The efficacy and safety of immunotherapy targeting the PD-1 pathway for advanced urothelial carcinoma: a meta-analysis of published clinical trials.INTRODUCTION
 Urothelial carcinoma (UC) is an aggressive malignancy and has a poor prognosis in the metastatic state.  Treatment of UC remains a challenge, and as a first-line regimen for advanced UC, standard platinum-based chemotherapy is unfit for many patients due to numerous comorbidities and poor performance status.  Recently, five immune checkpoint inhibitors have been approved for the treatment of patients with advanced UC who were ineligible for platinum-based regimens or suffered tumor progression in post-platinum setting.  However, not long ago, the U.S. Food and Drug Administration restricted the use of two common immune checkpoint blockades, atezolizumab and pembrolizumab, due to uncertain survival benefit as mono-therapy.  In this scenario, we reviewed rapidly surfacing clinical trials to assess the efficacy and safety of immunotherapy targeting the PD-1 pathway for advanced UC.


 A comprehensive search was conducted in PubMed, EMBASE and Cochrane Library for all clinical trials where the efficacy and safety were reported.  Our primary outcome was efficacy evaluated by objective response rate (ORR), 1-year overall survival (OS) rate and 1-year progression-free survival (PFS) rate, and second outcome was safety assessed by any grade and grade 3-4 treatment-related adverse events (TRAEs).  We chose percentages with 95% confidence intervals (CI) as the evaluation indexes and used a random-effects model to account for heterogeneity.


 We included 14 clinical trials with 2674 total patients in this meta-analysis.  The pooled data of ORR, 1-year OS rate, and 1-year PFS rate were 0.20 (95% CI 0.18-0.22, I2 = 38.4%, P = 0.078), 0.50 (95% CI 0.46-0.53, I2 = 30.3%, P = 0.186), and 0.17 (95% CI 0.14-0.20, I2 = 0.0%, P = 0.668), respectively.  Similarly, 13 trials were utilized to compute the pooled rate of any-grade TRAEs.  The pooled estimation of any-grade was 0.65 (95% CI 0.63-0.67, I2 = 1.7%, P = 0.429).  The pooled rate of grade 3-4 TRAEs subgroups with Atezolizumab, Pembrolizumab, Durvalumab, Nivolumab and Avelumab were 0.11 (95% CI 0.06-0.15, I2 = 83.5%, P = 0.000), 0.15 (95% CI 0.13-0.18, I2 = 0.0%, P = 0.971), 0.06 (95% CI 0.03-0.09, I2 = 0.0%, P = 0.566), 0.19 (95% CI 0.15-0.23, I2 = 0.0%, P = 0.480) and 0.08 (95% CI 0.05-0.11, I2 = 0.0%, P = 0.702), respectively.


 CONCLUSION
 This study showed that the immunotherapy targeting the PD-1 pathway had durable efficacy and acceptable safety in patients with advanced UC.  The comprehensive role of immune checkpoint inhibitors in comparison to other treatments needs further confirmation basing on RCTs.
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