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. 2025 Jul 23:17:17588359251357527.
doi: 10.1177/17588359251357527. eCollection 2025.

First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials

Yandong Xie  1 , Haoyang Liu  1 , Yanfeng Tang  1 , Yaowen Zhang  2 , Nanwei Xu  1 , Fengnian Zhao  1 , Jinge Zhao  1 , Guangxi Sun  1 , Zhenhua Liu  1 , Pengfei Shen  3 , Hao Zeng  3 , Junru Chen  3
Affiliations

First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials

Yandong Xie et al. Ther Adv Med Oncol. .

Abstract

Background: The emergence of immune checkpoint inhibitors and antibody-drug conjugates has revolutionized the first-line treatment landscape for locally advanced or metastatic urothelial carcinoma (la/mUC). However, the optimal treatment strategy remains uncertain.

Objectives: This network meta-analysis (NMA) aimed to evaluate the efficacy and safety of various first-line treatments for la/mUC.

Design: Systematic literature review with a Bayesian NMA.

Data sources and methods: Eligible studies were retrieved from PubMed, EMBASE, and Web of Science, with a search cutoff of July 2024. Randomized controlled trials (RCTs) evaluating first-line treatments for la/mUC were included. Pairwise comparisons and Bayesian NMA were conducted to compare overall survival (OS) and progression-free survival (PFS) using hazard ratios (HR) and 95% credible intervals (CrIs), and objective response rate (ORR) and treatment-related adverse events (TRAEs) using odds ratios and 95% CrIs.

Results: In total, 17 articles involving 11 RCTs and 7586 patients were included. Enfortumab vedotin (EV) plus pembrolizumab demonstrated the most significant improvement in OS (HR 0.47, 95% CrI 0.38-0.58) compared to platinum-based chemotherapy in the overall populations, with consistent benefits across cisplatin-eligible, cisplatin-ineligible, and PD-L1-positive/negative subgroups. EV plus pembrolizumab also ranked highest for PFS (HR 0.45, 95% CrI 0.38-0.54) and had a favorable ORR compared to other regimens. In terms of safety, atezolizumab monotherapy exhibited the lowest incidence of high-grade TRAEs, EV plus pembrolizumab had higher overall TRAE rates but lower rates of grade 3 or higher TRAEs than platinum-based chemotherapy and nivolumab plus gemcitabine-cisplatin.

Conclusion: This NMA provides the most comprehensive analysis of first-line treatments for la/mUC, integrating the latest clinical data. EV plus pembrolizumab demonstrated superior efficacy and acceptable safety profiles in overall and subgroup analyses, establishing it as a promising treatment option.

Trial registration: The study was registered in PROSPERO (CRD42024502320).

Keywords: clinical trials; enfortumab vedotin; first-line treatment; network meta-analysis; survival outcomes; urothelial carcinoma.

Plain language summary

Comparing first-line treatments for advanced bladder and urinary tract cancer: Which drug combinations work best and safest? Why was the study done? Advanced bladder and urinary tract cancer is challenging to treat. While newer drugs like immunotherapy and antibody-based therapies have improved care, doctors still debate which first-line treatment is most effective and safest. This study aimed to compare all available treatments to identify the best options. What did the researchers do? The research team reviewed 17 publications reporting results from 11 randomized controlled trials involving 7,586 patients. The network meta-analysis was used to compare survival outcomes, response rates, and side effects of different drug combinations. Treatments included chemotherapy, immunotherapy, and newer combinations like enfortumab vedotin (EV) plus pembrolizumab. What did the researchers find? The combination of EV and pembrolizumab showed the best results. Patients receiving this combination lived longer (47% lower risk of death) and had better disease control compared to standard chemotherapy. These benefits were consistent across patients of different ages, health statuses, and tumor characteristics. While EV plus pembrolizumab caused more mild-to-moderate side effects (e.g., skin reactions), it had fewer severe side effects than chemotherapy. What do the findings mean? This study suggests that EV combined with pembrolizumab is currently the most effective first-line treatment for advanced bladder and urinary tract cancer, offering better survival and manageable side effects. These results support using this combination as a preferred option for many patients. The ranking of all available treatments also helps guide therapy selection when EV-based regimens are not suitable or accessible.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

The flow diagram describes the PRISMA process of systematic review and meta-analysis for 17 studies, including records identification, screening, and inclusion.
Figure 1.
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart. la/mUC, locally advanced or metastatic urothelial carcinoma; RCT, randomized controlled trials.
The NMA results of OS. (a) The forest plot that contrasts the Bayesian NMA outcomes of the overall population shows HRs for OS with associated 95% CrIs of the comparisons between various IL treatments and standard chemotherapy; (b) The cumulative probability ranking plot of the overall population. The closer the color is to yellow and the larger the area, the higher the probability that the regimen is the best choice.
Figure 2.
The NMA results of OS. (a) The forest plot that contrasts the Bayesian NMA outcomes of the overall population shows HRs for OS with associated 95% CrIs of the comparisons between various first-line treatments and standard chemotherapy; (b) The cumulative probability ranking plot of the overall population. The closer the color is to yellow and the larger the area, the higher the probability that the regimen is the best choice. ATEZO, atezolizumab; ATEZO + GemPlat, atezolizumab plus platinum-based chemotherapy; AVE + GemPlat, platinum-based chemotherapy plus avelumab maintenance; BEV + GemPlat, bevacizumab plus gemcitabine–cisplatin; CrI, credible interval; DURVA, durvalumab; DURVA + TREME, durvalumab plus tremelimumab; EV + PEMBRO, enfortumab vedotin plus pembrolizumab; GemPlat, platinum-based chemotherapy (gemcitabine–cisplatin or gemcitabine-carboplatin); HD-MVAC, high-dose intensity MVAC; HR, hazard ratio; LTX + Cis, larotaxel plus cisplatin; MVAC, methotrexate, vinblatine, adriamycin, and cisplatin; NIVO + GemPlat, nivolumab plus gemcitabine–cisplatin; NMA, network meta-analysis; OS, overall survival; PAX + GemPlat, paclitaxel plus gemcitabine–cisplatin; PEMBRO, pembrolizumab; PEMBRO + GemPlat, pembrolizumab plus platinum-based chemotherapy; SUCRA, the surface under the cumulative ranking curve.
The forest plot compares the HR between different treatment combinations in the cisplatin-eligible, cisplatin-ineligible, PD-L1-positive, and PD-L1-negative settings. Variables include atezolizumab (ATEZO) in various combinations with either gemcitabine, carboplatin, or platinum-based chemotherapy. The plot shows different HR values and credible intervals, indicating the effect of each treatment combination on overall survival (OS) in patients with different tumor types.
Figure 3.
The forest plot of OS in the cisplatin-eligible setting (a), cisplatin-ineligible setting (b), PD-L1-positive population (c), and PD-L1-negative population (d). ATEZO, atezolizumab; ATEZO + GemCarbo, atezolizumab plus gemcitabine–carboplatin; ATEZO + GemCis, atezolizumab plus gemcitabine–cisplatin; ATEZO + GemPlat, atezolizumab plus platinum-based chemotherapy; AVE + GemCarbo, gemcitabine–carboplatin plus avelumab maintenance; AVE + GemCis, gemcitabine–cisplatin plus avelumab maintenance; AVE + GemPlat, platinum-based chemotherapy plus avelumab maintenance; BEV + GemCis, bevacizumab plus gemcitabine–cisplatin; CrI, credible interval; DURVA, durvalumab; EV + PEMBRO, enfortumab vedotin plus pembrolizumab; GemCarbo, gemcitabine–carboplatin; GemCis, gemcitabine–cisplatin; GemPlat, platinum-based chemotherapy (gemcitabine–cisplatin or gemcitabine-carboplatin); HDMVACis, high-dose intensity methotrexate, vinblatine, adriamycin, and cisplatin; HR, hazard ratio; LTX + Cis, larotaxel plus cisplatin. DURVA + TREME, durvalumab plus tremelimumab; MVAC, methotrexate, vinblatine, adriamycin, and cisplatin; NIVO + GemCis, nivolumab plus gemcitabine–cisplatin; NIVO + GemPlat, nivolumab plus gemcitabine–cisplatin; OS, overall survival; PAX + GemPlat, paclitaxel plus gemcitabine–cisplatin; PD-L1, programmed death-ligand 1; PEMBRO, pembrolizumab; PEMBRO + GemCarbo, pembrolizumab plus gemcitabine–carboplatin; PEMBRO + GemCis, pembrolizumab plus gemcitabine–cisplatin; PEMBRO + GemPlat, pembrolizumab plus platinum-based chemotherapy.
The Kaplan Meier Survival Analysis of Overall Survival (a) the forest plot and (b) the cumulative probability ranking plot of the overall population.
Figure 4.
The NMA results of PFS. (a) The forest plot and (b) the cumulative probability ranking plot of the overall population. ATEZO + GemPlat, atezolizumab plus platinum-based chemotherapy; AVE + GemPlat, platinum-based chemotherapy plus avelumab maintenance; BEV + GemPlat, bevacizumab plus gemcitabine–cisplatin; CrI, credible interval; EV + PEMBRO, enfortumab vedotin plus pembrolizumab; GemPlat, platinum-based chemotherapy (gemcitabine–cisplatin or gemcitabine–carboplatin); HD-MVAC, high-dose intensity MVAC; HR, hazard ratio; LTX + Cis, larotaxel plus cisplatin; MVAC, methotrexate, vinblatine, adriamycin, and cisplatin; NIVO + GemPlat, nivolumab plus gemcitabine–cisplatin; NMA, network meta-analysis; PAX + GemPlat, paclitaxel plus gemcitabine–cisplatin; PEMBRO, pembrolizumab; PEMBRO + GemPlat, pembrolizumab plus platinum-based chemotherapy; PFS, progression-free survival; SUCRA, the surface under the cumulative ranking curve.
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