Multi-omic analysis and overall survival update of phase II TRIDENT study: Durvalumab plus olaparib in extensive-stage small-cell lung cancer (ES-SCLC).

8101 Background: Chemotherapy plus anti-PD1/PD-L1 therapy has revolutionized the standard first-line treatment for patients with ES-SCLC. Durvalumab plus Olaparib as maintenance therapy showed encouraging anti-tumor activity in TRIDENT study as previous report. Here, we aim to identify molecular biomarkers of ES-SCLC through multi-omic analysis. Methods: 60 treatment-naïve ES-SCLC patients were enrolled in the TRIDENT study (NCT05245994), receiving Durvalumab plus Olaparib as maintenance therapy after Durvalumab plus chemotherapy as first line treatment. Frozen tumor tissues were collected before treatment to employ transcriptome sequencing and high-resolution quantitative DNA methylation. Next-Generation Sequencing (NGS) and Proximity Extension Assay (PEA) of cytokine were conducted using baseline plasma. Results: At the data cutoff on December 31, 2024, the median duration of follow-up was 13.0 months. The median PFS was 6.77 months (95% CI, 5.75-8.97), median overall survival was 14.59 months (95% CI 12.98–22.34). The 1-2-3 survival rate was 61.7%, 21.7% and 1.7%. For DNA methylation analysis, unsupervised clustering was performed based on Non-negative Matrix Factorization (NMF) and samples were classified into two clusters, with a clear difference in methylation levels. Patients in DNA hypomethylation group demonstrated better survival outcomes. Differentially methylated genes in pathway enrichment analysis revealed that immune-related and antigen processing and presentation signaling pathways were activated, while glycolysis and oxidative phosphorylation, DNA damage and repair signaling pathways were suppressed in the hypomethylation group. Moreover, transcriptome data further indicated a significant suppression in pathways related to epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and cell adhesion in the hypomethylation group. As for cytokine analysis, high serum levels of IL6, IL8, Gal-9, CCL23, CSF-1 and HO-1 were significantly associated with poorer OS, while pro-inflammatory cytokines MCP-2 was correlated with better survival outcomes. Conclusions: Our findings indicated that DNA hypomethylation levels may be associated with better efficacy and survival outcomes in ES-SCLC treated with the combination of Olaparib and Durvalumab. Clinical trial information: NCT05245994 .