EP08.02-041 NVL-520, a Highly Selective ROS1 Inhibitor, in Patients with Advanced ROS1-Positive Solid Tumors: The Phase 1/2 ARROS-1 Study

Document Type

Conference Proceeding

Publication Date


Publication Title

J Thorac Oncol


Introduction: Oncogenic ROS1 gene fusions are implicated in the pathogenesis of various adult and pediatric cancers, including up to 3% of non-small cell lung cancers (NSCLC), where up to 40% of patients present with central nervous system (CNS) metastases. Tyrosine kinase inhibitors (TKIs) approved by the FDA and EMA for ROS1-positive NSCLC (crizotinib and entrectinib) are limited by acquired resistance, frequently mediated by secondary ROS1 kinase domain mutations. In addition, dual TRK/ROS1 kinase inhibitors such as entrectinib are associated with neurologic adverse events. NVL-520 is a novel, brain-penetrant ROS1-selective kinase inhibitor that exhibits preclinical activity against a diverse array of ROS1 fusions and ROS1 mutations including G2032R, while sparing inhibition of TRK. The ARROS-1 study evaluates the safety and activity of NVL-520 in patients with solid tumors harboring ROS1 fusions, including those with ROS1 resistance mutations and CNS metastases.

Methods: ARROS-1 (NCT05118789) consists of a phase 1 dose escalation, followed by phase 2 expansion in cohorts defined by tumor type and prior therapies that are designed to support potential registration. Phase 1 includes adult patients with any solid tumor type harboring a ROS1 gene fusion (by local testing), with evaluable disease, who have received ≥ 1 prior ROS1 TKI. Prior platinum-based chemotherapies and/or immunotherapies, as well as stable CNS disease, are allowed. Patients will receive NVL-520 by daily oral administration. Primary phase 1 objectives are to determine the NVL-520 recommended phase 2 dose, and, if applicable, maximum tolerated dose. Additional objectives include evaluation of safety/tolerability, preliminary activity, and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-520. Longitudinal analysis of circulating tumor DNA will be performed, including ROS1 mutation profiling and other relevant biomarkers. The phase 1 portion of the study is ongoing.

Keywords: NVL-520, ROS1, NSCLC





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