Abstract Background The VICTORY study comprises dose-finding (Phase A) and expansion (Phase B) phases. Phase A was designed to determine the RP2D of vinblastine combined with tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor. Methods Eligible patients were 25 years of age with recurrent or progressive pLGG with confirmed BRAF/CRAF alterations, having received at least one prior line of systemic chemotherapy and/or targeted therapy. Phase A used a rolling six design with a 28-day dose-limiting toxicity (DLT) assessment period, across five planned dose levels, starting at dose level 0 (weekly vinblastine 4 mg/m² and tovorafenib 420 mg/m²), Safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity were assessed. Results Between March 2024 and July 2025, 11 patients were enrolled on phase A : 3 at dose level 0, 2 at dose level −1, and 6 at dose level −2. Median age was 7.8 years (range 2.25–14.3). Ten patients had BRAF fusions and one had a BRAF V600E mutation. Median number of prior systemic therapies was three (range 1–4), with 9/11 previously treated with BRAF and/or MEK inhibitors. Six patients experienced eight DLTs, including neutropenia (n = 4), grade 3 maculopapular rash (n = 3), and grade 3 ALT elevation (n = 1). At data cutoff (October 2025), all patients remained on combination therapy except one continuing tovorafenib monotherapy. The RP2D was vinblastine 2 mg/m² and tovorafenib 380 mg/m². Vinblastine PK did not show trend of dose proportionality likely due to sample size and data variability, while tovorafenib exposure was consistent with tovorafenib monotherapy PK. With a median follow-up of 10 months, best responses included partial response (n = 2), minor response (n = 4), and stable disease (n = 4). Conclusions The vinblastine–tovorafenib combination demonstrates manageable toxicity and encouraging anti-tumor activity in a heavily pretreated pLGG population. Phase B is ongoing to further evaluate efficacy and durability of response.
Thacker et al. (Tue,) studied this question.