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Zidesamtinib (Jideytro®): a new selective, brain-penetrant ROS1 inhibitor approved for the treatment of ROS1-positive

Sumi Lee1, Longqin Hu2,3

  • 1School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, 54907, Republic of Korea. chsmath27@jbnu.ac.kr.

Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents
|August 18, 2026
PubMed

Insights

Zidesamtinib offers a new treatment for ROS1-positive non-small cell lung cancer (NSCLC) by overcoming resistance and CNS progression. This next-generation inhibitor shows durable efficacy and manageable safety in patients previously treated with ROS1-targeted therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • ROS1-positive non-small cell lung cancer (NSCLC) treatment faces challenges from acquired resistance, central nervous system (CNS) progression, and off-target toxicities.
  • Existing ROS1-targeted therapies have improved outcomes but are limited by these factors.

Purpose of the Study:

  • To evaluate the efficacy and safety of zidesamtinib (NVL-520), a next-generation, brain-penetrant, tropomyosin receptor kinase (TRK)-sparing ROS1 inhibitor.
  • To assess zidesamtinib's activity against resistance mutations, including G2032R, and its intracranial efficacy.

Main Methods:

  • Preclinical studies demonstrated zidesamtinib's potent and selective ROS1 inhibition, broad resistance coverage, and durable intracranial activity.
  • The ARROS-1 phase 1/2 trial evaluated zidesamtinib (100 mg orally once daily) in previously treated ROS1-positive NSCLC patients.

Main Results:

  • Zidesamtinib showed durable clinical efficacy and a manageable safety profile in the ARROS-1 trial.
  • The drug demonstrated effectiveness in patients with CNS metastases and the G2032R resistance mutation.
  • Favorable pharmacokinetic properties were observed with oral administration.

Conclusions:

  • Zidesamtinib represents a promising therapeutic option for ROS1-positive NSCLC, addressing limitations of prior therapies.
  • Its ability to overcome resistance mutations and penetrate the CNS supports its role in managing advanced disease.
  • Accelerated FDA approval on July 22, 2026, highlights its clinical significance for previously treated patients.
Keywords:
G2032RROS1Zidesamtinibnon-small cell lung cancer

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