Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer

Clin Cancer Res. 2020 Jul 1;26(13):3287-3295. doi: 10.1158/1078-0432.CCR-19-2777. Epub 2020 Apr 8.


Purpose: Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models.

Experimental design: Antitumor activity of repotrectinib was evaluated in ROS1+ patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model.

Results: Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial.

Conclusions: Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / secondary
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Gene Rearrangement*
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Macrocyclic Compounds / pharmacology*
  • Macrocyclic Compounds / therapeutic use
  • Mice
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Xenograft Model Antitumor Assays


  • Macrocyclic Compounds
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazoles
  • repotrectinib
  • Protein-Tyrosine Kinases
  • ROS1 protein, human

Associated data