Abstract 1465: NUV-520 (NVL-520) is a brain-penetrant and highly selective ROS1 inhibitor with antitumor activity against the G2032R solvent front mutation

ROS1 is a proto-oncogene that encodes the receptor tyrosine kinase ROS1, which can be aberrantly activated by gene rearrangement to drive tumor cell proliferation, survival, and metastasis. In non-small cell lung cancer (NSCLC), ROS1 rearrangements are detected in 1% to 3% of patients; at the time of diagnosis, 20% to 30% of these patients present with accompanying central nervous system (CNS) metastases. The tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, lorlatinib and repotrectinib have been used to treat ROS1-positive patients, but have been limited by the emergence of ROS1 resistance mutations, progression of disease in the CNS, or treatment-related adverse events (AEs) associated with off-target kinase inhibition. Novel ROS1 inhibitor NUV-520 (NVL-520) was designed to address these challenges. Across a panel of 335 wild-type kinases, NUV-520 (NVL-520) was highly selective for ROS1; it only inhibited one kinase, ALK, by >50% within 10-fold of its IC50 for ROS1. In recombinant enzyme assays, NUV-520 (NVL-520) inhibited the kinase activity of ROS1 and ROS1 G2032R with Kiapp Citation Format: Henry E. Pelish, Anupong Tangpeerachaikul, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Joshua C. Horan. NUV-520 (NVL-520) is a brain-penetrant and highly selective ROS1 inhibitor with antitumor activity against the G2032R solvent front mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1465.