Expression of Programmed Cell Death Ligand 1 as a Predictive Biomarker in Metastatic Urothelial Carcinoma Patients Treated with First-line Immune Checkpoint Inhibitors Versus Chemotherapy: A Systematic Review and Meta-analysis

Context: Immune checkpoint inhibitors (ICIs) have reported durable responses in selected groups of patients with metastatic urothelial carcinoma (mUC). However, identification of biomarkers predictive of response to ICIs remains an unmet need in mUC management, and the role of programmed cell death ligand 1 (PD-L1) expression remains controversial. Objective: In this systematic review and meta-analysis, we aimed at assessing the predictive value of PD-L1 in mUC patients receiving first-line ICIs as monotherapy or in combination with other anticancer agents across randomized controlled clinical trials (RCTs). Evidence acquisition: We retrieved all the relevant RCTs through PubMed/Medline, Cochrane library, and EMBASE; proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs evaluating ICIs versus chemotherapy in PD-L1-positive mUCs; the primary endpoint was overall survival (OS). Evidence synthesis: Three phase III trials matched our eligibility criteria; a total of 2237 PD-L1-positive mUC patients (ICIs: 1125; chemotherapy: 1112) were included in the analysis. Compared with chemotherapy, ICIs were associated with higher OS in PDL1-positive patients (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.78-0.96; p = 0.007); conversely, no differences were observed in the PD-L1-negative patient population (HR 1.03, 95% CI 0.89-1.19; p < 0.001). Conclusions: Compared with standard chemotherapy, our results suggested a survival benefit in PD-L1-positive mUC patients receiving ICIs; conversely, no benefit was observed in patients with PD-L1-negative disease. Although this systematic review and meta-analysis should be interpreted with caution due to several issues, our results highlight the need for reliable predictive biomarkers of response to ICIs, providing a benchmark for future studies in this setting. Patient summary: Despite immune checkpoint inhibitors (ICIs) having revolutionized the treatment landscape of metastatic urothelial carcinoma (mUC), an important percentage of patients do not experience clinical benefit or durable responses. Identifi-cation of reliable biomarkers of response to ICIs remains a mandatory need in mUC management, and further efforts are needed to standardize the assessment of programmed cell death ligand 1 in urothelial carcinoma. (c) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Automated summary

ICIs show a survival benefit in PD-L1-positive mUC patients compared to chemotherapy, while no benefit is observed in PD-L1-negative patients. The need for reliable predictive biomarkers of response to ICIs remains a key challenge in mUC management.