Impact of Prior Systemic Chemotherapy on Response to <i>ROS1</i> Tyrosine Kinase Inhibitors in <i>ROS1</i>-Rearranged Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Abstract

<i>ROS1</i> rearrangements occur in approximately 1%-2% of non-small cell lung cancer and define a molecular subset characterized by marked sensitivity to tyrosine kinase inhibitors (TKIs). Although ROS1 inhibitors demonstrate high response rates, the potential impact of prior systemic chemotherapy exposure before ROS1 inhibition on subsequent ROS1-TKI efficacy has not been systematically evaluated. We conducted a systematic review and meta-analysis of prospective ROS1-TKI trials published through December 30, 2025. Outcomes were analyzed separately for TKI-naïve and post-crizotinib cohorts using random-effects models. Study-level meta-regression was performed to evaluate associations between the proportion of patients exposed to prior systemic chemotherapy and treatment response. Eleven TKI-naïve cohorts (N = 706) and four post-crizotinib cohorts (N = 186) were included in the primary analysis. The pooled objective response rate (ORR) was 79% (95% CI, 72 to 84) in TKI-naïve cohorts compared with 42% (95% CI, 32 to 51) in post-crizotinib cohorts. Among 11 TKI-naïve cohorts, prior systemic chemotherapy exposure was significantly and inversely associated with ORR (<i>β</i> = -1.12; OR, 0.33; <i>P</i> = .004). A similar directional association was observed in four post-crizotinib cohorts (<i>β</i> = -1.08; OR, 0.34; <i>P</i> = .077). No significant association was identified between prior systemic chemotherapy exposure and median progression-free survival. Beyond the expected difference between TKI-naïve and post-crizotinib cohorts, prior systemic chemotherapy exposure was associated with lower response rates to ROS1-TKIs in this study-level analysis. Although exploratory and limited by aggregate data, these findings suggest that treatment sequencing and cumulative treatment exposure may influence responsiveness to ROS1 inhibition and support early use of ROS1-directed therapy when clinically feasible.