Abstract LB405: Novel brain-penetrant BRAF paradox breaker HSK42360 demonstrates promising antitumor activity in patients with BRAF-mutant glioma

Abstract Background: BRAF V600E is one of the most frequent BRAF mutations across human cancers. It is present in various gliomas, including pediatric low-grade gliomas (LGG, ∼20%), pediatric high-grade gliomas (HGG, ∼5-15%), and adult glioblastomas (∼5%). Although BRAF inhibitors have brought transformative advances in glioma treatment, their efficacy remains limited by intrinsic or acquired resistance coupled with poor brain penetration. Paradoxical MAPK pathway activation represents a key resistance mechanism. To address these challenges, we developed HSK42360, a next-generation brain-penetrant BRAF paradox breaker, which has now entered Phase I clinical trials (NCT06536400). Methods: We evaluated the efficacy of HSK42360 in patient-derived xenograft (PDX) models of BRAF-mutant glioma and colorectal cancer. In the Phase I clinical trial, adults with advanced BRAF V600-mutant solid tumors or primary CNS tumors were enrolled; prior BRAFi therapy was permitted. The dose-escalation phase followed a "3+3" design with oral HSK42360 dosing ranging from 200 to 3600 mg/day. Primary endpoints were to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D). Results: Preclinical studies demonstrated that HSK42360 effectively inhibits signaling and disrupts BRAF homo- and hetero-dimers, with significantly reduced paradoxical activation compared to approved BRAF inhibitors. In BRAF V600E glioma PDX models, HSK42360 exhibited marked, dose-dependent antitumor activity, with tumor growth inhibition (TGI) rates of 67%, 108%, and 111.5% in three dose groups, respectively, without significant body weight changes, indicating favorable tolerability. Brain distribution studies revealed Kpuu values of 1.09 in mice and 2.8 in rats, suggesting best-in-class brain penetration potential. In a Vemurafenib plus Cetuximab-resistant colorectal cancer model, HSK42360 monotherapy outperformed the combination therapy and showed synergistic effects with the MEK inhibitor Trametinib. As of the data cutoff (Nov 15, 2025), 69 patients (including 23 PCNST patients) have been treated with HSK42360 monotherapy across five dose levels (200-3600 mg/day). Of these, 81.2% of patients experienced drug-related treatment-emergent adverse events (TRAEs). The most frequently reported TRAEs included: increased ALT (23.2%), increased AST (23.2%), and anemia (20.3%). Most TEAEs were grade 1. There were no DLTs, treatment-related discontinuations, or treatment-related deaths. 22 PCNST patients were efficacy evaluable: 19 with HGG and 3 with LGG. The overall ORR was 40.9% (9/22, include 1 CR ). In HGG, the ORR was 36.8% (7/19, including preliminary PR), and 1 patient had a confirmed CR. In LGG, the ORR was 66.7% (2/3). Conclusion: HSK42360 demonstrated significant efficacy in preclinical glioma PDX and resistant models, along with promising clinical antitumor activity in BRAF V600-mutant glioma patients, both treatment-naïve and previously treated with BRAF inhibitors. It was well-tolerated with a manageable safety profile, offering a new therapeutic paradigm for BRAF-mutant glioma. Citation Format: Shidong Gao, Meilin Qian, Ju Wang, Yangguang Li, Sicong Jiang, Qinghe Wu, Fangqiong Li, Pingmin Tang, Zongjun Shi, Yao Li, Pangke Yan. Novel brain-penetrant BRAF paradox breaker HSK42360 demonstrates promising antitumor activity in patients with BRAF-mutant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB405.