Nuvalent announces publication detailing design of NVL-520

Nuvalent announced the publication of a manuscript in Cancer Discovery, a journal of the American Association for Cancer Research, which describes the design and characterization of NVL-520 and details Nuvalent’s approach to rationally targeting ROS1. NVL-520 is currently being studied in the ongoing ARROS-1 Phase 1/2 clinical trial for patients with advanced ROS1-positive non-small cell lung cancer and other solid tumors. The paper details the design principles underlying the activity of NVL-520 against ROS1 and its most commonly occurring resistance mutation, ROS1 G2032R, and a molecular rationale for the selectivity of NVL-520 for ROS1 over the structurally-related TRK family. TRK inhibition in the CNS by approved or investigational ROS1 TKIs has been associated with neurological adverse events that can be dose limiting. Extensive preclinical characterization of the activity and selectivity of NVL-520 is presented, spanning biochemical and cellular assays, in vivo xenograft studies, and preclinical assessments of brain penetrance and intracranial activity. In addition, the paper includes three case studies of patients with ROS1 fusion-positive lung cancers that had relapsed on or were refractory to a range of ROS1 TKIs, and includes patients with tumors that harbored ROS1 G2032R or had intracranial metastases. NVL-520 elicited tumor responses in the patients with no observed neurological toxicities. These findings support the potential for NVL-520 to treat these patient populations while also enhancing tolerability through improved selectivity for ROS1.