Encorafenib/Cetuximab Plus Chemo Drives ORR Improvement in BRAF V600E+ mCRC

Treatment with the combination of encorafenib (Braftovi), cetuximab (Erbitux), and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) led to an statistically significant and clinically meaningful improvement in overall response rate (ORR) vs mFOLFOX6 alone in patients with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations, according to data from the phase 3 BREAKWATER trial (NCT04607421) presented at the 2025 Gastrointestinal Cancers Symposium.1

Findings demonstrated patients treated with encorafenib plus cetuximab and chemotherapy (n = 110) achieved an ORR of 60.9% (95% CI, 51.6%-69.5%) per blinded independent central review (BICR) compared with 40.0% (95% CI, 31.3%-49.3%) for patients treated with chemotherapy alone (n = 110; odds ratio, 2.443; 95% CI, 1.403-4.253; one-sided P = .0008).

In the experimental arm, best responses comprised complete response (CR; 2.7%), partial response (58.2%), stable disease (28.2%), progressive disease (PD; 2.7%) non-CR/non-PD (2.7%), and not evaluable (NE; 5.5%). In the control arm, these respective rates were 1.8%, 38.2%, 30.9%, 3.6%, 8.2%, and 17.3%.

“[Data from the BREAKWATER] study support encorafenib plus cetuximab and mFOLFOX6 as a new standard of care in the first line for patients with BRAF V600E–mutated mCRC and formed the basis of the accelerated approval by the FDA,” lead study author Scott Kopetz, MD, PhD, FACP, said in a presentation of the data. Kopetz is deputy chair for Translational Research and a professor in the Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine; leader of the Department of Cancer Center Support Grant, GI Program; TRACTION medical director in the Division of Therapeutics Discovery Division; and associate vice president for Translational Integration at The University of Texas MD Anderson Cancer Center in Houston.

In December 2024, the FDA granted accelerated approval to encorafenib in combination with cetuximab and mFOLFOX6 for the treatment of patients with mCRC harboring a BRAF V600E mutation, as detected by an FDA-approved test.2

BREAKWATER Breakdown

Investigators for the open-label, multicenter study enrolled patients at least 16 years of age (or at least 18 years of age based on the country) with BRAF V600E–mutated mCRC per local or central laboratory testing.1 Prior systemic therapy in the metastatic setting was not allowed. Key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria; an ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function.

Patients were excluded if they received prior treatment with a BRAF or EGFR inhibitor; had symptomatic brain metastases; or harbored a RAS mutation. Patients with mismatch repair–deficient/microsatellite instability–high disease were excluded; however, these patients were allowed to enroll if they were ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition.

The study enrolled 637 patients who were randomly assigned in a 1:1:1 fashion to receive encorafenib plus cetuximab alone (n = 158); encorafenib plus cetuximab and mFOLFOX6 (n = 236); or standard-of-care mFOLFOX6 alone (n = 243). Data for the encorafenib/cetuximab arm will be reported at a later date.

Patients were stratified by region (United States/Canada vs Europe vs rest of world) and ECOG performance status (0 vs 1).

Progression-free survival and ORR per BICR assessment for encorafenib plus cetuximab and mFOLFOX6 vs mFOLFOX6 alone served as the trial’s dual primary end points. Notably, for this analysis, ORR was assessed in the first 110 patients enrolled in the respective arms. Overall survival (OS) was a key secondary end point. OS was only tested if the ORR difference was statistically significant.

Among all enrolled patients between the encorafenib plus cetuximab and mFOLFOX6 arm and the mFOLFOX6 arm (n = 479), the median age was 61.0 years (range, 24-84). Most patients were male (50.5%), had an ECOG performance status of 0 (54.3%), right-sided tumors (61.0%), 2 or fewer organs involved (52.4%), liver metastases (62.6%), a carcinoembryonic antigen level of more than 5 µg/L (68.7%), and a C-reactive protein level of no more than 10 mg/L (50.9%).

The median treatment duration was 28.1 weeks (range, 1.3-107.4) in the encorafenib plus cetuximab and mFOLFOX6 arm vs 20.4 weeks (range, 1.1-98.3) in the mFOLFOX6 arm. All patients in both arms were randomly assigned; however, 2.1% and 5.8% of patients were not treated, respectively.

As of the data cutoff date of December 22, 2023, 58.1% of patients in the encorafenib plus cetuximab and mFOLFOX6 arm were still receiving treatment. Reasons for discontinuation included adverse effects (AEs; 4.7%), death (3.4%), PD (20.8%), patient withdrawal (5.5%), global deterioration of health status (3.4%), and other (4.2%). In the mFOLFOX6 arm, 33.7% of patients were still receiving treatment at data cutoff; reasons for discontinuation comprised AEs (9.1%), death (4.1%), PD (31.7%), patient withdrawal (11.5%), deterioration of global health status (1.6%), and other (8.2%).

Additional Efficacy and Safety Data

The median time to response was 7.1 weeks (range, 5.7-53.7) in the encorafenib plus cetuximab and mFOLFOX6 arm vs 7.3 weeks (range, 5.4-48.0) in the chemotherapy arm. The estimated duration of response (DOR) was 13.9 months (range, 8.5-not evaluable [NE]) and 11.1 months (range, 6.7-12.7), respectively. In the experimental arm, the 6- and 12-month DOR rates were 68.7% and 22.4%, respectively. In the control arm, these respective rates were 34.1% and 11.4%.

Kopetz noted that the ORR benefit was consistent across subgroups with the experimental regimen.

The median follow-up for OS was 10.3 months (95% CI, 8.6-11.6) in the experimental arm vs 9.8 months (95% CI, 7.5-11.3) in the control arm. The median OS was NE (95% CI, 19.8-NE) vs 14.6 months (95% CI, 13.4-NE) for the encorafenib plus cetuximab and mFOLFOX6 arm and the mFOLFOX6 arm, respectively (HR, 0.47; 95% CI, 0.318-0.691; P = .0000454). At the time of this analysis, the OS difference was not statistically significant.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) occurred in 99.6% of patients in the experimental arm (n = 231) vs 97.8% of patients in the control arm (n = 228). The rates of grade 3/4 TEAEs were 74.0% and 61.0%, respectively. The respective rates of grade 5 TEAEs were 4.3% and 4.4%. Serious TEAEs were reported in 37.7% of patients in the encorafenib plus cetuximab and mFOLFOX6 arm vs 34.6% of patients in the mFOLFOX6 arm.

In the encorafenib plus cetuximab and mFOLFOX6 group, TEAEs led to permanent discontinuation of any treatment, dose reduction of any treatment, and dose interruption of any treatment in 20.8%, 61.0%, and 84.8% of patients, respectively. These respective rates were 14.9%, 47.8%, and 64.0% in the control arm.

Specifically in the experimental arm, TEAEs led to the discontinuation of encorafenib, cetuximab, and mFOLFOX6 in 11.7%, 13.0%, and 15.6% of patients, respectively. The respective rates of dose reduction for each treatment due to TEAEs were 22.1%, 6.1%, and 55.8%. The rates of dose interruptions due to TEAEs were 56.7% for encorafenib, 58.4% for cetuximab, and 75.8% for mFOLFOX6.

Treatment-related AEs (TRAEs) of any grade were observed in 98.7% of patients in the experimental arm and 93.0% of patients in the mFOLFOX6 arm. The rates of grade 3/4 TRAEs were 69.7% and 53.9%, respectively. No grade 5 TRAEs occurred in the encorafenib plus cetuximab and mFOLFOX6 group; 1 patient (0.4%) experienced a grade 5 TRAE in the control arm. The rates of serious TRAEs were 18.2% and 19.3%, respectively.

The most common TEAEs reported in the experimental arm included nausea (grade 1/2, 48.5%; grade ≥3, 2.6%), anemia (25.5%; 10.8%), diarrhea (32.9%; 1.3%), decreased appetite (31.2%; 2.2%), vomiting (29.9%; 3.5%), decreased neutrophil count (13.9%; 18.2%), asthenia (22.5; 4.3%), pyrexia (24.2%; 1.7%), peripheral sensory neuropathy (19.0%; 5.6%), rash (23.8%, 0.9%), fatigue (21.6%; 2.6%), peripheral neuropathy (16.5%; 6.9%), arthralgia (21.2%; 0.9%), neutropenia (7.4%; 14.7%), alopecia (21.2%; 0%), and constipation (19.9%; 0.4%).

In the control arm, the most frequently reported TEAEs comprised nausea (grade 1/2, 45.2%; grade ≥3, 3.1%), anemia (19.3%; 3.5%), diarrhea (43.4%; 3.5%), decreased appetite (23.7%; 1.3%), vomiting (18.9%; 2.2%), decreased neutrophil count (11.4%; 16.7%), asthenia (13.2%; 1.3%), pyrexia (12.7%; 0.4%), peripheral sensory neuropathy (19.3%; 2.2%), rash (2.6%, 0%), fatigue (22.4%; 2.6%), peripheral neuropathy (18.4%; 2.6%), arthralgia (3.5%; 0%), neutropenia (13.2%; 9.2%), alopecia (9.6%; 0%), and constipation (18.9%; 0.4%).

Disclosures: Dr Kopetz reported stock and ownership interests in Lylon, Lutris, MolecularMatch, and Navire; serving in a consulting or advisory role for AbbVie, Amal Therapeutics, AstraZeneca/Medlmmune, Bayer Health, BicaraTherapeutics, Boehringer Ingelheim, Boston Biomedical, Carina Biotech, Daichi Sankyo, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, GSK, HalioDx, Holy Stone Healthcare, Inivata, Ipsen, lylon, Jacobio, Jazz Pharmaceuticals, Lilly, Lutris, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, RedxPharma, Repare Therapeutics, Servier, and Xilis; and receiving research funding from Amgen, Array BioPharma, Biocartis, Daichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, Medlmmune, Novartis, and Sanofi.

References

1. Kopetz S, Yoshino T, Van Cutsem E, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. J Clin Oncol. 2025;43(supp 4):16. doi:10.1200/JCO.2025.43.4_suppl.16
2. 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 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf