Braftovi and Erbitux Plus Chemo Improves Outcomes for BRAF V600E+ mCRC

Updated data from the phase 3 BREAKWATER trial showed that combining Braftovi (encorafenib) and Erbitux (cetuximab) with mFOLFOX6 chemotherapy (modified fluorouracil, leucovorin and oxaliplatin) elicited a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care therapy in the first-line treatment for patients with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations.

Findings were presented in a press briefing ahead of the 2025 ASCO Annual Meeting and published in the New England Journal of Medicine. Of the 236 patients treated with Braftovi plus Erbitux and mFOLFOX6, the median PFS was 12.8 at a median follow-up of 16.8 months. This number was 7.1 months at a median follow-up of 9.8 months among the 243 patients given standard-of-care treatment.

Additionally, Braftovi plus Erbitux and mFOLFOX6 generated a median overall survival of 30.3 months versus 15.1 months with standard-of-care. The estimated 12- and 24-month overall survival rates in the experimental arm were 80.1% and 52.0%, respectively. These respective rates were 66.0% and 29.0% in the standard-of-care treatment arm.

“Braftovi [in combination with] Erbitux and mFOLFOX6 — the BREAKWATER regimen — is a practice-changing, new standard-of-care for [patients] with mCRC with a BRAF V600E mutation,” lead study author Elena Elez, MD, PhD, said during the press briefing.

Elez is an attending physician in the Gastrointestinal Tumors Service of the Medical Oncology Service at Vall d’Hebron University Hospital and principal investigator of the Gastrointestinal Tumor Group and Endocrine of Vall d'Hebron Instituto de Oncología in Barcelona, Spain.

In December 2024, the FDA granted accelerated approval to Braftovi in combination with Erbitux and mFOLFOX6 for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test. The regulatory decision was based on previously reported data from BREAKWATER, which showed that among the first 110 patients treated in each arm, the overall response rate was 61% for the combination versus 40% for standard-of-care. The median duration of response was 13.9 months and 11.1 months, respectively.

Breaking Down BREAKWATER

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 mCRC who had measurable disease per RECIST 1.1 criteria and had not received prior systemic therapy in the metastatic setting. The presence of a BRAF V600E mutation was required, per local or central testing. Patients also needed to have an ECOG performance status of 0 or 1, along with adequate bone marrow, hepatic and renal function.

Combining Braftovi and Erbitux with mFOLFOX6 elicited a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care therapy in the first-line treatment for patients with mCRC harboring BRAF V600E mutations.

Key exclusion criteria comprised prior exposure to BRAF or EGFR inhibitors; symptomatic brain metastases; microsatellite instability-high/mismatch repair-deficient tumors, unless patients were ineligible for immune checkpoint inhibitors; and RAS-mutated disease.

Investigators randomly assigned 637 patients fashion to receive Braftovi plus Erbitux alone (158 patients); Braftovi in combination with Erbitux and chemo (236 patients); or standard-of-care (243 patients). Enrollment to the Braftovi/Erbitux alone cohort was stopped following a protocol amendment and subsequently enrolled patients were randomly assigned between the other two arms.

Treatment in the standard-of-care arm included mFOLFOX6, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan), or CAPOX (capecitabine and oxaliplatin) with or without Avastin (bevacizumab).

Stratification factors included region (United States/Canada versus Europe versus rest of world) and ECOG performance status (0 versus 1).

Overall response rate and progression-free survival per blinded independent central review served as the trial’s dual primary end points. Overall survival was a key secondary end point.

Additional Efficacy and Safety Findings

Data from the cohort of patients who received Braftovi plus Erbitux without chemo showed that the median progression-free survival was 6.8 months and the median overall survival was 19.5 months.

Updated response data demonstrated that the overall response rate for Braftovi plus Erbitux and chemo was 65.7%; the rates of complete response, partial response, stable disease and progressive disease in this arm were 4.7%, 61.0%, 21.2% and 3.4%, respectively. In the standard-of-care arm, the overall response rate was 37.4% (95% CI, 31.6%-43.7%) with a complete response rate of 3.3%, a partial response rate of 34.2%, a stable disease rate of 35.0% and a progressive disease rate of 8.6%. In the Braftovi/Erbitux alone arm, the ORR was 45.6% with complete, partial response, stable disease and progressive rates of 1.9%, 43.7%, 36.1% and 7.6%, respectively.

The median time to response was 7.0 weeks (range, 5.1-103.6) for Braftovi/Erbitux/mFOLFOX6, 7.3 weeks (range, 5.4-48.0) for standard-of-care and 6.6 weeks (range, 4.3-86.4) for Braftovi/Erbitux. The median duration of response was 13.9 months, 10.8 months and 7.0 months, respectively.

In the Braftovi/Erbitux/chemo arm, the 6- and 12-month duration of response rates were 71.0% and 34.8%, respectively. These respective rates were 41.8% and 17.6% in the standard-of-care arm; they were 40.3% and 20.8%, respectively, for Braftovi/Erbitux alone.

At data cutoff, 28.4% of patients in the Braftovi/Erbitux/chemo arm remained on treatment compared with 6.6% in the standard-of-care arm and 7.6% of patients in the Braftovi/Erbitux arm. Subsequent therapy was administered to 63.9% of patients in the Braftovi/Erbitux/chemo group versus 61.2% in the standard-of-care group and 73.3% in the Braftovi/Erbitux group. A BRAF inhibitor–based regimen was given as subsequent therapy to 71.9% of the 139 patients in the standard-of-care arm who received additional treatment.

The median time to second disease progression or death was 20.7 months in the Braftovi/Erbitux/chemo arm, 12.7 months in the standard-of-care arm and 14.3 months in the Braftovi/Erbitux arm.

Regarding safety, the Braftovi plus Erbitux and chemo regimen was generally tolerable with a consistent safety profile. No substantial increases in chemotherapy dose reductions or discontinuation were observed compared with the standard-of-care arm.

Any-grade side effects were reported in all patients in the Braftovi/Erbitux/chemo arm, 99.1% of patients in the standard-of-care arm and 97.4% of patients in the Braftovi/Erbitux arm. The rates of grade 3 (severe) or grade 4 (life-threatening) side effects were 81.5%, 66.8% and 42.5%, respectively. The respective rates of grade 5 (death) events were 4.3%, 4.4% and 2.6%. One grade 5 side effect in the standard-of-care arm was deemed treatment related.

The most common grade 1/2 side effects included nausea (combination, 51%; standard-of-care, 46%), anemia (31%; 21%), diarrhea (41%; 46%), decreased appetite (35%; 26%), vomiting (32%; 20%), decreased neutrophil count (15%; 12%), arthralgia (29%; 5%), rash (29%; 4%), asthenia (24%; 14%), pyrexia (27%; 15%), peripheral neuropathy (20%; 20%), constipation (27%; 22%), peripheral sensory neuropathy (20%; 20%) and fatigue (24%; 24%).1

The most frequently reported grade 3/4 side effects included nausea (combination, 3%; standard-of-care, 4%), anemia (15%; 4%), diarrhea (1%; 5%), decreased appetite (2%; 1%), vomiting (4%; 2%), decreased neutrophil count (19%; 17%), arthralgia (3%; <1%), rash (1%; 0%), asthenia (5%; 1%), pyrexia (2%; <1%), peripheral neuropathy (8%; 4%), constipation (<1%; <1%), peripheral sensory neuropathy (7%; 4%) and fatigue (3%; 4%).

Side effects led to permanent discontinuation of any study treatment in 26.7% of patients in the Braftovi/Erbitux/chemo arm, 17.5% of patients in the standard-of-care arm and 13.1% of patients in the Braftovi/Erbitux arm. Side effects led to dose reductions of any treatment in 65.5%, 54.1% and 10.5% of patients, respectively. The rates of side effects leading to dose reductions were 59.9% in the Braftovi/Erbitux/chemo arm and 54.1% in the standard-of-care arm. Side effects led to the discontinuation of chemotherapy (with or without Avastin) in 20.7% of the patients in the Braftovi/Erbitux/chemo group versus 17.5% in the standard-of-care group.

References

• Elez E, Yoshino T, Shen L, et al. First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): progression-free survival and updated overall survival analyses. J Clin Oncol. 2025;43(suppl 17):LBA3500. doi:10.1200/JCO.2025.43.17_suppl.LBA3500
• Elez E, Yoshino T, Shen L, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med. Published online May 30, 2025. doi:10.1056/NEJMoa2501912

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