medwireNews: Encorafenib plus cetuximab (EC) combined with chemotherapy improves progression-free survival (PFS) and overall survival (OS) compared with standard care in patients with BRAF V600E-mutated metastatic colorectal cancer, suggests an analysis from the phase 3 BREAKWATER trial.
Encorafenib is a highly selective, small-molecule BRAF inhibitor that has a longer pharmacodynamic activity than other approved BRAF inhibitors, write Scott Kopetz (University of Texas MD Anderson Cancer Center, Houston, USA) and colleagues in The New England Journal of Medicine.
The current findings, which were simultaneously presented at the 2025 ASCO Annual Meeting in Chicago, Illinois, USA, support the previously published results for the trial’s co-primary endpoint of objective response, the rate of which was significantly greater with the addition of EC.
“This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy,” note the researchers.
The open-label study involved untreated patients with stage IV colorectal adenocarcinoma with a BRAF V600E mutation. A total of 50.4% of the participants were men, 58.6% were White, and they were a median of 59–62 years old. Just over half (52.1%) of the patients had two or fewer organs involved and 63.0% had liver metastases.
The participants were randomly assigned to receive EC, comprising oral encorafenib 300 mg/day plus intravenous cetuximab 500 mg/m2 once every 2 weeks, with or without chemotherapy (mFOLFOX6) every 2 weeks in a 28-day cycle, or standard care (investigator’s choice of mFOLFOX6, FOLFOXIRI, or CAPOX).
The latest results for the second primary outcome of PFS were measured over a median follow-up of 16.8 months for the 236 patients receiving EC plus mFOLFOX6 and 9.8 months for the 243 patients receiving standard care.
The EC plus mFOLFOX6 group had a significantly longer PFS than the standard care group, at a median of 12.8 versus 7.1 months, and a hazard ratio (HR) for disease progression or death of 0.53.
Meanwhile, the 158 patients receiving EC without chemotherapy, whose enrollment was stopped based on a low likelihood of superiority over standard care based on results reported while BREAKWATER was ongoing, had a similar PFS to that of the standard care group, at a median of 6.8 months over a median follow-up of 18.0 months. However, the risk for disease progression or death was doubled for patients taking EC alone versus those taking EC plus mFOLFOX6 (HR=2.05).
Patients in the EC plus mFOLFOX6 group also had longer OS than those in the standard care group, at a median of 30.3 months versus 15.1 months, as measured over a median follow-up of 21.8 months and 22.2 months, respectively, giving a significant HR for death of 0.49. The estimated OS rate in the EC plus mFOLFOX6 group was 80.1% at 12 months and 52.0% at 24 months, compared with a respective 66.0% and 29.0% in the standard care group.
The researchers note that, in the EC group, the median OS was longer than in the standard care group, at 19.5 months over a median follow-up of 26.3 months, giving a significant HR for death of 0.69. They therefore suggest that “[f]irst-line EC may be considered for patients who are unable to receive chemotherapy.”
Kopetz and colleagues say that the findings “underscore the need for an intensive first-line regimen, such as EC [plus] mFOLFOX6, to control aggressive tumor growth.”
They also report that the safety profiles for the EC combination “were consistent with those known for each agent.” Adverse events (AEs) of grades 3 or 4 occurred in 81.5%, 42.5%, and 66.8% of the EC plus mFOLFOX6, EC, and standard care groups, respectively.
Serious AEs were observed in a corresponding 46.1%, 30.1%, and 38.9%, the most common of which were intestinal obstruction, pyrexia, anemia, and disease progression, although they were “largely manageable,” says the team. Fatal AEs occurred in a respective 4.3%, 2.6%, and 4.4% of patients.
Overall, the results “provide evidence for the importance of combining dual targeted therapy (EC) with chemotherapy in BRAF V600E–mutated colorectal cancer in the first-line context to improve patient outcomes,” the researchers conclude.
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N Engl J Med 2025; doi:10.1056/NEJMoa2501912
2025 ASCO Annual Meeting; Chicago, Illinois, USA: 30 May–3 June