Comparative efficacy and safety of ROS1 tyrosine kinase inhibitors for advanced ROS1-positive non–small cell lung cancer: A systematic review and network meta-analysis.

Abstract

e20733 Background: ROS1 rearrangements occur in approximately 1–2% of non–small cell lung cancers and define a clinically distinct subset responsive to tyrosine kinase inhibitors. Multiple ROS1 inhibitors are available; the recent 2025 approval of taletrectinib expands treatment options beyond crizotinib, repotrectinib, and entrectinib, yet the absence of head-to-head trials complicates selection. Methods: Databases and trial registries were systematically searched, followed by Bayesian network meta-analysis using R NetMeta and risk of bias assessment with RoB 2.0. Results: Ten studies comprising 1,246 patients with advanced ROS1-positive NSCLC were included. Patient numbers by treatment were crizotinib (n = 275), entrectinib (n = 247), repotrectinib (n = 127), and taletrectinib (n = 597). For overall response rate, taletrectinib showed superior efficacy (RR 1.24, 95% CI 1.14–1.35; SUCRA 92%), followed by repotrectinib (RR 1.10, 95% CI 1.01–1.20; SUCRA 71%), while entrectinib was comparable to crizotinib (SUCRA 41%). For progression-free survival, taletrectinib ranked highest (HR 0.45, 95% CI 0.32–0.63; SUCRA 95%), followed by repotrectinib (HR 0.54, 95% CI 0.40–0.74; SUCRA 82%), with entrectinib showing no benefit (SUCRA 29%). Regarding safety, taletrectinib demonstrated the most favorable profile, with a significantly lower risk of treatment discontinuation due to adverse events (HR 0.70, 95% CI 0.50–0.98; SUCRA 90%) and reduced neurologic toxicity. In contrast, repotrectinib showed a comparable risk of treatment discontinuation (HR 1.10, 95% CI 0.85–1.40; SUCRA 48%), alongside a higher incidence of neurologic adverse events, while entrectinib was associated with an increased risk of treatment discontinuation (HR 1.25, 95% CI 1.00–1.56; SUCRA 22%) and greater overall adverse-event burden. Conclusions: Taletrectinib demonstrated the most favorable overall efficacy and safety profile, repotrectinib showed strong efficacy with higher toxicity, and entrectinib provided comparable efficacy with less favorable safety; overall risk of bias across included studies was low.