NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations.

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Cancer Discov


ROS1 tyrosine kinase inhibitors (TKIs) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion-positive cancers, although none 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 a ~100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As 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 neurological toxicities.

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ePub ahead of print