Encorafenib/Cetuximab Plus Chemo Improves Survival in BRAF V600E+ mCRC

Encorafenib plus cetuximab and mFOLFOX6 improved PFS and OS vs chemotherapy in BRAF V600E–mutant metastatic colorectal cancer.

Frontline treatment with encorafenib (Braftovi) in combination with cetuximab (Erbitux) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs chemotherapy alone in patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, meeting one of the dual primary end points of the phase 3 BREAKWATER trial (NCT04607421).1

Additionally, the combination elicited a clinically meaningful and statistically significant improvement in overall survival (OS) vs chemotherapy alone, meeting a key secondary end point in the study.

“We are extremely pleased with the clinically meaningful PFS and OS results from the BREAKWATER study, which have the potential to be practice-changing for this patient population that has historically had limited treatment options and poor outcomes,” Roger Dansey, MD, chief oncology officer at Pfizer, stated in a news release.

These results come after the FDA granted accelerated approval to the combination on December, 20, 2024, for the treatment of patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test.2 The accelerated approval was based on overall response rate (ORR) data, which was the other primary end point of the study.

Response data from BREAKWATER were presented at the 2025 Gastrointestinal Cancers Symposium and showed that patients with treatment-naive BRAF V600E– mutated mCRC experienced an ORR of 60.9% (95% CI, 51.6%-69.5%) when treated with encorafenib plus cetuximab and mFOLFOX6 (n = 110) vs 40% (95% CI, 31.3%-49.3%) when treated with chemotherapy alone (n = 110; odds ratio, 2.443; 95% CI, 1.403-4.253; P = .0008).3

BREAKWATER was a randomized, open-label, multicenter study that enrolled patients at least 16 years of age with mCRC harboring a BRAF V600E mutation. In the randomized portion of the study, no prior systemic therapy for metastatic disease was permitted. Additional inclusion criteria included measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib at 300 mg once daily plus cetuximab (n = 158); encorafenib at 300 mg once daily plus cetuximab and mFOLFOX6 (n = 236); or mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab (Avastin; n = 243).1,3

The primary end points were PFS and ORR for encorafenib plus cetuximab and mFOLFOX6 vs chemotherapy alone. Secondary end points consisted of OS, duration of response, time to response, and safety. Notably, data for encorafenib plus cetuximab alone will be reported at a later date.1

The most frequently reported treatment-related adverse effects (TEAEs) in the encorafenib plus cetuximab and mFOLFOX6 arm included nausea (48.5%), diarrhea (32.9%), decreased appetite (31.2%), vomiting (29.9%), and anemia (25.5%).3

Grade 3 or higher TEAEs included decreased neutrophil count (18.3%), anemia (10.8%), and neutropenia (14.7%). Peripheral sensory neuropathy was observed in 19.0% of patients, including 5.6% who had grade 3 or higher effects.

In comparison, the safety profile of standard-of-care (SOC) chemotherapy showed similar trends with nausea (45.2%), diarrhea (43.4%), and decreased appetite (23.7%) being the most common TEAEs. Grade 3 or higher TEAEs with SOC chemotherapy included decreased neutrophil count (16.7%) and anemia (19.3%).

“The [encorafenib] regimen is emerging as a new SOC as the first targeted therapy approved for use as early as first line for patients with mCRC with a BRAF V600E mutation. We look forward to discussing these data with global health authorities to bring this treatment to more patients around the world, as soon as possible,” Dansey concluded.1

References

  1. Pfizer's Braftovi combination regimen demonstrated a significant improvement in progression-free survival and overall survival in the phase 3 BREAKWATER trial. Pfizer. News release February 3, 2025. Accessed February 3, 2025. https://investors.pfizer.com/Investors/News/news-details/2025/Pfizers-BRAFTOVI-Combination-Regimen-Significantly-Improved-Progression-Free-Survival-and-Overall-Survival-in-Phase-3-BREAKWATER-Trial/default.aspx
  2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed February 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
  3. Kopetz S, Yoshino T, Cutsem EV, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastaticcolorectal cancer. J Clin Oncol. 2025;43(suppl 4):16. doi10.1200/jco.2025.43.4_suppl.16