Abstract 5801: NRX-0305 is an orally bioavailable, pan-mutant BRAF degrader that exhibits single-agent and combination efficacy with MEKi or anti-EGFR across Class 1/2/3 BRAF-mutant cancers

Abstract Activating mutations in BRAF, a central kinase within the MAPK pathway, promote sustained pathway signaling and drive oncogenic transformation across multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). BRAF mutations are categorized into three functional classes: Class 1 (e.g., V600X), which are RAS-independent and targetable with approved BRAF inhibitors; Class 2, which signal as constitutive dimers; and Class 3, which are kinase-impaired and depend on upstream RAS activation. While approved BRAF inhibitors provide significant survival benefit to patients with Class 1 mutations, they are ineffective against tumors harboring Class 2 or 3 mutations, which remain refractory to current BRAF-targeted therapies. Motivated by the lack of therapeutic options for patients with Class 2 and 3 BRAF mutations, we developed NRX-0305, a potent and orally bioavailable pan-mutant BRAF degrader that selectively eliminates mutant BRAF while sparing the wild-type protein. In vitro, NRX-0305 potently degraded Class 1/2/3 mutant BRAF and suppressed downstream pERK1/2 signaling, resulting in strong antiproliferative effects across a diverse panel of Class 1/2/3 BRAF-mutant cell lines, including those expressing BRAF fusion proteins. In vivo, daily oral administration of NRX-0305 induced robust, dose-dependent BRAF degradation and pathway inhibition, producing marked single-agent efficacy in multiple Class 1/2/3 cell lines-derived xenograft and patient-derived xenograft models. Furthermore, combination studies of NRX-0305 with MEK inhibitor or anti-EGFR demonstrated enhanced antitumor activity, supporting its potential use in clinically relevant combination regimens. Collectively, these studies demonstrate NRX-0305 is a potent, mutant-selective BRAF degrader that can overcome the limitations of approved BRAF inhibitors, offering broad therapeutic potential both as a single agent and in combination with MEKi or anti-EGFR antibodies across Class 1/2/3 BRAF-mutant cancers. Citation Format: Ya-Wen Lu, Alexandra Borodovsky, 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 is an orally bioavailable, pan-mutant BRAF degrader that exhibits single-agent and combination efficacy with MEKi or anti-EGFR across Class 1/2/3 BRAF-mutant cancers [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 5801.