PFS Improves in BRAF V600E+ CRC With Encorafenib Combo

“Encorafenib [in combination with] cetuximab and mFOLFOX6—the BREAKWATER regimen—is a practice-changing, new SOC for [patients] with mCRC with a BRAF V600E mutation,” according to lead study author Elena Elez, MD, PhD.

A statistically significant and clinically meaningful progression-free survival (PFS) improvement occurred among patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) who received frontline encorafenib (Braftovi) plus cetuximab (Erbitux) and modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6), according to updated results from the phase 3 BREAKWATER study (NCT04607421) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1,2

Findings presented in a press briefing ahead of the meeting and published in the New England Journal of Medicine demonstrated that at a median follow-up of 16.8 months (95% CI, 15.1-18.4) for the experimental arm and 9.8 months (95% CI, 8.5-13.0) for the SOC arm, patients treated with encorafenib plus cetuximab and mFOLFOX6 (n = 236) achieved a median PFS of 12.8 months (95% CI, 11.2-15.9) compared with 7.1 months (95% CI, 6.8-8.5) for those given SOC (n = 243; HR, 0.53; 95% CI, 0.41-0.68; P < .001).2

Additionally, encorafenib plus cetuximab and mFOLFOX6 generated a median overall survival (OS) of 30.3 months (95% CI, 21.7-not estimable [NE]) vs 15.1 months (95% CI, 13.7-17.7) for SOC (HR, 0.49; 95% CI, 0.38-0.63 P < .001). The estimated 12- and 24-month OS rates in the experimental arm were 80.1% and 52.0%, respectively. These respective rates were 66.0% and 29.0% in the SOC arm.

“Encorafenib [in combination with] cetuximab and mFOLFOX6—the BREAKWATER regimen—is a practice-changing, new SOC 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 encorafenib in combination with cetuximab and mFOLFOX6 for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test.3 The regulatory decision was based on previously reported data from BREAKWATER, which showed that the among the first 110 patients treated in each arm, the overall response rate (ORR) was 61% (95% CI, 52%-70%) for the combination vs 40% (95% CI, 31%-49%) for SOC (P = .0008).3,4 The median duration of response (DOR) was 13.9 months (95% CI, 8.5-NE) and 11.1 months (95% CI, 6.7-12.7), respectively.3

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.1 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.

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 patients (n = 637) in a 1:1:1 fashion to receive encorafenib plus cetuximab alone (n = 158); encorafenib in combination with cetuximab and mFOLFOX6 (n = 236); or SOC (n = 243). Enrollment to the encorafenib/cetuximab alone cohort was stopped following a protocol amendment, and subsequently enrolled patients were randomly assigned 1:1 between the other 2 arms. Treatment in the SOC arm included mFOLFOX6, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), or CAPOX (capecitabine and oxaliplatin) with or without bevacizumab (Avastin).

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

ORR and PFS per blinded independent central review served as the trial’s dual primary end points. OS was a key secondary end point.

In the encorafenib/cetuximab plus mFOLFOX6 (n = 236) and SOC (n = 243) arms, the median age was 60 years (range, 24-81) and 62 years (range, 28-84), respectively. Fifty-one percent of patients in the SOC arm were female compared with 47.9% in the experimental arm. Most patients had an ECOG performance status of 0 (encorafenib/cetuximab/mFOLFOX6, 54.2%; SOC, 53.9%), a right-sided tumor (61.9%; 59.7%), 2 or fewer organs involved (50.4%; 52.3%), and liver metastases (62.3%; 65.8%).

At baseline, 70.8% of patients in the encorafenib/cetuximab/mFOLFOX6 arm had a carcinoembryonic antigen (CEA) level of more than 5 µg/L compared with 67.1% in the SOC arm. The rates of patients with a C-reactive protein (CRP) level of 10 mg/L or less were 53.0% and 48.6%, respectively.

In the encorafenib/cetuximab alone arm, the median age was 59 years (range, 26-84), and half of patients were female. Most patients had an ECOG performance status of 0 (50.0%), had right-sided tumors (56.3%), had 2 or fewer organs involved (54.4%), had liver metastases (59.5%), had a baseline CEA level above 5 µg/L (64.6%), and had a baseline CRP level of no more than 10 mg/L (57.6%).

Additional Efficacy and Safety Findings

Data from the cohort of patients who received encorafenib plus cetuximab without mFOLFOX6 showed that the median PFS was 6.8 months (95% CI, 5.7-8.3), and the median OS was 19.5 months (95% CI, 17.6-22.5).

Updated response data demonstrated that the ORR for encorafenib plus cetuximab and mFOLFOX6 was 65.7% (95% CI, 59.4%-71.4%); the rates of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) in this arm were 4.7%, 61.0%, 21.2%, and 3.4%, respectively. In the SOC arm, the ORR was 37.4% (95% CI, 31.6%-43.7%) with a CR rate of 3.3%, a PR rate of 34.2%, a SD rate of 35.0%, and a PD rate of 8.6%. In the encorafenib/cetuximab alone arm, the ORR was 45.6% (95% CI, 38.0%-53.3%) with CR, PR, SD, and PD 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 encorafenib/cetuximab/mFOLFOX6, 7.3 weeks (range, 5.4-48.0) for SOC, and 6.6 weeks (range, 4.3-86.4) for encorafenib/cetuximab. The median DOR was 13.9 months (95% CI, 10.9-18.5), 10.8 months (95% CI, 7.6-13.4), and 7.0 months (95% CI, 4.2-11.6), respectively.

In the encorafenib/cetuximab/mFOLFOX6 arm, the 6- and 12-month DOR rates were 71.0% and 34.8%, respectively. These respective rates were 41.8% and 17.6% in the SOC arm; they were 40.3% and 20.8%, respectively, for encorafenib/cetuximab alone.

At data cutoff, 28.4% of patients in the encorafenib/cetuximab/mFOLFOX6 arm remained on treatment compared with 6.6% in the SOC arm and 7.6% of patients in the encorafenib/cetuximab arm.2 Subsequent therapy was administered to 63.9% of patients in the encorafenib/cetuximab/mFOLFOX6 group vs 61.2% in the SOC group and 73.3% in the encorafenib/cetuximab group. A BRAF inhibitor–based regimen was given as subsequent therapy to 71.9% of the 139 patients in the SOC arm who received additional treatment.

The median time to second disease progression or death was 20.7 months (95% CI, 19.0-23.9) in the encorafenib/cetuximab/mFOLFOX6 arm, 12.7 months (95% CI, 11.2-13.7) in the SOC arm, and 14.3 months (95% CI, 12.7-16.6) in the encorafenib/cetuximab arm.

Regarding safety, the encorafenib plus cetuximab and mFOLFOX6 regimen was generally tolerable with a consistent safety profile.1 No substantial increases in chemotherapy dose reductions or discontinuation were observed compared with the SOC arm.

Any-grade adverse effects (AEs) were reported in all patients in the encorafenib/cetuximab/mFOLFOX6 arm, 99.1% of patients in the SOC arm, and 97.4% of patients in the encorafenib/cetuximab arm.2 The rates of grade 3/4 AEs were 81.5%, 66.8%, and 42.5%, respectively. The respective rates of grade 5 AEs were 4.3%, 4.4%, and 2.6%. One grade 5 AE in the SOC arm was deemed treatment related.

The most common grade 1/2 AEs included nausea (encorafenib/cetuximab/mFOLFOX6, 51%; SOC, 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 AEs included nausea (encorafenib/cetuximab/mFOLFOX6, 3%; SOC, 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%).

AEs led to permanent discontinuation of any study treatment in 26.7% of patients in the encorafenib/cetuximab/mFOLFOX6 arm, 17.5% of patients in the SOC arm, and 13.1% of patients in the encorafenib/cetuximab arm.2 AEs led to dose reductions of any treatment in 65.5%, 54.1%, and 10.5% of patients, respectively. The rates of AEs leading to dose reductions were 59.9% in the encorafenib/cetuximab/mFOLFOX6 arm and 54.1% in the SOC arm. AEs led to the discontinuation of chemotherapy (with or without bevacizumab) in 20.7% of the patients in the encorafenib/cetuximab/mFOLFOX6 group vs 17.5% in the SOC group.

References

1. 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
2. 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
3. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed May 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
4. U.S. FDA approves Pfizer’s Braftovi combination regimen as first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. News release. Pfizer. December 20, 2024. Accessed May 28, 2025. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-combination-regimen-first