Abstract 4617: NRX-0305, an orally bioavailable, CNS penetrant pan-mutant BRAF degrader demonstrates robust efficacy in intracranial models of melanoma brain metastasis and primary glioma

Abstract Mutations in BRAF, a key component of the MAPK pathway, drive constitutive pathway activation and oncogenic transformation across multiple tumor types. BRAF V600 mutations occur in approximately 40–50% of cutaneous melanomas, of which 30–50% develop brain metastases during disease. CNS progression is common following acquired resistance to BRAF inhibitor and MEK inhibitor combination therapy, with 40–60% of patients experiencing intracranial relapse despite initial systemic response. BRAF mutations are also detected in ∼5–8% of primary gliomas, predominantly in pediatric and epithelioid subtypes. Although approved BRAF inhibitors provide meaningful benefit to patients with Class 1 mutations, there is a high unmet need for patients with brain involvement due to limited CNS activity of existing therapies.We developed NRX-0305, a CNS-penetrant, pan-mutant BRAF degrader designed to selectively degrade mutant BRAF across Class 1/2/3 mutant tumors while sparing wildtype BRAF. Pharmacokinetic and pharmacodynamic studies following oral dosing confirmed brain exposure, robust BRAF degradation, and pathway inhibition. Daily oral administration of NRX-0305 demonstrated potent single-agent efficacy in multiple intracranial models of BRAF-mutant melanoma and glioma. In a BRAF inhibitor-resistant melanoma brain metastasis PDX model, NRX-0305 achieved dose-dependent efficacy and significantly improved survival relative to vehicle and dabrafenib treatment, demonstrating superiority to clinically approved BRAF inhibitors.These findings establish pan-mutant BRAF degradation as a promising therapeutic strategy for BRAF-mutant CNS malignancies and highlight NRX-0305’s potential to overcome the limited CNS activity and treatment-emergent resistance associated with BRAF targeted therapies. Citation Format: Alexandra Borodovsky, Ya-Wen Lu, Ge Peng, Karthik Arumugam, Paul L. Auger, Delia Bradford, Lilly G. Carlson, Scott K. Kimura, Daniel Medina-Cleghorn, Mariah J. Mesner, Davorka Messmer, Madeleine P. Nemchek, Ryan B. Rountree, Rusha M. Sardhara, Sangita Sridharan, Jennifer M. Stokes, Leslie Tong, Alexandra M. Trotier, Jennifer S. Tung, Ge Wei, Jeffrey Wu, Jordan Ye, Gwenn M. Hansen, . NRX-0305, an orally bioavailable, CNS penetrant pan-mutant BRAF degrader demonstrates robust efficacy in intracranial models of melanoma brain metastasis and primary glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4617.