WCLC 2025 - Posters & ePosters-P2.06.101 Neuroendocrine-Like Subtype or TMB-High Predicts Long-Term Survival Benefit From Sequential Thoracic Radiotherapy and ICI in ES-SCLC

P2.06.101 Neuroendocrine-Like Subtype or TMB-High Predicts Long-Term Survival Benefit From Sequential Thoracic Radiotherapy and ICI in ES-SCLC

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This study examines predictive biomarkers for long-term survival benefits from sequential thoracic radiotherapy (TRT) combined with immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer (ES-SCLC) following first-line etoposide/cisplatin and immunotherapy. Integrating data from a Phase II clinical trial (30 patients) and a real-world cohort (27 patients), a total of 57 patients underwent comprehensive genomic profiling and transcriptomic analyses.<br /><br />Key findings include that the TRT group showed a significantly longer median progression-free survival (mPFS: 11.3 vs. 6.1 months, p<0.001) compared to no TRT, although median overall survival (mOS) was similar (22.9 vs. 18.0 months). Notably, patients with high tumor mutational burden (TMB-high; ≥10 mutations/megabase) receiving TRT exhibited significant improvements in both progression-free survival (mPFS not reached vs. 7.6 months, p=0.004) and overall survival (22.9 vs. 11.6 months, p=0.025), whereas TMB status did not impact outcomes in the no TRT group.<br /><br />Transcriptomic analysis classified patients into three subtypes. In particular, the neuroendocrine-like (NE-like) subtype, enriched for NEUROD1/ASCL1 expression (NMF3 subgroup), showed a significant PFS benefit from TRT (HR=0.28, p=0.042). Patients with either TMB-high or NE-like features derived substantial survival advantages with TRT, with hazard ratios for PFS and OS around 0.18 and 0.12, respectively (both p<0.02).<br /><br />Gene ontology enrichment revealed that patients with durable clinical benefit (DCB) post-TRT exhibited immune-active and cell signaling pathways, contrasting with immunosuppressive pathways seen in no durable benefit (NDB) patients, suggesting immune-related mechanisms underlie differential treatment responses.<br /><br />The study's baseline characteristics were balanced between clinical trial and real-world cohorts, supporting the generalizability of results. Future research is recommended to validate TMB-high and NE-like subtype as predictive biomarkers for TRT efficacy in ES-SCLC.<br /><br />In summary, TMB-high status or neuroendocrine-like molecular subtype predicts enhanced long-term survival from sequential TRT combined with immune checkpoint inhibitors in ES-SCLC, offering potential for personalized treatment strategies.

Asset Subtitle

Linlin Wang

Meta Tag

Speaker Linlin Wang

Topic Pathology and Biomarkers

Keywords

extensive-stage small-cell lung cancer

thoracic radiotherapy

immune checkpoint inhibitors

tumor mutational burden

neuroendocrine-like subtype

progression-free survival

overall survival

predictive biomarkers

transcriptomic analysis

personalized treatment