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
Drilon A, Ou SHI, Gadgeel S, Johnson M, Spira A, Lopes G, Besse B, Felip E, van der Wekken AJ, Calles A, de Miguel MJ, Camidge DR, Elamin Y, Liu S, Bauman J, Haggstrom D, Riley G, Pelish HE, Zhu VW, and Lin JJ. 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. J Thorac Oncol 2022; 17(9):S416.
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