A phase 1, multicenter, open-label study of HSK42360, a brain-penetrant BRAF inhibitor, in patients with BRAF V600-mutated solid tumors.

3109 Background: Limitations of approved BRAF V600E inhibitors include toxicity from paradoxical activation of RAF dimerization as well as limited brain penetration. In contrast to approved agents, investigational pan-RAF inhibitors both inhibit mutant RAF proteins and wild-type (wt) RAF proteins, leading to a narrow therapeutic index. HSK42360 is a next-generation, small-molecule BRAF paradox breaker with high brain penetration. It displays significantly less paradoxical activation than approved BRAF inhibitors and spares wtBRAF-containing RAF dimers. Treatment with HSK42360 results in excellent and durable anti-tumor effect in BRAF Class I and II mutant CDX or PDX models. Here we report the interim results from a Phase 1 study of HSK42360 in patients (pts) with BRAF V600 mutations (NCT06536400). Methods: This multicenter, open-label, two-part study enrolled adult pts with advanced BRAF V600-mutated solid tumors, including those with recurrent or metastatic solid tumors or primary CNS tumors. Previous BRAF±MEK inhibitor treatment is permitted. In the dose-escalation (Part 1), HSK42360 (200-3600 mg/day) monotherapy was given orally. Escalation followed a “3+3 design” with dose-limiting toxicities assessed during Cycle 1. Part 2 was cohort expansion. Primary objectives were maximum tolerated dose and recommended phase 2 dose of HSK42360. Secondary objectives included safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy. Results: As of January 15, 2025, 17 pts (47.1% male; median age 57.0 years) have been treated with HSK42360 monotherapy across five dose levels (200-3600 mg/day). Of these, 64.7% pts experienced adverse events (TEAEs), most frequently increased ALT (23.5%) and increased AST (23.5%). Most (89.7%) of TEAEs were grade 1. Two pts had drug-related grade 3 AEs (increased creatinine and increased ALT) and one had drug-related serious AEs (SAEs) (increased creatinine). There were no DLT, grade 4 TEAEs, treatment-related discontinuations, or treatment-related deaths. Among 11 efficacy evaluable pts, the ORR was 18.2%. Two (1 CRC and 1 ganglioglioma) had a partial response (PR) and three had stable disease (SD) with shrinkage (per RECIST or RANO). This trial is ongoing. Conclusions: HSK42360 monotherapy was well tolerated without unexpected safety issues. Preliminary efficacy data demonstrate favorable activity of HSK42360 in pts with BRAF V600-mutated solid tumors, including primary CNS tumors. Clinical trial information: NCT06536400 .