Positive topline progression-free (PFS) survival results from Cohort 3, a separate randomized cohort of the pivotal, randomized Phase 3, BREAKWATER trial (NCT04607421), evaluating encorafenib (Braftovi®; Pfizer)* in combination with cetuximab (Erbitux®; Eli Lilly and Company) and FOLFIRI (a combination chemotherapy that includes fluorouracil, leucovorin, and irinotecan) in patients with previously untreated metastatic colorectal cancer (mCRC) with a BRAFV600E- mutation.**
Colorectal cancer (CRC) is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022.[1] It is the second leading cause of cancer-related deaths.[2] Overall, the lifetime risk of developing colorectal cancer is about 1 in 24 for men and 1 in 26 for women.[2]
In the United States alone, an estimated 154,270 people will be diagnosed with cancer of the colon or rectum in 2025, and approximately 53,000 are estimated to die from the disease each year.[3] For 20% of those diagnosed with colorectal cancer, the disease has metastasized, or spread, making it harder to treat, and up to 50% of patients with localized disease eventually develop metastases.[4]
BRAF mutations are estimated to occur in 8-12% of people with mCRC and represent a poor prognosis for these patients.[5] The BRAF V600E -mutation is the most common BRAF mutation, and the risk of mortality in CRC patients with BRAF V600E is more than twice that of patients without a known mutation.[5][6] Despite the high unmet need in BRAFV600E-mutant mCRC, no biomarker-driven therapies were approved prior to December 20, 2024, specifically indicated for people with previously untreated BRAFV600E-mutant metastatic colorectal cancer (mCRC).[7][8]
Encorafenib: Statistically Significant
Encorafenib is an oral small-molecule kinase inhibitor that targets BRAFV600E. Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been observed in certain cancers, including colorectal cancer.
The encorafenib regimen demonstrated a statistically significant and clinically meaningful improvement in PFS, a key secondary endpoint, as assessed by blinded independent central review (BICR), compared with FOLFIRI with or without Avastin® (Bevacizumab, Genentech/Roche). Overall survival (OS), a descriptive secondary endpoint, also showed clinically meaningful prolonged improvement with the encorafenib regimen.
“These results build on the positive objective response rate data we recently shared, providing further evidence of the meaningful benefit this encorafenib-based targeted approach may offer patients with BRAFV600E–mutant metastatic colorectal cancer,” noted Jeff Legos, Chief Oncology Officer, Pfizer.
“The combination of significant responses and now improvement in progression‑free survival underscores the potential of encorafenib as a potentially practice-changing treatment option for patients and families facing this challenging diagnosis,” Legos added.
Primary endpoint
The primary endpoint of this cohort of the BREAKWATER trial was objective response rate (ORR) by BICR. Positive ORR results were achieved and recently presented at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI®) Cancers Symposium, held January 8–10, 2026, at Moscone West in San Francisco, California.
At the time of the PFS analysis, the safety profile of encorafenib in combination with cetuximab and FOLFIRI was consistent with the known profile of each regimen component, and no new safety signals were identified.
- Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (3.5%) and pyrexia (3.5%).
- Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.
- Most common adverse reactions(≥25%, all grades) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were peripheral neuropathy (62% vs 53%), nausea (51% vs 48%), fatigue (49% vs 38%), rash (31% vs 4%), diarrhea (34% vs 47%), decreased appetite (33% vs 25%), vomiting (33% vs 21%), hemorrhage (30% vs 18%), abdominal pain (26% vs 27%), and pyrexia (26% vs 14%).
- Most common laboratory abnormalities(≥10%, grade 3 or 4) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were: increased lipase (51% vs 25%), decreased neutrophil count (36% vs 34%), decreased hemoglobin (13% vs 5%), decreased white blood cell count (12% vs 7%), and increased glucose (11% vs 2%).
Regulatory Status
Encorafenib in combination with cetuximab and FOLFIRI is an investigational regimen and is not currently approved. Detailed results from this cohort will be submitted for presentation at an upcoming medical meeting and shared with the U.S. Food and Drug Administration (FDA) to support potential approval for BRAFTOVI in combination with cetuximab and FOLFIRI in patients with BRAF V600E-mutant mCRC.
Encorafenib in combination with cetuximab and mFOLFOX6 received accelerated approval by the FDA in December 2024 for patients with BRAF V600E-mutant mCRC based on a clinically meaningful and statistically significant improvement in confirmed ORR in treatment-naïve patients, one of the study’s primary endpoints. Continued approval for this indication is contingent upon verification of clinical benefit.
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Note: * The phase 3, active-controlled, open-label, multicenter BREAKWATER trial of encorafenib + cetuximab, alone or in combination with chemotherapy (mFOLFOX6 or FOLFIRI) in participants with previously untreated BRAF V600E-mutant mCRC. Participating patients were randomized to receive encorafenib 300 mg orally once daily in combination with cetuximab (discontinued after randomization of 158 patients), encorafenib 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n=236), or mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab (control arm) (n=243). The dual primary endpoints for these study groups are ORR and PFS as assessed by BICR. OS is a key secondary endpoint. In Cohort 3, patients were randomized to receive encorafenib 300 mg orally once daily in combination with cetuximab and FOLFIRI (n=73) or FOLFIRI, with or without bevacizumab (control arm) (n=74). The primary endpoint of Cohort 3 is ORR as assessed by BICR. PFS is a key secondary endpoint; OS is a secondary endpoint.
** Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada, Latin America, the Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize the product in Japan and South Korea, Medison has exclusive rights to commercialize the product in Israel, and Pierre Fabre Laboratories has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea).
Clinical trials
A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer
ClinicalTrials.gov ID NCT04607421
Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer (BEACON CRC)
ClinicalTrials.gov ID NCT02928224
References
[1] American Cancer Society. Global Cancer Facts & Figures 5th Edition. Online. Last accessed in February 2026.
[2] American Cancer Society. Key Statistics for Colorectal Cancer. Online. Last accessed in February 2026.
[3] American Cancer Society. Cancer Facts & Figures 2025. Online. Online. Last accessed in January 2026.
[4] Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022 Jul;72(4):372-401. doi: 10.3322/caac.21728. Epub 2022 Apr 26. PMID: 35472088.
[5] Tabernero J, Ros J, Élez E. The Evolving Treatment Landscape in BRAF-V600E-Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol Educ Book. 2022 Apr;42:1-10. doi: 10.1200/EDBK_349561. PMID: 35503983.
[6] Safaee Ardekani G, Jafarnejad SM, Tan L, Saeedi A, Li G. The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012;7(10):e47054. doi: 10.1371/journal.pone.0047054. Epub 2012 Oct 9. PMID: 23056577; PMCID: PMC3467229.
[7] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer. V.5.2024 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Last accessed in February 2026. To view the most recent and complete version of the guideline, visit NCCN.org.
[8] Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.
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