Prognostic impact of actionable driver alterations and efficacy of targeted therapy in lung squamous cell carcinoma: A large-scale nationwide genomic screening (LC-SCRUM-Asia).

8631 Background: Precision medicine based on multi-gene analysis improves prognosis and has established multigene analysis as the standard of care in lung adenocarcinoma.However, the clinical utility of multi-gene analysis in lung squamous cell carcinoma (LUSC) remains controversial due to the rarity of actionable driver alterations and the uncertain therapeutic benefits of targeted therapy. This study aimed to elucidate the prognostic value of driver alterations and the efficacy of targeted therapy in LUSC. Methods: We have prospectively analyzed patients with non-small cell lung cancer (NSCLC) enrolled in a nationwide genomic screening project in Japan (LC-SCRUM-Asia) using NGS (Oncomine Comprehensive/Precision Assay). We evaluated clinical outcomes in patients with LUSC, comparing overall survival (OS) according to the presence of actionable driver alterations and receipt of targeted therapy. Results: From March 2015 to October 2025, 19,357 patients were enrolled, of whom 2,917 had LUSC. Among these LUSC patients, actionable driver alterations were identified in 180 patients (6.2%) cases, including EGFR mutations (n = 78), KRAS G12C (n = 33), MET exon 14 skipping (n = 28), ALK fusions (n = 18), EGFR exon 20 insertions (n = 7), RET fusions (n = 6), ROS1 fusions (n = 5), BRAF V600E (n = 4), and HER2 exon 20 insertions (n = 1).In the survival analysis of 2,017 patients with advanced/recurrent disease, median OS was significantly longer in patients with actionable driver alterations compared to those without (18.2 vs. 15.0 months; HR 0.79, p = 0.02). However, among patients with actionable driver alterations, there was no significant difference in median OS between patients who received targeted therapies (n = 97) and those who did not (n = 45) (18.3 vs. 17.0 months, p = 0.94). The efficacy of targeted therapies was notably limited; median progression-free survival was 12.4 months for ALK tyrosine kinase inhibitors (TKIs) (n = 17), 8.4 months for EGFR TKIs (n = 46), 4.5 months for KRAS G12C inhibitors (n = 10), 3.6 months for MET TKIs (n = 15), and 3.4 months for ROS1 TKIs (n = 5). Collectively, these outcomes were consistently inferior to those reported in pivotal clinical trials. Conclusions: Although actionable driver alterations were identified in approximately 6% of LUSC and were associated with a favorable prognosis, targeted therapy demonstrated limited efficacy and failed to extend overall survival compared to non-targeted approaches. These findings indicate that the clinical utility of multi-gene analysis in LUSC is currently limited, highlighting the need for the development of novel therapeutic strategies specific to this histology.