Among patients with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations, treatment with the combination of Braftovi (encorafenib), Erbitux (cetuximab), and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) led to a statistically significant and clinically meaningful improvement in overall response rate (ORR) versus mFOLFOX6 alone, according to data from the phase 3 BREAKWATER trial presented at the 2025 Gastrointestinal Cancers Symposium.
Findings demonstrated patients treated with Braftovi plus Erbitux and chemotherapy (110 patients) achieved an ORR of 60.9% compared with 40% for patients treated with chemotherapy alone (110 patients).
In the experimental arm, best responses comprised complete response (CR; 2.7%), partial response (PR; 58.2%), stable disease (SD; 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%.
Glossary:
Overall response rate (ORR): patients who responded partially or completely to treatment.
ECOG performance status: patient's ability to perform daily activities.
Neutropenia: low white blood cells.
Peripheral neuropathy: nerve damage in limbs.
Arthralgia: joint pain.
Alopecia: hair loss.
Duration of response (DOR): time cancer responds to treatment.
Overall survival (OS): time from treatment to death.
Complete response (CR): no detectable cancer.
Partial response: significant cancer reduction.
Stable disease: no significant cancer change.
Progressive disease (PD): cancer growth or spread.
Progression-free survival: the time a patient lives without their disease spreading or worsening.
“[Data from the BREAKWATER] study support [Braftovi] plus [Erbitux] 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 Dr. Scott Kopetz 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 Braftovi in combination with Erbitux and mFOLFOX6 for the treatment of patients with mCRC harboring a BRAF V600E mutation, as detected by an FDA-approved test.
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. Prior systemic therapy in the metastatic setting was not allowed.
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 to receive Braftovi plus Erbitux alone (158 patients); Braftovi plus Erbitux and mFOLFOX6 (236 patients); or standard-of-care mFOLFOX6 alone (243 patients). Data for the Braftovi/Erbitux arm will be reported at a later date.
Patients were stratified by region (United States/Canada versus Europe versus rest of world) and ECOG performance status (0 versus 1).
Progression-free survival and ORR for Braftovi plus Erbitux and mFOLFOX6 versus 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 Braftovi plus Erbitux and mFOLFOX6 arm and the mFOLFOX6 arm (479 patients), the median age was 61 years. Most patients were male (50.5%), had an ECOG performance status of 0 (54.3%), right-sided tumors (61%), two 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 milligrams/L (50.9%).
The median treatment duration was 28.1 weeks in the Braftovi plus Erbitux and mFOLFOX6 arm versus 20.4 weeks 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 Dec. 22, 2023, 58.1% of patients in the Braftovi plus Erbitux and mFOLFOX6 arm were still receiving treatment. Reasons for discontinuation included side 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 Braftovi plus Erbitux and mFOLFOX6 arm versus 7.3 weeks (range, 5.4-48.0) in the chemotherapy arm. The estimated duration of response (DOR) was 13.9 months and 11.1 months, respectively. In the experimental arm, the six- 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.
Regarding safety, any-grade treatment-emergent AEs (TEAEs) occurred in 99.6% of patients in the experimental arm (231 patients) versus 97.8% of patients in the control arm (228 patients). The rates of grade 3 (severe) or 4 (life-threatening) TEAEs were 74% and 61%, respectively. The respective rates of grade 5 (death) TEAEs were 4.3% and 4.4%. Serious TEAEs were reported in 37.7% of patients in the Braftovi plus Erbitux and mFOLFOX6 arm versus 34.6% of patients in the mFOLFOX6 arm.
In the Braftovi plus Erbitux 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% and 84.8% of patients, respectively. These respective rates were 14.9%, 47.8% and 64% in the control arm.
Specifically in the experimental arm, TEAEs led to the discontinuation of Braftovi, Erbitux and mFOLFOX6 in 11.7%, 13% 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 Braftovi, 58.4% for Erbitux 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% of patients in the mFOLFOX6 arm. The rates of grade 3 or 4 TRAEs were 69.7% and 53.9%, respectively. No grade 5 TRAEs occurred in the Braftovi plus Erbitux and mFOLFOX6 group; one 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 or worse, 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%; 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 were nausea (grade 1/2, 45.2%; grade 3 or worse, 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%).
Reference:
“BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer,” By Dr. Scott Kopetz, et al. J Clin Oncol.
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