INTRODUCTION: Platinum-based combination chemotherapy is the standard treatment for patients with chemotherapy-eligible metastatic urothelial carcinoma (mUC). Immune-checkpoint inhibitors (ICIs) are currently assessed in this setting. This review aimed to assess the role of ICIs alone or in combination as first-line treatment in chemotherapy-eligible patients with mUC. METHODS: Multiple databases were searched for articles published until November 2020. Studies were deemed eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), durations of response (DORs) and adverse events (AEs) in chemotherapy-eligible patients with mUC. RESULTS: Three studies met our eligibility criteria. ICI combination therapy was associated with significantly better OS and PFS, higher CRR and longer DOR than chemotherapy alone (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.76-0.94, P = 0.002; HR: 0.80, 95% CI: 0.71-0.90, P = 0.0002; odds ratio [OR]: 1.48, 95% CI: 1.12-1.96, P = 0.006; and mean difference: 1.39, 95% CI: 0.31-2.46, P = 0.01, respectively). ICI-chemotherapy combination therapy was also associated with significantly better OS and PFS, higher ORR and CRR and longer DOR than chemotherapy alone. Although OS and PFS benefits of ICI combination therapy were larger in patients with high expression of programmed death-ligand 1 (PD-L1), PD-L1 low expression patients also had a benefit; HR for OS (high PD-L1: HR 0.79 versus low PD-L1: HR 0.89) and PFS (high PD-L1: HR 0.74 versus low PD-L1: HR 0.82). ICI monotherapy was not associated with better oncological outcomes but was associated with better safety outcomes than chemotherapy alone. CONCLUSIONS: Our analysis indicates a superior oncologic benefit to first-line ICI combination therapies in patients with chemotherapy-eligible mUC over standard chemotherapy. In contrast, ICI monotherapy was associated with favorable safety outcomes compared with chemotherapy but failed to show its superiority over chemotherapy in oncological benefits. PD-L1 status alone cannot help guide treatment decision-making. However, caution should be exercised in interpreting the conclusions drawn from this study, given that there is the heterogeneity of the population of interest, risk of bias and the nature of the studies evaluated whose data remain immature or unpublished.

Centre for Experimental Cancer Medicine Barts Cancer Institute Queen Mary University of London London UK

Department of Surgery S H Ho Urology Centre The Chinese University of Hong Kong Hong Kong China

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology Medical University of Vienna Vienna Austria; Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology Medical University of Vienna Vienna Austria; Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology Medical University of Vienna Vienna Austria; Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Department of Urology Medical University of Vienna Vienna Austria; Institute for Urology and Reproductive Health Sechenov University Moscow Russia; Research Division of Urology Department of Special Surgery The University of Jordan Amman Jordan; Department of Urology University of Texas Southwestern Medical Center Dallas TX USA; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic; Department of Urology Weill Cornell Medical College New York NY USA; Karl Landsteiner Institute of Urology and Andrology Vienna Austria; European Association of Urology Research Foundation Arnhem Netherlands

Department of Urology Medical University of Vienna Vienna Austria; Men's Health and Reproductive Health Research Center Shahid Beheshti University of Medical Sciences Tehran Iran

Department of Urology Medical University of Vienna Vienna Austria; Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

Department of Urology The Jikei University School of Medicine Tokyo Japan

Division of Urology Department of Surgical Sciences University of Studies of Torino Turin Italy

Klinik für Urologie Luzerner Kantonsspital Lucerne Switzerland

References provided by Crossref.org

Novel combination therapy for platinum-eligible patients with locally advanced or metastatic urothelial carcinoma: a systematic review and network meta-analysis

Adjuvant Immune Checkpoint Inhibitors for Muscle-Invasive Urothelial Carcinoma: An Updated Systematic Review, Meta-analysis, and Network Meta-analysis

Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

Pretreatment clinical and hematologic prognostic factors of metastatic urothelial carcinoma treated with pembrolizumab: a systematic review and meta-analysis