Non-small cell lung cancer (NSCLC) is operated commonly by diverse genetic alterations, and oncogenic fusions represent a significant therapeutic role. Common fusions include ALK, ROS1, RET, and NTRK, signaling pathways in tumorigenesis. Recent advances in investigating tumor molecular biology include underlying fusions, including chromosomal rearrangements, highlighting their role as oncogenic drivers. The development of targeted therapies, such as tyrosine kinase inhibitors (TKIs), has impacted most patients’ NSCLC treatment. Despite the greater profiles, such as remarkable efficiency and tolerable side effects compared to traditional chemotherapy, challenges, such as acquired mutations, lead to more ongoing research-optimized future NSCLC therapies.

Actionable ALK, ROS1, RET, NTRK, and NRG1 fusions define biologically distinct subsets of advanced non-small cell lung cancer (NSCLC), yet real-world data across these rare populations remain limited. We retrospectively evaluated patients with advanced NSCLC treated at Memorial Healthcare System who received genotype-matched fusion-directed therapy; the first fusion-directed agent defined the index treatment, and survival was measured from its initiation. Progression was determined from radiographic reports and treating-oncologist documentation. After patient-level reconciliation, 59 unique patients were included: 29 ALK, 14 ROS1, 11 RET, 3 NTRK, and 2 NRG1. Median follow-up was 47.7 months (95% CI, 28.6–58.7), median progression-free survival was 44.8 months (95% CI, 17.1–not estimable), and median overall survival was not reached. No statistically significant survival differences were detected among ALK, ROS1, and RET subgroups, although limited sample sizes preclude exclusion of clinically meaningful differences. Later-line index therapy was not significantly associated with progression-free survival in exploratory unadjusted analysis. These findings provide descriptive real-world evidence of precision-oncology implementation across actionable fusion-defined NSCLC while underscoring that pooled outcomes should not be interpreted as evidence of equivalent efficacy across molecular subtypes or therapies.

Structured Abstract Background Actionable oncogenic gene fusions involving ALK, ROS1, RET, NTRK, and NRG1 define distinct molecular subsets of advanced non-small cell lung cancer (NSCLC) that derive substantial benefit from fusion-directed targeted therapies. Although pivotal clinical trials have demonstrated impressive efficacy, comparative real-world outcomes across multiple actionable fusion subtypes remain limited. Methods We conducted a retrospective cohort study of patients with advanced NSCLC harboring actionable gene fusions who received fusion-directed targeted therapy within Memorial Healthcare System. Eligible patients were diagnosed between May 14, 2014, and October 10, 2025, with follow-up through April 24, 2026. Comprehensive molecular profiling was performed using Tempus, Caris Life Sciences, and Guardant360. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Median follow-up was estimated using the reverse Kaplan–Meier method, and exploratory Cox proportional hazards models evaluated associations between treatment line and survival outcomes. Results Sixty-eight patients met the eligibility criteria, including 34 (50.0%) with ALK, 15 (22.1%) with ROS1, 13 (19.1%) with RET, 4 (5.9%) with NTRK, and 2 (2.9%) with NRG1 fusions. The median age was 62 years; 58.8% were female and 54.4% were never-smokers. Median follow-up was 43.1 months (95% CI, 24.4–50.0). Median PFS was 44.8 months (95% CI, 17.1 months to not estimable), whereas median OS was not reached. Patients who received targeted therapy in the first-line setting had longer PFS than those treated in later lines (HR, 2.16; 95% CI, 1.05–4.44; P = .036), although this exploratory association should be interpreted cautiously because treatment line was not randomized. PFS and OS did not differ significantly among the major fusion subtypes (ALK, ROS1, and RET). Survival outcomes were broadly consistent with those reported in landmark clinical trials, providing supportive real-world evidence for the effectiveness of fusion-directed targeted therapies. Conclusions In this retrospective health-system cohort, patients with advanced NSCLC harboring actionable gene fusions experienced durable disease control with fusion-directed targeted therapy. Real-world survival outcomes were broadly consistent with those reported in landmark clinical trials, supporting the effectiveness of fusion-directed targeted therapies in routine clinical practice and reinforcing the importance of comprehensive genomic profiling to identify patients eligible for precision oncology approaches.