Efficacy Of Immune-Checkpoint Inhibitors In Pd-L1 Selected Or Unselected Patients Vs. Control Group In Patients With Advanced Or Metastatic Urothelial Carcinoma

Most patients with advanced or metastatic urothelial carcinoma do not benefit significantly from Immune checkpoint inhibitors (ICIs) use. A systematic review and meta-analysis of randomized controlled trials to assess the efficacy and activity of ICIs, in terms of Overall Survival (OS), Progression-free survival (PFS), and Objective Response Rate (ORR). We systematically searched for articles from PubMed, Cochrane Library, Embase, and Web of science from their inception to December 1, 2020 with no language restrictions. The search was performed to identify all clinical trials (phase I, phase II, phase III) of ICIs for treating urothelial carcinoma. The endpoints of the meta-analysis were OS, PFS, and ORR, compared unselected patients and in the subgroup of patients characterized by high expression of PD-L1 (PD-L1 selected patients). Sixteen studies comprising 5559 patients were identified, of which data for OS comparison were available from 4 RCTs (2342 patients), two studies for PFS (649 patients), and four RCTs were eligible for ORR analysis (2921 patients). Both pembrolizumab and atezolizumab have showed to improve OS compared to chemotherapy in unselected patients (HR 0.86, 95% CI 0.80-0.93, P = .0001, I-2 = 60%), while the difference was not significant in PD-L1 selected patients (HR 0.91, 95% CI 0.77-1.07, P = .23, I-2 = 0%). PFS difference was not observed in neither unselected population nor PD-L1 selected patients, the pooled HR of PFS for immunotherapy compared to control treatment was 1.05 (95% CI 0.74-1.49, P = .79, I-2 = 85%) and 0.84 (95% CI 0.68-1.03, P = .09, I-2 = 0%, respectively. Similar result was observed in ORR, the pooled HR of ORR for immunotherapy compared to control treatment was 1.45 (95% CI 0.53-3.98, P = .47, I-2 = 95%) and 2.19 (95% CI 0.79-6.08, P = .13, I-2 = 83%), respectively. Immunotherapy could significantly improve survival advantage in unselected patients but not in PD-L1 selected population, indicating that PD-L1 expression may not be a reliable marker in previously platinum-treated patients.