On February 24, 2026, the U.S. Food and Drug Administration granted full approval to BRAFTOVI (encorafenib) in combination with cetuximab and fluorouracil-based chemotherapy for adult patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, as detected by an FDA-authorized test. The approval is based on results from the global Phase 3 BREAKWATER trial.
Previously, on February 17, 2026, Pfizer announced positive topline results from Cohort 3 of BREAKWATER evaluating BRAFTOVI + cetuximab + FOLFIRI in the first-line setting. The regimen demonstrated improvement in PFS versus FOLFIRI ± bevacizumab, with overall survival also showing clinically meaningful prolonged improvement (descriptive endpoint).
“These results build on the positive objective response rate data we recently shared, providing further evidence of the meaningful benefit this BRAFTOVI-based targeted approach may offer patients with BRAF V600E–mutant metastatic colorectal cancer. The combination of significant responses and now improvement in progression‑free survival underscores the potential of BRAFTOVI as a potentially practice-changing treatment option for patients and families facing this challenging diagnosis.”
Jeff Legos, Chief Oncology Officer, Pfizer
Colorectal Cancer and BRAF V600E
Colorectal cancer is the third most common cancer globally, with approximately 1.8 million new diagnoses reported in 2022, and it remains the second leading cause of cancer-related deaths. According to American Cancer Society, in the United States, an estimated 158,850 new cases and approximately 55,000 deaths are projected for 2026. Approximately 20% of patients present with metastatic disease at diagnosis, and up to half of those initially diagnosed with localized disease eventually develop metastases.
BRAF mutations occur in approximately 8–12% of metastatic colorectal cancers. The V600E variant is the most common and is associated with significantly poorer prognosis compared to BRAF wild-type disease.
The lifetime risk of developing CRC is approximately 1 in 24 for men and 1 in 26 for women. For patients with BRAF V600E–mutant CRC, the risk of mortality is described as more than double that of patients with no known mutation present.
Read more about BRAF-Mutant Colorectal Cancer on OncoDaily.
Approval History
As of February 24, 2026, the U.S. Food and Drug Administration has granted full approval to encorafenib (BRAFTOVI) in combination with cetuximab and fluorouracil-based chemotherapy for the treatment of adult patients with BRAF V600E–mutant metastatic colorectal cancer.
The regimen initially received FDA accelerated approval in December 2024 based on confirmed objective response rate (ORR) results from the Phase 3 BREAKWATER trial. Full approval was subsequently granted after demonstration of statistically significant improvements in progression-free survival and overall survival in the mFOLFOX6 cohort of BREAKWATER. The current indication allows use of encorafenib plus cetuximab in combination with fluorouracil-based chemotherapy, including mFOLFOX6 or FOLFIRI.
Scott Kopetz, MD, PhD, FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at MD Anderson and co–principal investigator of BREAKWATER, stated:
“This approval gives oncologists confidence to use encorafenib plus cetuximab in combination with fluorouracil-based chemotherapy as a first-line standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer. The BREAKWATER study demonstrated that these targeted combination regimens provided statistically significant benefit, providing the robust evidence we need to make treatment decisions that can meaningfully impact patient outcomes.”
Scott Kopetz, MD, PhD, FACP
The Results Behind the Decision
BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial evaluating BRAFTOVI with cetuximab, alone or in combination with chemotherapy (mFOLFOX6 or FOLFIRI), in previously untreated BRAF V600E–mutant metastatic colorectal cancer.
At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the pivotal Phase III BREAKWATER trial (NCT04607421) results were presented, demonstrating that encorafenib + cetuximab + mFOLFOX6 (EC + mFOLFOX6) significantly improved outcomes in first-line BRAF V600E–mutant metastatic colorectal cancer (mCRC).
In this cohort, the triplet demonstrated statistically significant and clinically meaningful improvements in both progression-free and overall survival:
- 47% reduction in risk of disease progression or death
(HR 0.53; 95% CI 0.41–0.68; p<0.0001) - Median PFS: 12.8 vs 7.1 months
- 51% reduction in risk of death
(HR 0.49; 95% CI 0.38–0.63; p<0.0001) - Median OS: 30.3 vs 15.1 months
These pivotal data were simultaneously published in The New England Journal of Medicine.
Results from ESMO 2025
Later that year, at the ESMO Congress in Berlin, additional translational analyses were presented by Scott Kopetz, focusing on encorafenib + cetuximab + mFOLFOX6 (EC + mFOLFOX6) in previously untreated BRAF V600E–mutant metastatic colorectal cancer.
The triplet demonstrated high objective response rates across molecular subgroups, reaching 75% in patients with high baseline BRAF V600E ctDNA burden and 63% in those with lower burden, with favorable overall survival hazard ratios of 0.50 and 0.39, respectively. Early ctDNA clearance at Cycle 2 Day 15 was observed in 67% of patients treated with EC + mFOLFOX6 and was strongly associated with prolonged survival. Importantly, acquired resistance mutations in KRAS, NRAS, and MAP2K1 were markedly less frequent with the triplet (6.6%) compared with encorafenib + cetuximab alone (37.9%), suggesting that the addition of mFOLFOX6 enhances depth of response while suppressing clonal evolution.
These ESMO 2025 data provided the mechanistic and clinical foundation for EC + mFOLFOX6 as a first-line standard in BRAF V600E–mutant mCRC.
Read more about BREAKWATER Study Results at ESMO 2025 on OncoDaily.
Results From ASCO GI 2026
At the 2026 ASCO Gastrointestinal Cancers Symposium (Kopetz et al., J Clin Oncol 44, 2_suppl:13), investigators presented the primary analysis of BREAKWATER Cohort 3 evaluating first-line encorafenib plus cetuximab combined with FOLFIRI in patients with BRAF V600E–mutant metastatic colorectal cancer.
In this randomized cohort, 147 previously untreated patients were assigned to receive encorafenib + cetuximab + FOLFIRI (n=73) or FOLFIRI with or without bevacizumab (n=74). Baseline characteristics were balanced between treatment arms.
Key Findings
- The regimen met its primary endpoint of confirmed objective response rate (ORR) by blinded independent central review. ORR was 64.4% with the triplet versus 39.2% with control (odds ratio 2.76; 95% CI 1.42–5.35; one-sided P=0.001).
- Responses were rapid, with a median time to response of approximately 7 weeks in both arms.
- Responses were durable: 57.4% of responders in the triplet arm maintained responses for at least six months compared with 34.5% in the control group. Median duration of response had not yet been reached.
- Overall survival data were immature at a median follow-up of around 10 months; however, the hazard ratio of 0.49 (95% CI 0.24–1.03) suggested a potential survival benefit.
- Serious treatment-emergent adverse events occurred in 39.4% of patients receiving the triplet compared with 36.8% in the control arm. The addition of encorafenib did not substantially increase FOLFIRI discontinuation rates. No new safety signals were identified.
Safety and Side Effects
Across BREAKWATER, the safety profile of both BRAFTOVI combination regimens was consistent with the known safety profile of the individual agents, and no new safety signals were identified.
Key safety warnings/precautions include the risk of new primary malignancies (cutaneous and non-cutaneous), tumor promotion in BRAF wild-type tumors (so BRAF mutation status should be confirmed with an FDA-authorized test before starting therapy), cardiomyopathy with decreased LVEF, hepatotoxicity, hemorrhage, uveitis, QT prolongation, and embryo-fetal toxicity. BRAFTOVI can render hormonal contraceptives ineffective; effective non-hormonal contraception is recommended during treatment and for 2 weeks after the last dose.
BRAFTOVI + cetuximab + mFOLFOX6
In the press release, the most common side effects (≥25%) with the mFOLFOX6 regimen were: peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation.
Adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in 14% of patients. Pfizer also reported no substantial difference in chemotherapy discontinuation due to side effects versus chemotherapy (with or without bevacizumab).
BRAFTOVI + cetuximab + FOLFIRI (Cohort 3 regimen)
For the FOLFIRI regimen, the most common side effects (≥25%) were: nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.
Adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in 9% of patients.
For full dosing and risk-management recommendations, the press release directs clinicians to the prescribing information for cetuximab and the individual components of mFOLFOX6 and FOLFIRI.
Drug Interactions
BRAFTOVI is metabolized via CYP3A4 and should not be coadministered with strong or moderate CYP3A4 inhibitors (including grapefruit juice) or strong CYP3A4 inducers. If unavoidable, dose adjustment may be required. Caution is advised when used with sensitive CYP3A4 substrates, including hormonal contraceptives, due to potential reduced efficacy. Concomitant use with QT-prolonging agents should be avoided. Dose adjustments may also be necessary for substrates of OATP1B1, OATP1B3, or BCRP.
Conclusion
The full approval of encorafenib in combination with cetuximab and fluorouracil-based chemotherapy marks a pivotal moment in the treatment of BRAF V600E–mutant metastatic colorectal cancer. Supported by robust survival data from BREAKWATER and reinforced by consistent activity across chemotherapy backbones, this biomarker-driven strategy now establishes a first-line standard for a historically poor-prognosis population. For patients and clinicians alike, the shift toward targeted intensification in the frontline setting signals a meaningful evolution in precision oncology for colorectal cancer.
The full press release is available on Pfizer.