Comparative Treatment Outcomes Across Actionable Genomic Alterations in NSCLC: A Large Multicenter Real-World Study

Introduction: Although the efficacy of molecular targeted therapies varies across actionable genomic alterations in NSCLC, comparisons within a single real-world cohort remain limited. Methods: We conducted a retrospective multi-institutional study of 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy from 2017 to 2023. Patients were classified into the following three genomic groups: EGFR mutations (group A), ALK/ROS1/RET fusion oncogenes (group B), and others, including MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations (group C). Treatment efficacy and safety were compared across the groups. Results: Treatment outcomes differed between the subgroups. Group B demonstrated the highest objective response rate (85.8%) and the longest median real-world progression-free survival (rwPFS; 42.5 mo); median overall survival (OS) was not reached. Group A had intermediate outcomes. Group C exhibited the shortest rwPFS (9.2 mo), poorer OS, and higher rates of treatment discontinuation due to adverse events. Such hierarchical differences were observed in patients with baseline central nervous system metastases and in those receiving first-line treatment. In multivariate analysis, genomic subgroup remained associated with rwPFS and OS, with fusion-driven tumors maintaining superior outcomes irrespective of other factors. Conclusions: This large real-world analysis yielded a hierarchy of therapeutic benefits across actionable genomic alterations in NSCLC. Patients with fusion-driven tumors benefited from targeted therapy, whereas those with EGFR-mutated tumors had intermediate outcomes. Treatment of patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations had limited efficacy and higher toxicity, underscoring the need for improved therapeutic strategies.