By Fineline Cube Pfizer Inc. (NYSE: PFE) announced that Cohort 3 of the pivotal Phase 3 BREAKWATER trial met its primary endpoint, demonstrating a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) for the combination of BRAFTOVI (encorafenib), cetuximab (ERBITUX), and FOLFIRI versus standard‑of‑care in previously untreated metastatic colorectal cancer (mCRC) patients harboring a BRAF V600E mutation.
Clinical Milestone
| Item | Detail |
|---|---|
| Trial | BREAKWATER, Cohort 3 (Phase 3) |
| Design | Randomized, open‑label |
| Population | First‑line BRAF V600E mCRC (n = ~200) |
| Regimen | BRAFTOVI + cetuximab + FOLFIRI |
| Comparator | FOLFIRI ± bevacizumab |
| Primary Endpoint | Confirmed ORR by BICR |
| Key Secondary | Duration of response ≥6 months |
Drug Profile & Mechanism of Action
- Molecule: Oral small‑molecule kinase inhibitor targeting BRAF V600E oncogenic driver
- Combination Rationale: Dual EGFR (cetuximab) and BRAF blockade overcomes MAPK pathway feedback activation, while FOLFIRI provides cytotoxic backbone
- Innovation: First triplet regimen to show superior ORR in first‑line BRAF V600E mCRC, a historically poor‑prognosis subgroup
- Regulatory Status:
- BRAFTOVI + cetuximab + mFOLFOX6 received FDA accelerated approval in December 2024
- BRAFTOVI + cetuximab + FOLFIRI remains investigational; Pfizer plans full approval submission in H2 2026
Clinical Evidence – BREAKWATER Cohort 3
| Endpoint | BRAFTOVI + Cetuximab + FOLFIRI | FOLFIRI ± Bevacizumab | Treatment Difference | p‑value |
|---|---|---|---|---|
| Confirmed ORR (BICR) | 64.4 % | 39.2 % | +25.2 ppt | < 0.001 |
| Response ≥6 months | 57.4 % | 34.5 % | +22.9 ppt | < 0.001 |
| Median PFS (est.) | 11.8 months | 8.4 months | +3.4 months | TBD |
| Grade ≥ 3 AEs | Neutropenia (32 %), diarrhea (18 %) | Neutropenia (28 %), HTN (15 %) | – | – |
Safety profile was consistent with known toxicities of each agent, with no new safety signals identified.
Market Impact & Outlook
| Parameter | 2026E | 2027E | 2028E |
|---|---|---|---|
| Global BRAF V600E mCRC Incidence | 52,000 | 54,000 | 56,000 |
| First‑Line Eligible Patients | 41,000 | 43,000 | 45,000 |
| BRAFTOVI + FOLFIRI Market Share | 0 % | 18 % | 28 % |
| Est. Monthly Cost (US) | – | $24,000 | $23,000 |
| Pfizer Revenue Forecast | – | $1.1 billion | $2.3 billion |
- US Market Access: Pending approval, Pfizer expects preferred coverage by major payers in Q1 2027, leveraging existing BRAFTOVI contracts
- Competitive Landscape:
- Exact Sciences (BRAF mutations) and Roche (EGFR portfolio) are developing competing triplet regimens
- Differentiation: BREAKWATER’s robust ORR and durability data may position BRAFTOVI‑FOLFIRI as the backbone of choice for BRAF V600E mCRC
- Strategic Value: Success in Cohort 3 broadens BRAFTOVI’s label beyond the mFOLFOX6‑approved population, capturing ~60 % of US oncologists who prefer FOLFIRI in first‑line mCRC
Forward‑Looking Statements
This brief contains forward‑looking statements regarding regulatory submissions, commercial forecasts, and competitive positioning for BRAFTOVI. Actual results may differ due to FDA review outcomes, market access negotiations, and emerging combination therapies.-Fineline Info & Tech