a DOR of 12 months or longer. In the control arm, 34.5% of patients responded to treatment for at least 6 months, and no patients responded for at least 1 year.

Although the data are immature, a trend for an OS improvement was also observed with EC plus FOLFIRI vs the control regimen (HR, 0.49; 95% CI, 0.237-1.032).

“BREAKWATER cohort 3 supports the option of FOLFIRI as a backbone in combination with EC as a potential new first-line standard of care for patients with BRAF V600E–mutant mCRC,” Scott Kopetz, MD, PhD, FACP, said in a presentation of the data. Kopetz is the deputy chair for Translational Research and professor in the Department of Gastrointestinal (GI) Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. He is also a leader of the Department of Cancer Center Support Grant, GI Program; TRACTION medical director in the Division of Therapeutics Discovery; and associate vice president for Translational Integration.

What is the design of the BREAKWATER study in BRAF V600E–mutant mCRC?

The open-label, multicenter, phase 3 study included those with BRAF V600E–mutant mCRC by local or central laboratory testing who were at least 16 years of age, had measurable disease by RECIST 1.1 criteria, and who had not previously received systemic treatment for metastatic disease. To enroll, they were required to have an ECOG performance status that was no higher than 1, and acceptable bone marrow, hepatic, and renal function. If they had prior exposure to BRAF or EGFR inhibition, symptomatic brain metastases, microsatellite instability–high or mismatch repair–deficient tumors, or RAS-mutated disease, they were excluded.

Study participants were randomly assigned 1:1 to receive EC plus FOLFIRI or the control regimen of FOLFIRI with or without bevacizumab. They were stratified by ECOG performance status. In addition to the primary end point of ORR by BICR, a key secondary end point was progression-free survival (PFS) by BICR. Other secondary end points comprised OS, DOR, TTR, and safety.

Previous data from the study indicated that EC plus mFOLFOX6 led to significant improvements in ORR and PFS by BICR, as well as OS, compared with the control regimen in this population.^2,3 In December 2024, the FDA granted accelerated approval to EC plus mFOLFOX6 for patients with mCRC harboring a BRAF V600E mutation based on earlier data from BREAKWATER.⁴

Additional findings from the safety lead-in portion of the study revealed “encouraging response rates” with EC plus FOLFIRI, according to Kopetz, as well as PFS.⁵ He noted,¹ “This promising activity was seen despite modestly lower exposure to irinotecan when combined with encorafenib, in line with the predicted CYP3A-meditated interaction between encorafenib and irinotecan.”

Those data supported the examination of EC plus FOLFIRI as first-line treatment in patients with BRAF V600E­–mutant mCRC as part of cohort 3 of BREAKWATER. At this year’s ASCO GI, Kopetz shared findings from the primary analysis of ORR by BICR, data from an OS analysis, and safety with regard to EC plus FOLFIRI vs the control regimen.

What were the patient disposition and baseline characteristics for those included in the current BREAKWATER analyses?

The median follow-up for OS in the EC plus FOLFIRI arm was 10.5 months (95% CI, 10.1-11.2) vs 10.3 months (95% CI, 9.7-11.2) in the control arm. In the EC/FOLFIRI arm, 69.9% of patients were still on treatment at the time of the data cutoff date of March 1, 2025; of the 30.1% who discontinued, most did so because of PD (12.3%), followed by adverse effect (AE; 5.5%) and patient withdrawal (5.5%). In the control arm, 33.8% of patients were still on treatment at the cutoff; 66.2% of patients discontinued. The most common reason for discontinuation in the control arm was PD (32.4%), followed by patient withdrawal (10.8%) and other (8.1%). The median duration of treatment in the EC plus FOLFIRI arm (n = 71) was 9.9 months (95% CI, 0.5-13.7) vs 7.4 months (95% CI, 0.5-14.1) in the control arm (n = 68).

The median patient age across the investigative and control arms was 61.5 years (range, 28-84), and slightly more than half of patients were female (54.8% vs 52.7%). Slightly more than half of patients had an ECOG performance status of 0 (64.4% vs 55.4%). In the EC plus FOLFIRI arm, 42.5% of patients had left-sided tumors and 56.2% had right-sided tumors; these rates were 48.6% and 51.4% in the control arm. Moreover, 52.1% of those in the EC/FOLFIRI arm had up to 2 organs involved, and 47.9% had 3 or more involved organs; in the control arm, these respective rates were 45.9% and 54.1%. More than half of patients had baseline liver metastases (58.9% vs 62.2%). Most patients in the EC plus FOLFIRI arm had a carcinoembryonic antigen level higher than 5 μg/L (61.6%) and a C-reactive protein of 10 mg/L or less (61.6%); this was also true for the control arm (66.2%; 54.1%).

What is the safety profile of EC plus FOLFIRI in patients with BRAF V600E–mutated mCRC?

Treatment-emergent AEs (TEAEs) occurred in all patients who received EC plus FOLFIRI vs 98.5% of those given the control regimen; they were grade 3 or 4 in severity for 63.4% and 70.6% of patients, respectively. Three TEAEs in the investigative arm and 1 in the control arm proved fatal. Serious TEAEs occurred in 39.4% of those in the EC/FOLFIRI arm vs 36.8% of those in the control arm.

Moreover, TEAEs led to dose reduction or interruption for 64.8% and 74.6% of those who received EC plus FOLFIRI; 11.3% of patients in this arm experienced TEAEs that led to permanent discontinuation of any study treatment. In the control arm, 41.2% of patients experienced TEAEs that led to dose reduction, and 67.6% experienced TEAEs that led to dose interruption; TEAEs resulted in discontinuation for 8.8% of patients. Treatment-related AEs (TRAEs) were experienced by 97.2% of those in the EC plus FOLFIRI arm vs 95.6% of those in the control arm; they were grade 3 or 4 for 53.5% and 54.4% of patients, and grade 5 for 1.4% and 1.5% of patients, respectively. Serious TRAEs occurred in 23.9% of those given EC plus FOLFIRI vs 19.1% of those given the control regimen.

“No new safety signals were observed, and AEs were consistent with those that were expected for each of the study drugs,” Kopetz noted.

The most common TRAEs experienced by at least 15% of patients in the EC plus FOLFIRI arm included nausea (grade 1/2, 56%; grade ≥ 3, 3%), diarrhea (41%; 10%), vomiting (38%; 3%), alopecia (31%; 1%), anemia (25%; 7%), decreased neutrophil count (15%; 15%), decreased appetite (25%; 4%), fatigue (30%; 0%), neutropenia (14%; 11%), skin hyperpigmentation (23%; 0%), dry skin (21%; 0%), asthenia (15%; 3%), weight decrease (18%; 0%), arthralgia (17%; 0%), Palmar-plantar erythrodysesthesia syndrome (17%; 0%), rash (17%; 0%), decreased white blood cell count (10%; 7%), and constipation (15%; 0%).

Disclosures: Dr Koptez reported stock and other ownership interests with regard to Lylon, Lutris, MolecularMatch, and Navire. He serves in a consulting or advisory role for AbbVie, Amal Therapeutics, AstraZeneca/MedImmune, Bayer Health, Bicara Therapeutics, Boehringer Ingelheim, Boston Biomedical, Carina Biotech, Daiichi Sankyo, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, GSK, HailoDx, Holy Stone Healthcare, Inivata, Ipsen, Iylon, Jacobio, Jazz Pharmacueticals, Lilly, Lutris, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, RedxPharma, Repare Therapeutics, Servier, and Xilis. Research funding was provided by Amgen, Array BioPharma, Biocartis, Daiichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, and Sanofi.

References

1. Kopetz S, Wasan HS, Yoshino T, et al. BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2026;44(suppl 2):13. doi:10.1200/JCO.2026.44.2_suppl.13
2. Kopetz S, Yoshino T, Van Cutsem E, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901-908. doi:10.1038/s41591-024-03443-3
3. Elez E, Yoshiino T, Shen L, et al. Encorafenib, cetuximab and mFOLFOX6 in BRAF-mutant colorectal cancer. N Engl J Med. 2025;392(24):2425-2437. doi:10.1056/NEJMoa2501912
4. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed January 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
5. Tabernero J, Yoshino T, Kim TW, et al. 515MO Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI). Ann Oncol. 2025;35(suppl 2):S435-S436. doi:10.1016/j.annonc.2024.08.584