Abstact

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 TRK inhibition that can be treatment limiting. We evaluated zidesamtinib in accelerated mutagenesis screens and a brain tumor model, comparing it to 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 co-crystal structure with ROS1 G2032R, the most frequently identified ROS1 resistance mutation, reveals that zidesamtinib uniquely accommodates the mutated residue while potentially clashing with TRK, 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.