First-line immune-checkpoint inhibitor combination therapy for chemotherapy-eligible patients with metastatic urothelial carcinoma: A systematic review and meta-analysis

TY - JOUR

T1 - First-line immune-checkpoint inhibitor combination therapy for chemotherapy-eligible patients with metastatic urothelial carcinoma: A systematic review and meta-analysis

AU - Mori, Keiichiro

AU - Pradere, Benjamin

AU - Moschini, Marco

AU - Mostafaei, Hadi

AU - Laukhtina, Ekaterina

AU - Schuettfort, Victor M

AU - Sari Motlagh, Reza

AU - Soria, Francesco

AU - Teoh, Jeremy Y C

AU - Egawa, Shin

AU - Powles, Thomas

AU - Shariat, Shahrokh F

AU - European Association of Urology – Young Academic Urologists (EAU-YAU), Urothelial Carcinoma Working Group

N1 - Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - B7-H1 Antigen/antagonists & inhibitors

KW - Carcinoma/drug therapy

KW - Clinical Decision-Making

KW - Female

KW - Humans

KW - Immune Checkpoint Inhibitors/adverse effects

KW - Male

KW - Middle Aged

KW - Patient Selection

KW - Progression-Free Survival

KW - Time Factors

KW - Urinary Bladder Neoplasms/drug therapy

KW - Urothelium/drug effects

U2 - 10.1016/j.ejca.2021.03.049

DO - 10.1016/j.ejca.2021.03.049

M3 - SCORING: Review article

C2 - 33962359

VL - 151

SP - 35

EP - 48

JO - EUR J CANCER

JF - EUR J CANCER

SN - 0959-8049

ER -