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

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Efficacy of molecular targeted therapies in non-small cell lung cancer (NSCLC) varies significantly based on specific genomic alterations.
• Real-world data comparing these therapies across different actionable mutations in a single cohort is limited.

Purpose of the Study:

• To compare the real-world treatment efficacy and safety of molecular targeted therapies across distinct genomic alteration groups in advanced or recurrent NSCLC.
• To establish a hierarchy of therapeutic benefits based on specific actionable genomic alterations.

Main Methods:

• Retrospective multi-institutional study of 810 Japanese patients with advanced/recurrent NSCLC treated with molecular targeted therapy (2017-2023).
• Patients were categorized into three genomic groups: EGFR mutations (Group A), ALK/ROS1/RET fusions (Group B), and others (MET exon 14 skipping, BRAF V600E, KRAS G12C; Group C).
• Treatment outcomes (objective response rate, real-world progression-free survival, overall survival) and safety were compared across groups.

Main Results:

• Group B (fusion oncogenes) demonstrated the highest objective response rate (85.8%) and longest median real-world progression-free survival (rwPFS) of 42.5 months.
• Group A (EGFR mutations) showed intermediate outcomes, while Group C (MET, BRAF, KRAS mutations) had the shortest rwPFS (9.2 months), poorer overall survival, and higher treatment discontinuation rates due to adverse events.
• These hierarchical differences persisted in patients with baseline CNS metastases and those receiving first-line treatment; genomic subgroup remained a significant predictor in multivariate analysis.

Conclusions:

• A clear hierarchy of therapeutic benefit exists for molecular targeted therapies in NSCLC based on actionable genomic alterations.
• Fusion-driven NSCLC tumors exhibit superior responses to targeted therapy, followed by EGFR-mutated tumors, while MET, BRAF, and KRAS alterations show limited efficacy and higher toxicity.
• Improved therapeutic strategies are needed for NSCLC patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations.