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BREAKWATER (Cohort 3) — Encorafenib + cetuximab + FOLFIRI, 1L BRAF V600E mCRC

Abstract: LBA3503 · Session: Gastrointestinal Cancer — Colorectal and Anal, Oral Abstract Session, Sun May 31, 2026 (CT) · Presenter: Scott Kopetz, MD, PhD, FACP (UT MD Anderson Cancer Center, Houston) · Embargo: May 31, 2026

Note on cohorts: The ASCO 2026 Annual Meeting late-breaking readout (LBA3503) is the Cohort 3 FOLFIRI final analysis, summarized below. The widely-cited mFOLFOX6 OS data (median OS 30.3 vs 15.1 mo, HR 0.49; PFS 12.8 vs 7.1 mo, HR 0.53) come from the mFOLFOX6 cohort, LBA3500, presented at ASCO 2025 (JCO 2025;43:17_suppl, LBA3500; NEJM 2026) — not a 2026 Annual Meeting presentation. Both cohorts are part of the same BREAKWATER phase 3 program.

At a glance

  • Sponsor: Pfizer Inc.
  • PI / presenter: Scott Kopetz, MD, PhD (UT MD Anderson Cancer Center)
  • NCT ID: NCT04607421
  • Phase: 3
  • Design: Open-label, multicenter, randomized; Cohort 3 randomized 1:1 to encorafenib + cetuximab (EC) + FOLFIRI vs FOLFIRI ± bevacizumab (investigator's choice control)
  • N: Cohort 3 — 147 (EC + FOLFIRI n=73; control n=74)
  • Primary endpoint(s): Progression-free survival (PFS, by BICR) and objective response rate (ORR)
  • Comparator: FOLFIRI ± bevacizumab
  • Indication: BRAF V600E-mutant metastatic colorectal cancer (mCRC)
  • Line: First-line (1L)

Headline result

In the final Cohort 3 analysis presented at ASCO 2026, first-line EC + FOLFIRI nearly doubled median PFS (BICR) versus FOLFIRI ± bevacizumab: 15.2 mo (95% CI 13.6–NE) vs 8.3 mo (95% CI 6.8–8.9), HR 0.44 (95% CI 0.27–0.70; one-sided p=0.0002) — a 56% reduction in risk of progression or death. ORR was 64.4% vs 39.2% (odds ratio 2.756, 95% CI 1.420–5.348; p=0.0011). Overall survival favored the EC arm with a 44% reduction in risk of death: median OS not reached (95% CI 21.0–NE) vs 20.3 mo (95% CI 13.2–NE), HR 0.56 (95% CI 0.34–0.94); 18-month OS 72.0% vs 54.9%, at ~20 months median follow-up. No new safety signals; serious adverse event rates were comparable between arms (37.7% vs 34.6%). Results were simultaneously published in Annals of Oncology (May 31, 2026).

Mechanism / class

Encorafenib is an oral small-molecule BRAF kinase inhibitor; cetuximab is an anti-EGFR monoclonal antibody. The doublet blocks BRAF V600E signaling while suppressing EGFR-mediated MAPK pathway reactivation, paired here with a FOLFIRI cytotoxic backbone. The EC + mFOLFOX6 regimen received FDA accelerated approval in Dec 2024 (BREAKWATER mFOLFOX6 cohort) and full/traditional approval on Feb 24, 2026 for 1L BRAF V600E mCRC with a fluorouracil-based chemotherapy backbone.

Discussant takeaway

Framed as confirming EC + chemotherapy (FOLFOX or FOLFIRI) as a standard 1L option for BRAF V600E mCRC, with Cohort 3 extending backbone flexibility beyond mFOLFOX6 to FOLFIRI behind the traditional FDA approval. (Named discussant not captured in available sources.)

Practice-changing?

Yes. Cohort 3 reinforces EC + chemotherapy as 1L standard of care for BRAF V600E mCRC and validates FOLFIRI as an alternative chemotherapy backbone to mFOLFOX6, supporting the Feb 2026 traditional FDA approval of the BRAFTOVI combination regimen.

  • Other GI / CRC ASCO 2026 trials: ./horizon-crc01-trastuzumab-rezetecan-her2-crc.md · ./episode-iii-adjuvant-aspirin-stage-iii-crc.md
  • Other ASCO 2026 trials: see GI track index — ./index.md
  • JPM 2026: Pfizer — ../../jpm-2026/index.md

Sources

  • ASCO Meeting Library (LBA3503 / abstract 483124): https://www.asco.org/abstracts-presentations/ABSTRACT483124
  • ASCO Daily News: https://dailynews.ascopubs.org/do/first-line-encorafenib-and-cetuximab-folfiri-improves-outcomes-over-folfiri-and
  • CancerNetwork: https://www.cancernetwork.com/view/encorafenib-cetuximab-plus-folfiri-improved-survival-responses-in-braf-v600e-mcrc
  • Pfizer press release (BusinessWire, May 31, 2026): https://www.businesswire.com/news/home/20260531990280/en/Pfizers-BRAFTOVI-Regimen-Nearly-Doubles-Median-Progression-Free-Survival-in-Metastatic-Colorectal-Cancer
  • ASCO press release: https://www.asco.org/about-asco/press-center/news-releases/combining-encorafenib-cetuximab-folfiri-may-be-effective-first-line-treatment-some-people-advanced-colorectal-cancer
  • mFOLFOX6 cohort context (LBA3500, ASCO 2025): https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA3500
  • FDA traditional approval (encorafenib, mCRC): https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic-colorectal-cancer-braf-v600e-mutation