Laboratoires Pierre Fabre has received European Commission approval for BRAFTOVI (encorafenib) in combination with cetuximab and FOLFOX (fluorouracil, leucovorin and oxaliplatin) as first-line treatment for adults with BRAFV600E-mutant metastatic colorectal cancer. The decision makes this regimen the first and only combination including a BRAF‑targeted therapy cleared in the European Union for this patient population in the first-line setting.
The approval is based on the Phase 3 BREAKWATER trial, which compared encorafenib plus cetuximab and mFOLFOX6 against oxaliplatin‑based chemotherapy with or without bevacizumab in previously untreated BRAFV600E-mutant metastatic colorectal cancer. The triplet regimen met the dual primary endpoints, showing a statistically significant improvement in progression‑free survival, with median PFS of 12.8 months versus 7.1 months (hazard ratio 0.53; 95% CI 0.41–0.68; P<0.001), and higher objective response rates in the primary analysis set (60.9% versus 40.0%; odds ratio 2.44; 95% CI 1.40–4.25; P<0.001).
In the overall population, confirmed objective responses were reported in 65.7% of patients (95% CI 59.4–71.4) receiving the encorafenib-based combination, compared with 37.4% (95% CI 31.6–43.7) for those treated with oxaliplatin‑based chemotherapy with or without bevacizumab. An interim analysis also showed a statistically significant and clinically meaningful overall survival benefit, with median OS of 30.3 months for the encorafenib regimen versus 15.1 months for the control arm (hazard ratio 0.49; 95% CI 0.38–0.63; P<0.001), corresponding to a 51% reduction in the risk of death.
The most frequent adverse events (≥30%) with BRAFTOVI plus cetuximab and mFOLFOX6 included nausea (53.9%), anemia (46.1%), diarrhea (41.8%), decreased appetite (37.5%), vomiting (36.2%), decreased neutrophil count (34.1%), arthralgia (31.5%) and rash (30.2%). Grade 3 or 4 adverse events occurred in 81.5% of patients and grade 5 events in 4.3%. In the oxaliplatin‑based chemotherapy group, diarrhea (50.2%) and nausea (49.8%) were the most common adverse events, with grade 3 or 4 events in 66.8% and grade 5 events in 4.4%. Safety findings were consistent with the known profiles of the individual agents.
The new indication builds on the EC’s 2020 approval of BRAFTOVI in combination with cetuximab for adults with BRAFV600E-mutated metastatic colorectal cancer previously treated with systemic therapy. Pierre Fabre said it plans to continue clinical development of targeted therapies in colorectal cancer and other tumor types where specific molecularly defined subgroups have limited treatment options.
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