Use of immune checkpoint inhibitors as first line therapy for untreated, unresectable pleural mesothelioma: A systematic review and meta-analysis of randomized controlled trials.

Abstract

e20098 Background: Malignant pleural mesothelioma represents an uncommon malignancy, typically found in adults with prior exposure to asbestos. Despite the benefits of surgical resection in the early stages of disease, the survival rate for patients with advanced, unresectable disease remains low with median survival of 11 months in stage IV disease. Immune checkpoint inhibitors (ICIs) are included in current guidelines as first line therapy, but data on the overall effect of (ICIs) as group remains limited. We sought to conduct a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) regarding use of ICI as part of first-line therapy for advanced, unresectable pleural mesothelioma. Methods: We performed a systematic search in Medline and Embase, following PRISMA guidelines. We included phase 3 RCTs describing the use of ICIs as first-line therapy for advanced, unresectable pleural mesothelioma (either as monotherapy or in combination with chemotherapy), reporting at least one outcome of interest. Studies describing the use of ICI in previously treated, resected or potentially resectable mesothelioma were excluded. Data was collected for the outcomes of interest (primary endpoint included median overall survival, and secondary endpoints were median progression free survival, median overall survival for epithelioid mesothelioma, and rate of adverse events). A meta-analysis was performed in R studio version R 4.4.2, using Hazard Ratios (HR) and relative risk (RR) to report results. A common effects model was used considering low heterogeneity, due to exclusive inclusion of RCTs. Results: We screened 950 studies, and 3 studies met inclusion for final analysis (CheckMate 743, KEYNOTE 483, and BEAT-Meso), with a total of 725 patients in the intervention group and 720 patients in the control group. Median overall survival (mOS) demonstrated a HR of 0.78 (95%CI 0.69-0.89), favoring the intervention group. For the secondary endpoints, median progression free survival (mPFS) showed a HR of 0.84 (95%CI 0.75-0.94), with statistically significant benefit for intervention group; mOS in patients with epithelioid histology demonstrated a HR of 0.91 (95%CI 0.79-1.04), which was not statistically significant. RR for grade 3-4 adverse events was 1.17 (95%CI 1.01-1.35), with a statistically significant increase in intervention group. Conclusions: Use of immune checkpoint inhibitors as part of first-line therapy for advanced, unresectable mesothelioma demonstrated statistically significant benefits in survival outcomes (OS and PFS), but also a higher risk of grade 3-4 adverse events. Notably, benefits in mOS were not statistically significant for subgroup analysis of patients with epithelioid histology, and additional research is needed to better understand the benefits of ICI across various subgroups.