Small Cell Lung Cancer

This phase II study investigated the efficacy and safety of durvalumab plus olaparib as maintenance therapy in 60 previously untreated extensive-stage small-cell lung cancer (ES-SCLC) patients. The combination regimen demonstrated promising efficacy, with a 12-month progression-free survival rate of 25.0%, a median progression-free survival of 6.8 months, and a median overall survival of 14.6 months. Multi-omics analysis identified a DNA hypomethylation subgroup associated with significantly improved survival outcomes. This subgroup exhibited enhanced antigen presentation, a favorable cytokine profile, and suppressed DNA damage repair pathways, suggesting a potential biomarker for patient selection.

This study identified three distinct molecular phenotypes of small cell lung cancer (SCLC): proliferative, iNotch, and infiltrated, characterized by high proliferation, inhibitory Notch signaling, and immune-rich microenvironments, respectively. These phenotypes were reproducible across multiple independent cohorts. Further analysis revealed that a subset of patients within the infiltrated phenotype, exhibiting high ANXA1 expression, resisted immune checkpoint inhibitors (ICIs) due to M2 macrophage polarization and CD8+ T cell suppression. Only ANXA1Low infiltrated patients derived significant benefit from chemotherapy combined with ICIs. These findings offer new strategies to enhance immunotherapy efficacy in SCLC.