Ono Pharmaceutical Secures Approvals for BRAFTOVI Combination Therapy in BRAF-Mutant Colorectal Cancer
Key Insights
Ono Pharmaceutical received supplemental approval in Japan and additional approval in South Korea for BRAFTOVI (encorafenib) combination therapy as first-line treatment for unresectable, advanced or recurrent colorectal cancer (search) with BRAF mutation (search).
The Phase 3 BREAKWATER study demonstrated statistically significant improvements in objective response rate (60.9% vs 40.0%, p = 0.0008) and progression-free survival (12.8 vs 7.1 months, p < 0.0001) compared to chemotherapy alone.
The combination therapy addresses a significant unmet medical need, as BRAF (search)-mutant colorectal cancer (search) patients represent 4.5-6.7% of cases in Japan and have poorer prognosis than those without the mutation.
Ono Pharmaceutical Co., Ltd. (search) has achieved regulatory milestones in both Japan and South Korea for its BRAF (search) inhibitor BRAFTOVI (encorafenib) in combination with cetuximab and chemotherapy for the first-line treatment of unresectable, advanced or recurrent colorectal cancer (search) with BRAF mutation (search). The Japanese approval was announced on November 20, 2025, followed by South Korean approval on January 9, 2026.
Clinical Trial Results Drive Regulatory Success
The approvals are based on results from the global multicenter Phase 3 BREAKWATER study (ONO-7702-03/C4221015), which evaluated the efficacy and safety of BRAFTOVI in combination with cetuximab and FOLFOX (search) (5-FU/levoleucovorin/oxaliplatin) compared with chemotherapy alone in patients with unresectable advanced or recurrent colorectal cancer (search) harboring BRAFV600E mutations.
In the randomized Phase 3 portion of the trial, patients receiving the BRAFTOVI combination therapy demonstrated statistically significant and clinically meaningful improvements in both primary endpoints. The objective response rate (ORR) assessed by blinded independent central review (BICR) reached 60.9% in the combination arm versus 40.0% in the chemotherapy arm (p = 0.0008). Additionally, progression-free survival (PFS) showed substantial improvement with a median of 12.8 months compared to 7.1 months for chemotherapy alone (hazard ratio = 0.53; 95% confidence interval: 0.407 to 0.677; p < 0.0001).
The safety profile of the BRAFTOVI combination therapy was consistent with the known safety profiles of each individual drug, with no new safety signals identified during the trial.
Treatment Protocol and Patient Population
The approved regimen consists of 300 mg of BRAFTOVI administered orally once daily, combined with cetuximab given once every two weeks and FOLFOX (search) administered once every two weeks until disease progression or safety concerns arise. The treatment targets patients with unresectable advanced or recurrent colorectal cancer (search) specifically harboring the BRAFV600E mutation (search).
Addressing Significant Unmet Medical Need
Colorectal cancer (search) represents a substantial global health burden, with approximately 1,926,000 new cases diagnosed worldwide annually and approximately 904,000 deaths reported globally. In Japan, colorectal cancer is the most common cancer with approximately 145,000 new cases diagnosed annually and approximately 60,000 deaths reported each year, making it the second most common cause of cancer death after lung cancer.
BRAFV600E mutation (search)-positive patients comprise 4.5 to 6.7% of colorectal cancer (search) patients in Japan and 4.7% in South Korea, compared to 5 to 12% in the US and EU. Critically, patients with BRAF (search) mutations have a poorer prognosis than those without the mutation, and no drugs had previously been approved for first-line treatment of BRAF-mutant colorectal cancer, creating a significant unmet medical need.
Expanding Treatment Options
Prior to these approvals, BRAFTOVI was already approved in both countries for second-line treatment of unresectable advanced or recurrent colorectal cancer (search) with BRAF mutation (search) that had progressed following chemotherapy. The drug was available in triplet combination therapy with BRAFTOVI, MEKTOVI (binimetinib), and cetuximab, as well as in doublet combination therapy with BRAFTOVI and cetuximab.
On June 19, 2024, BRAFTOVI received orphan drug designation from Japan's Ministry of Health, Labour and Welfare for the indication of unresectable, advanced or recurrent colorectal cancer (search) with BRAF mutation (search), highlighting the rarity and medical significance of this patient population.
Mechanism of Action and Development Partnership
BRAFTOVI is a small molecule BRAF (search) kinase inhibitor that targets key enzymes in the MAPK signaling pathway (RAS-RAF-MEK (search)-ERK), which regulates cellular activities including proliferation, differentiation, survival, and angiogenesis. Inappropriate activation of proteins in this pathway occurs in many cancer types, including melanoma (search), thyroid cancer (search), and colorectal cancer (search).
The development and commercialization of BRAFTOVI in Japan and South Korea stems from a licensing agreement Ono entered into with Array BioPharma Inc. in May 2017. Array BioPharma subsequently became a subsidiary of Pfizer Inc. in July 2019, establishing the ongoing collaboration between Ono and Pfizer for these markets.