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 entrec-tinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion-positive cancers, although none of them simultaneously address the need for broad resist-ance 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 similar to 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 pen-etration mark the development of a distinct ROS1 TKI with the potential to surpass the limitations of earlier-generation TKIs for ROS1 fusion-positive patients.