Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations Open Access

Zidesamtinib (NVL-520) is a ROS1-selective macrocyclic tyrosine kinase inhibitor designed with the aim to address clinical challenges for patients with non–small cell lung or other cancers that are ROS1 fusion–positive. These challenges include emergent ROS1 resistance mutations and brain metastases that can lead to disease progression and central nervous system adverse events attributed to off-target tropomyosin-related kinase inhibition that can be treatment-limiting. We evaluated zidesamtinib in accelerated mutagenesis screens and a brain tumor model, comparing it with other approved or investigational ROS1 inhibitors. At clinically relevant concentrations, zidesamtinib robustly inhibited >1,500 pooled ROS1 mutants with virtually no resistance emerging (≤1%), outperforming comparators crizotinib, entrectinib, and repotrectinib. Zidesamtinib also induced more durable responses than repotrectinib and taletrectinib in an aggressive intracranial ROS1 G2032R xenograft model. A 2.2 Å cocrystal structure with ROS1 G2032R, the most frequently identified ROS1 resistance mutation, reveals that zidesamtinib uniquely accommodates the mutated residue while potentially clashing with tropomyosin-related kinases, consistent with its selective ROS1-targeting design and supported by computational modeling. Taken together, these data support zidesamtinib’s potential as a novel best-in-class ROS1 inhibitor.