NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations

ROS1 tyrosine kinase inhibitors (TKI) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion–positive cancers, although none of them simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10-to 1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has an ∼100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As a clinical proof of concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion–positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurologic toxicities. SIGNIFICANCE: The combined preclinical features of NVL-520 that include potent targeting of ROS1 and diverse ROS1 resistance mutations, high selectivity for ROS1 G2032R over TRK, and brain penetration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion–positive patients.