CTNI-28. PHASE 1 STUDY OF BRAIN-PENETRANT BRAF INHIBITOR HSK42360 IN ADULT PATIENTS WITH BRAF V600-MUTATED ADVANCED SOLID TUMORS OR RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM TUMORS

Abstract 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 wild-type BRAF-containing RAF dimers. Treatment with HSK42360 resulted in excellent and durable anti-tumor effects in BRAF Class I/II mutant CDX and PDX models. An approved BRAF V600E inhibitor combined with a MEK inhibitor, had ORRs of 33% and 50% in BRAF V600E-mutated high-grade glioma (HGG) and low-grade glioma (LGG), respectively (dabrafenib US Prescribing Information, 2025). Here we report the interim results from a Phase 1 study of HSK42360 (NCT06536400). This is a single-arm phase 1 study in patients with BRAF V600-mutated solid tumors or recurrent primary central nervous system tumors (PCNST) to assess RP2D, safety, PK, and efficacy of oral HSK42360. Previous BRAF±MEK inhibitor treatment is permitted. As of 23 May 2025, 38 patients (including 9 PCNST patients) have been treated with HSK42360 monotherapy across five dose levels (200-3600 mg/day). Of these, 81.6% of patients experienced treatment-emergent adverse events (TEAEs), of which 68.4% were considered drug-related (TRAEs). Most (79.6%) of TRAEs were grade 1. Grade 3 TRAEs occurred in 7.9% of patients, 2 patients experienced drug-related serious adverse events (SAEs): a grade 3 increased creatinine and a grade 2 pyrexia. There were no DLTs, grade 4 TRAEs, treatment-related discontinuations, or treatment-related deaths. The incidence of TRAEs in PCNST patients was comparable to that in the total study population. 8 PCNST patients were efficacy evaluable: 7 with HGG and 1 with LGG, 4 patients with HGG and 1 patient with LGG had partial response (PR), while 2 patients had stable disease (SD). The ORR was 62.5% (5/8). HSK42360 demonstrated a favorable safety profile and a high ORR in patients with BRAF V600-mutant PCNST. This trial is ongoing.