An Effective New Tyrosine Kinase Inhibitor for ROS1 Fusion-Positive Non–Small-Cell Lung Cancer

ROS1 fusions occur in 2% of non–small-cell lung cancers (NSCLCs) and represent a targetable oncogene. Although two highly active ROS1 tyrosine kinase inhibitors (TKIs), crizotinib and entrectinib, have been available for years, resistance inevitably develops — often via on-target ROS1 mutations such as G2032R — and they have limited central nervous system efficacy; this there is a need for more effective therapies.

In this international, industry-sponsored, phase 1–2 trial, investigators assessed the efficacy and safety of repotrectinib in patients with ROS1 fusion-positive NSCLC. Repotrectinib is a next-generation ROS1 and NTRK TKI that was designed to inhibit both wild type and G2032R-mutant ROS1 and to have significant central nervous system (CNS) efficacy.

The primary efficacy population included 71 patients who had not previously received a ROS1 TKI and 56 patients who had received a ROS1 TKI and had never received chemotherapy. An objective response occurred in 79% of the TKI-naive patients; median progression free-survival was 35.7 months. In the patients previously treated with a ROS1 TKI, 38% had an objective response and median progression-free survival was 9.0 months. Notably, 59% of the 17 patients with acquired ROS1 G2032R mutations demonstrated a response. Intracranial responses were noted across all cohorts.

The safety analysis included 426 patients who were treated with the phase 2 dose. The most common treatment-related adverse events of any grade were dizziness (58%), dysgeusia (50%), and paresthesia (30%), which were managed by supportive care, dose reduction, or both. The most common clinically significant grade 3 or higher adverse events were anemia (4%) and dizziness (3%).