Canafenib/encofenib/bimetinib/nivolumab improves PFS in patients with BRAF V600+ melanoma with symptomatic brain metastases

Based on2 issues of SWOG submitted in 2025 Data from the S2000 trial (NCT04511013) triple therapy with encorafenib, binimetinib and nivolumab improved BRAF compared with nivolumab plus ipilimumab Progression-free survival (PFS) in patients with V600 mutationmelanomabrain metastases. More research and improved guidelines are needed to optimize treatment in this patient population, which has historically had poor outcomes with immunotherapy.

Results from the phase 2 study showed that median PFS was 6.2 months (95% CI, 3-14.4) for patients who received triple therapy (n = 16) compared with 1.5 months (95% CI, 0.7-1.7) for patients who received nivolumab plus ipilimumab (n = 15; HR, 0.47; one-sided 90% CI, 0-0.82; P = 0.04). The 6-month progression-free survival rates were 54% (95% CI, 27%-75%) and 20% (95% CI, 5%-42%) respectively. Median intracranial PFS was 8.7 months (95% CI, 3-19.4) in the canafenib plus bimetinib and nivolumab arm compared with 1.5 months (95% CI, 0.7-1.7) in the doublet arm (HR, 0.39; one-sided 90% CI, 0-0.68; P=0.01). The 18-month overall survival (OS) rate was 36% (95% CI, 13%-60%) in the canafenib plus bimetinib and nivolumab group, compared with 37% (95% CI, 12%-62%) in the nivolumab plus ipilimumab group (HR, 1.21; 95% CI, 0.49-2.98; P=0.66). Triple therapy may be therapeutically useful in this still difficult-to-treat patient population, but further study is needed.

Phase 2Principle and Design: Even with radiation therapy and/or surgery, the prognosis for patients with melanoma symptomatic brain metastases remains poor. Triplet regimens have been shown to be feasible in the first-line treatment of patients with advanced melanoma; clinical improvements with these regimens have been minimal and have not been compared with upfront immunotherapy. Due to poor efficacy of immunotherapy in melanoma brain metastases, SWOG S2000 was launched to compare triple therapy in this setting.

SWOG S2000 enrolled melanoma patients who were at least 18 years old, had brain metastases of at least 0.5 cm in size, and had an ECOG performance status of 0 to 2. PFS according to RECIST 1.1 criteria served as the primary endpoint. Secondary endpoints include overall response rate (ORR), intracranial PFS and ORR, OS, safety, and radiographic response.

Among evaluable patients, the ORR was 67% (95% CI, 43%-91%) in the canafenib plus bimetinib and nivolumab group (n=15) and 14% (95% CI, 0%-33%) in the nivolumab plus ipilimumab group (n=14). All responses were partial in both groups, and the disease stabilization rate was 7% in both groups. Thirteen percent of patients in the triplet group had progressive disease, compared with 79% of patients in the control group. Symptoms worsened before treatment in 14% of patients in the triple arm.

The intracranial ORR was 75% (95% CI, 54%-96%) in the triplet group (n=16) and 13% (95%CI, 0%-31%) in the doublet group (n=15). One patient in each group had a complete intracranial response. The disease stabilization and progression rates were both 6% in the experimental group; these rates in the control group were 7% and 80%, respectively.

Regarding safety, 69% of patients in the triplet arm experienced grade 3/4 treatment-related adverse events (TRAE), compared with 75% in the double arm arm. TRAEs led to treatment discontinuation in 19% and 32% of patients, respectively. TRAE-induced dose changes were reported in 75% and 32% of patients, respectively. The toxicity profiles of both regimens were consistent with the known characteristics of each drug. The trial was limited by difficulties recruiting patients with severe symptoms into the study, which was not designed to compare triple therapy with a sequential targeted therapy and immunotherapy approach.

References:https://www.onclive.com/view/encorafenib-binimetinib-nivolumab-improves-pfs-in-braf-v600-melanoma-with-symptomatic-brain-metastases