Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer

Abstract

The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

Keywords: ROS1 fusions; non‐small cell lung cancer; repotrectinib; tyrosine kinase inhibitors.

FIGURE 1

Panel A: Model of Repotrectinib (Cyan) binding mode on ROS1 (white). Panel B: Model of Repotrectinib (Cyan) successful binding mode on ROS1 G2032R (Green). Panel C: Structural basis of Repotrectinib (Cyan) steric clash with ROS1 L2086F (Red). Panel D: Model of Crizotinib (Purple) and Entrectinib (Yellow) steric clash with ROS1 G2032R (Red). Panel E: Structural basis of Crizotinib (Purple) and Entrectinib (Yellow) steric clash with cross‐resistant ROS1 L2086F (Red) mutant. Panel F: Comparison of PFS of Repotrectinib in TKI‐naïve patients with reported PFS of FDA‐approved or other guideline‐listed ROS1 TKIs., , , , ,