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Published on: September 8, 2023
Comparative Treatment Outcomes Across Actionable Genomic Alterations in NSCLC: A Large Multicenter Real-World Study
Yasuhiro Kato1,2, Nobuhiko Nishijima3, Satoshi Takahashi4
1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
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.
Insights
Molecular targeted therapy efficacy in non-small cell lung cancer (NSCLC) varies by genomic alteration. Fusion-driven tumors showed superior outcomes, while EGFR mutations had intermediate results, and other alterations had limited benefit.
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.
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