Abstract
BACKGROUND: Pleural mesothelioma (PM) has a poor prognosis, and immune checkpoint inhibitors (ICIs) have reshaped first-line therapy. However, real-world data comparing first-line immunotherapy with chemotherapy ± targeted therapy and defining optimal second-line strategies in Chinese patients remain limited. This multicenter retrospective real-world study aimed to compare survival outcomes between first-line immunotherapy and chemotherapy-based regimens and to evaluate the effectiveness of different subsequent systemic therapies in patients with PM. METHODS: This multicenter retrospective real-world cohort included patients with pathologically confirmed PM who received at least one line of systemic therapy at tertiary hospitals in China between January 2015 and January 2025. Patients were grouped by first-line regimen (immunotherapy vs. chemotherapy ± targeted therapy). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Generalized propensity scores with overlap weighting (OW) were used to balance baseline covariates, followed by weighted Kaplan-Meier and Cox regression analyses. For post-first-line analyses, chemo-start and immuno-start cohorts were used to compare OS across second-line chemotherapy, chemo-immunotherapy, and dual immunotherapy. Hazard ratio (HR), 95% confidence interval (CI), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were reported. RESULTS: Seventy-eight patients were included (chemotherapy ± targeted, n=50; immunotherapy, n=28; median follow-up, 35.7 months). After weighting, first-line immunotherapy improved OS vs. chemotherapy ± targeted therapy (weighted HR, 0.47; 95% CI: 0.23-0.95) and showed a trend toward longer PFS (weighted HR, 0.64; 95% CI: 0.34-1.17). OS benefit was greater in patients with ECOG PS 0-1 (HR, 0.44; 95% CI: 0.21-0.93), non-epithelioid histology (HR, 0.30; 95% CI: 0.10-0.97), or no prior radiotherapy (HR, 0.29; 95% CI: 0.12-0.68). In multivariate models, first-line immunotherapy (HR, 0.34; 95% CI: 0.13-0.90) and prior radiotherapy (HR, 0.35; 95% CI: 0.14-0.86) were independent protective factors for OS. ORR and DCR were similar between groups, and immune-related adverse events occurred in 14/28 (50.0%) immunotherapy patients, mostly grade 1-2, with no immune-related deaths. In the chemo-start cohort, second-line dual immunotherapy improved OS vs. chemo-immunotherapy (HR, 0.13; 95% CI: 0.03-0.62) but not vs. chemotherapy alone (HR, 0.43; 95% CI: 0.17-1.11), and chemo-immunotherapy did not differ from chemotherapy (HR, 2.08; 95% CI: 0.94-4.57). In the smaller immuno-start cohort, no significant OS differences were seen between second-line strategies (weighted Cox P=0.31). CONCLUSIONS: In this multicenter real-world Chinese cohort, first-line immunotherapy was associated with a clinically meaningful OS improvement in PM, particularly among patients with good PS, non-epithelioid histology, or no prior radiotherapy. Dual immunotherapy may be a promising second-line option after chemotherapy, warranting confirmation in larger prospective studies.