Abstract 1651: NRX-0305: a pan-mutant BRAF degrader with broad preclinical efficacy, brain penetrance, and synergistic potential with MEKi across class 1/2/3 BRAF-mutant cancers

Mutations in BRAF, a key component of the mitogen-activated protein kinase (MAPK) pathway, drive constitutive pathway activation and oncogenic transformation and are commonly found in a variety of cancers including melanoma, NSCLC and CRC. BRAF mutations are categorized into three classes: Class 1 (e.g., V600X), which are RAS-independent and targetable with currently approved BRAF inhibitors (BRAFi); Class 2, which require dimerization; and Class 3, which are kinase-impaired and rely on upstream RAS activation. While approved BRAFi provide significant survival benefit to Class 1 patients, drug durability and efficacy are limited by the emergence of primary and acquired resistance that often involves RAF dimerization and BRAF amplification. Furthermore, patients who have progressed on BRAFi, especially in melanoma, frequently present with brain metastases, for which there are limited treatment options due to poor CNS penetrance of available drugs. To address this, we developed NRX-0305, a pan-mutant BRAF degrader that selectively degrades mutant BRAF across all classes while sparing wildtype BRAF. In vitro, NRX-0305 potently degrades mutant BRAF protein and suppresses downstream pERK1/2 signaling. NRX-0305 exhibits strong anti-proliferative effects across a panel of Class 1/2/3 BRAF-mutant cell lines including those expressing BRAF fusion proteins. In vivo, daily oral dosing with NRX-0305 induces robust BRAF degradation and exhibits single agent efficacy in several cell line and patient-derived xenograft models of Class 1/2/3 BRAF mutant cancers. Notably, NRX-0305 demonstrates robust single agent activity in BRAFi resistant Class 1 PDX models and a melanoma brain metastasis model, highlighting its brain penetrant properties. Furthermore, NRX-0305 in combination with MEK inhibition achieves complete tumor regression in a Class 3 bladder cancer PDX model, demonstrating its synergistic potential. These findings establish mutant-specific BRAF degradation as a promising therapeutic strategy, displaying activity across a broad range of mutations and addressing the limitations of BRAFi in Class 1/2/3 BRAF-mutant cancers. Citation Format: Alexandra Borodovsky, Ya-Wen Lu, Ge Peng, Karthik Arumugam, Paul Auger, Robert Cass, Stefan Gajewski, Scott Kimura, Daniel Medina-Cleghorn, Mariah Mesner, Davorka Messmer, Madeleine Nemchek, Prabu Raman, Ryan Rountree, Rusha Sardhara, Sangita Sridharan, Jennifer Stokes, Leslie Tong, Jennifer Tung, Ge Wei, Jeffrey Wu, Jordan Ye, Gwenn M. Hansen. NRX-0305: a pan-mutant BRAF degrader with broad preclinical efficacy, brain penetrance, and synergistic potential with MEKi across class 1/2/3 BRAF-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1651.