Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) and other cancers can be driven by ROS1 fusions.
• Emergent resistance mutations and brain metastases pose significant challenges in ROS1-positive cancer treatment.
• Off-target TRK inhibition by some inhibitors can cause limiting central nervous system adverse events.

Purpose of the Study:

• To evaluate zidesamtinib (NVL-520), a novel ROS1-selective inhibitor, against ROS1 resistance mutations and brain metastases.
• To compare zidesamtinib's efficacy and resistance profile with existing ROS1 inhibitors.
• To elucidate the molecular mechanism behind zidesamtinib's selectivity and efficacy.

Main Methods:

• Accelerated mutagenesis screens to assess resistance development.
• Intracranial xenograft models to evaluate efficacy against brain metastases.
• Co-crystal structure determination and computational modeling to understand drug-target interactions.

Main Results:

• Zidesamtinib inhibited >1,500 ROS1 mutants with ≤1% resistance, outperforming crizotinib, entrectinib, and repotrectinib.
• Zidesamtinib demonstrated more durable responses than repotrectinib and taletrectinib in an aggressive intracranial ROS1 G2032R xenograft model.
• Structural analysis revealed zidesamtinib uniquely accommodates the ROS1 G2032R mutation while potentially clashing with TRK, supporting its selective design.

Conclusions:

• Zidesamtinib exhibits potent inhibition of a broad range of ROS1 resistance mutations with minimal emergence of resistance.
• The drug shows superior efficacy in preclinical models of brain metastases compared to other ROS1 inhibitors.
• Zidesamtinib's selective targeting mechanism suggests potential as a best-in-class therapy for ROS1-fusion-positive cancers.