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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).

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.

Keywords

clinical trials enfortumab vedotin first-line treatment network meta-analysis survival outcomes urothelial carcinoma

Introduction

For the past decades, platinum-based chemotherapy has been the standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). Cisplatin-based combination regimens demonstrated a median overall survival (OS) ranging from 12 to 14 months.^1–4 However, approximately 50% of patients with la/mUC are ineligible for cisplatin, for whom carboplatin-based chemotherapy yielded a median OS of only 9–10 months.^5–10 The limited survival benefits associated with platinum-based chemotherapy underscore the urgent need for more effective and innovative treatment strategies for this patient population.

The recent advent of immune checkpoint inhibitors (ICIs), particularly programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, has significantly altered the treatment landscape of la/mUC. Atezolizumab was the first ICI approved by the U.S. Food and Drug Administration (FDA) for mUC, but subsequent phase III trials showed limited survival benefits as first-line therapy, especially in patients with low PD-L1 expression.^11,12 This led to its approval being restricted to second-line treatment for PD-L1-high patients.¹² Similarly, while pembrolizumab showed benefit as monotherapy for cisplatin-ineligible mUC patients, its combination with chemotherapy did not improve outcomes in later trials.^13,14 As a result, pembrolizumab is now FDA-approved for first-line therapy only in cisplatin-ineligible mUC patients with PD-L1-high expression (combined positive score ⩾10), based on KEYNOTE-052.¹³ Two landmark trials have further reshaped the first-line treatment paradigm for la/mUC. The JAVELIN Bladder 100 trial established avelumab as a maintenance therapy for patients whose disease did not progress after first-line platinum-based chemotherapy.¹⁵ Nevertheless, a substantial proportion of patients are unable to receive maintenance therapy due to early disease progression or death.¹⁶ More recently, the CheckMate-901 trial demonstrated that the combination of nivolumab with gemcitabine–cisplatin significantly improved both progression-free survival (PFS) and OS compared to gemcitabine–cisplatin alone, offering a promising new first-line treatment option for previously untreated la/mUC patients.¹⁷

In addition to ICIs, antibody–drug conjugates (ADCs), a novel class of therapies that combine the specificity of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutic agents, have also attracted increasing interest in the treatment of la/mUC.¹⁸ Enfortumab vedotin (EV), which targets nectin-4, a protein highly expressed on urothelial cancer cells, was initially approved for la/mUC patients who have progressed after receiving chemotherapy and ICIs.^19–21 Lately, the EV-302 phase III trial has demonstrated substantial survival improvement with EV plus pembrolizumab combination compared to chemotherapy in previously untreated la/mUC patients, providing a practice-changing option for the first-line treatment setting.²²

Despite the promising advancements, the optimal first-line treatment strategy for patients with la/mUC remains uncertain, with limited direct comparisons between these novel treatments. This systematic review and network meta-analysis (NMA) aims to evaluate the efficacy and safety of these therapeutic options in the first-line setting for la/mUC. This study integrates direct and indirect evidence to inform clinical decision-making in the evolving therapeutic landscape and provide patient-specific insights to support individualized treatment strategies.

Materials and methods

The systematic review and NMA were conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement²³ (checklist in the Supplemental Material). This study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42024502320).

Search strategy

Systematic literature searches of the EMBASE, PubMed, and Web of Science databases were performed to identify relevant randomized controlled trials (RCTs) evaluating first-line treatments for la/mUC published before July 2024. References of the included trials were also manually reviewed to identify additional eligible studies. Detailed search strategies are provided in the Supplemental Material.

Outcomes

The main objective of this NMA was to investigate the association between different first-line treatment regimens and survival outcomes in la/mUC patients. The primary outcomes include OS and PFS, while secondary outcomes include objective response rate (ORR) and treatment-related adverse events (TRAEs).

Inclusion and exclusion criteria

The Population, Intervention, Comparison, Outcome, and Study Design (PICOS) framework was employed to assess eligibility criteria.²⁴ Eligible studies must meet the following criteria: (1) phase III RCTs evaluating first-line treatment options for patients with la/mUC; (2) studies must report at least one survival outcome; and (3) only studies published in English were considered.

Exclusion criteria: (1) observational studies, reviews, cohort studies, author responses, case reports, and conference abstracts; (2) patients without confirmed diagnosis of la/mUC; (3) non-first-line treatment for la/mUC patients or absence of survival outcome data; and (4) studies not published in English.

Data extraction

Data from the eligible studies were independently extracted by two reviewers and cross-checked. The extracted data included the following: (1) study details: authors, publication year, and clinical trial identifier; (2) patient characteristics: number of patients, intervention type, median age, gender, race, stage, primary tumor sites, metastatic sites, cisplatin eligibility, performance status, PD-L1 status, and histopathological classification; (3) outcomes: follow-up time, OS, PFS, ORR, and AEs, along with the corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and PFS, and odds ratios (ORs) and 95% CIs for ORR and AEs. Any discrepancies in data extraction were reconciled through consensus among the authors.

In our analysis, when multiple publications reported data from the same clinical trial (e.g., IMvigor130), we employed a structured approach to data inclusion. Specifically, for overlapping data, we selected the most recent and comprehensive publication to avoid duplication. For non-overlapping data, we extracted complementary information (e.g., subgroup data or adverse events) from all relevant sources to compile the most complete dataset available for each study.

Risk of bias assessment

The revised Cochrane risk of bias tool for randomized trials (RoB 2) from the Cochrane Collaboration was employed to assess the risk of bias of included studies across five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results.²⁵ Randomized trials were assessed as “low risk,” “some concerns,” and “high risk” accordingly. The assessment was performed independently by two reviewers, with a discrepancy check by a third reviewer.

Statistical analyses

The relative risks of OS and PFS across different treatment regimens were assessed using HRs with corresponding 95% credible intervals (CrIs), while ORs and 95% CrIs were used to evaluate ORR and AEs. A Bayesian NMA approach was applied to facilitate both direct and indirect comparisons of efficacy and safety across treatment arms.²⁶ The gemtc and JAGS packages were employed for survival outcomes, BUGSnet was used for ORR and AEs. Heterogeneity between studies was assessed using Cochrane’s Q test and the I² statistic, with significant heterogeneity indicated by a p-value <0.1 and an I² statistic >50%. The subgroup analyses were performed to reduce the impact of heterogeneity on the study outcomes. The data analysis utilized both fixed-effect and random-effect models, with model selection guided by the Bayesian Deviance Information Criterion (DIC). A DIC difference of 2−5 was considered meaningful, favoring the model with the lower score. If the DIC difference was not significant, the decision was based on heterogeneity: the random-effect model was used in the presence of heterogeneity; otherwise, the fixed-effect model was applied. Model convergence was checked with trace plots and Gelman–Rubin–Brook plots. The surface under the cumulative ranking curve (SUCRA) metrics was employed to rank the relative efficacy of each treatment.²⁶ All analyses were conducted using R software (version 4.3.0; R Core Team, 2023), with two-tailed statistical tests and a significance threshold of p < 0.05.

Results

Study selection

A total of 8770 publications were initially identified through the systematic search. After removing duplicates, 5775 publications were screened by titles and abstracts, among which 116 articles were further selected for full-text review. Ultimately, 17 articles involving 11 RCTs were included for the systematic review and NMA (Figure 1).^{12,14,15,17,22,27–38} Table 1 provides an overview of the included studies, summarizing the outcome data from 7586 patients across 15 first-line treatment regimens in 11 RCTs. The baseline characteristics of the participants in these trials are shown in Tables 1 and 2.

Figure 1.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart.

Table 1.

The overview of the included studies in the network meta-analysis.

Author (year)	Trial	Design of the trial	Study period	Regimen (no.)	Median follow-up (months)	mOS, months (95% CI)	OS, HR (95% CI)	mPFS, months (95% CI)	PFS, HR (95% CI)	ORR, (no.)	AEs, (no.)	TRAEs (no.)
Joaquim Bellmunt (2012)²⁷	EORTC 30987	Multicenter, open-label, RCT	May 2001 to June 2004	Paclitaxel plus gemcitabine–cisplatin (312)	55.2	15.8 (13.6–17.5)	0.85 (0.72–1.02)	8.3	0.87 (0.74–1.03)	55.5% (173)	—	—
				Gemcitabine–cisplatin (314)		12.7 (11.0–14.4)	Ref.	7.6	Ref.	43.6% (137)	—	—
Matthew D. Galsky (2020)¹²	IMvigor130	Multicenter, partially blinded, RCT	July 15, 2016 to July 20, 2018	Atezolizumab plus platinum-based chemotherapy (451)	11.8 (IQR: 6.1–17.2)	16.0 (13.9–18.9)	0.83 (0.69–1.00)	8.2 (6.5–8.3)	0.82 (0.70–0.96)	47% (212)	>99% (451)	96% (434)
				Atezolizumab monotherapy (362)		15.7 (13.1–17.8)	1.02 (0.83–1.24)	—	—	23% (82)	93% (329)	60% (211)
				Placebo plus platinum-based chemotherapy (400)		13.4 (12.0–15.2)	Ref.	6.3 (6.2–7.0)	Ref.	44% (174)	99% (386)	96% (373)
Enrique Grande (2024)²⁸	IMvigor130	Multicenter, partially blind, RCT	July 15, 2016 to July 20, 2018	Atezolizumab plus platinum-based chemotherapy (451)	13.4 (IQR: 6.2–30.8)	16.1 (14.2–18.8)	0.85 (0.73–1.00)	—	—	48.1% (215)	>99% (452)	96% (435)
				Placebo plus platinum-based chemotherapy (400)		13.4 (12.0–15.3)	Ref.	—	—	44.8% (178)	99% (385)	96% (372)
Aristotelis Bamias (2024)²⁹	IMvigor130	Multicenter, partially blind, RCT	July 15, 2016 to July 20, 2018	Atezolizumab monotherapy (360)	13.4 (IQR: 6.2–30.8)	15.2 (13.1–17.7)	0.98 (0.82–1.16)	—	—	24.2% (87)	94% (331)	61% (217)
				Placebo plus platinum-based chemotherapy (359)		13.3 (11.9–15.6)	Ref.	—	—	44.4% (158)	99% (385)	96% (372)
Thomas Powles (2021)¹⁴	KEYNOTE-361^a	Multicenter, open-label, RCT	Oct 19, 2016 to June 29, 2018	Pembrolizumab plus platinum-based chemotherapy (351)	31.7 (IQR: 27.7–36.0)	17.0 (14.5–19.5)	0.86 (0.72–1.02)	8.3 (7.5–8.5)	0.78 (0.65–0.93)	54.7% (192)	87% (305)	75% (262)
				Pembrolizumab monotherapy (307)		15.6 (12.1–17.9)	0.92 (0.77–1.11)	—	—	30.3% (93)	63% (190)	17% (51)
				Platinum-based chemotherapy (352)		14.3 (12.3–16.7)	Ref.	7.1 (6.4–7.9)	Ref.	44.9% (158)	82% (280)	72% (245)
Thomas Powles (2020)¹⁵	JAVELIN Bladder 100	Multicenter, open-label, RCT	May 11, 2016 to June 4, 2019	Platinum-based chemotherapy plus avelumab maintenance (350)	More than 19 months	21.4 (18.9–26.1)	0.69 (0.56–0.86)	3.7 (3.5–5.5)	0.62 (0.52–0.75)	9.7%	98% (337)	77% (266)
				Platinum-based chemotherapy plus BPC (350)		14.3 (12.9–17.9)	Ref.	2.0 (1.9–2.7)	Ref.	1.4%	78% (268)	1% (4)
Thomas Powles (2023)³⁰	JAVELIN Bladder 100^b	Multicenter, open-label, RCT	May 11, 2016 to June 4, 2019	Platinum-based chemotherapy plus avelumab maintenance (350)	38	23.8 (19.9–28.8)	0.76 (0.63–0.91)	5.5 (4.2–7.2)	0.54 (0.46–0.64)	14.3%	98% (338)	78% (269)
				Platinum-based chemotherapy plus BPC (350)	39.6	15.0 (13.5–18.2)	Ref.	2.1 (1.9–3.0)	Ref.	4.0%	—	—
Petros Grivas (2023)³¹	JAVELIN Bladder 100^b	Multicenter, open-label, RCT	May 11, 2016 to June 4, 2019	Platinum-based chemotherapy plus avelumab maintenance (350)	19.6 (95% CI: 18.0–20.6)	—		—		—	—	—
				Platinum-based chemotherapy plus BPC (350)	19.2 (95% CI: 17.4–21.6)	—		—		—	—	—
Miguel Ángel Climent (2024)³²	JAVELIN Bladder 100^b	Multicenter, open-label, RCT	May 11, 2016 to June 4, 2019	Platinum-based chemotherapy plus avelumab maintenance (350)	21	—		—		—	—	—
				Platinum-based chemotherapy plus BPC (350)		—		—		—	—	—
Thomas Powles (2020)³³	DANUBE	Multicenter, open-label, RCT	Nov 24, 2015 to Mar 21, 2017	Durvalumab monotherapy (346)	41.2 (IQR: 37.9–43.2)	13.2 (10.3–15.0)	0.99 (0.83–1.17)	2.3 (1.9–3.5)	—	26% (89)	96% (330)	56% (193)
				Durvalumab plus tremelimumab (342)		15.1 (13.1–18.0)	0.85 (0.72–1.02)	3.7 (3.4–3.8)	—	36% (124)	97% (330)	75% (255)
				Platinum-based chemotherapy (344)		12.1 (10.9–14.0)	Ref.	6.7 (5.7–7.3)	—	49% (169)	98% (308)	90% (283)
Jonathan E (2021)³⁴	CALGB 90601^c	Multicenter, double blind, RCT	July 15, 2009 to Dec 2, 2014	Bevacizumab plus gemcitabine–cisplatin (252)	76.3 (95% CI: 69.1–83.0)	14.5 (13.5–16.2)	0.87 (0.72–1.05)	8.0 (7.1–8.5)	0.77 (0.63–0.95)	40.4%	—	—
				Gemcitabine–cisplatin (254)		14.3 (12.2–16.2)	Ref.	6.7 (6.3–7.4)	Ref.	36.4%	—	—
C.N. Sternberg (2006)³⁵	—	Multicenter, open-label, RCT	June 1993 to Nov 1998	MVAC (129)	87.6	14.9	Ref.	8.1 (7.0–9.9)	Ref.	58% (65)	—	—
				HD-MVAC (134)		15.1	0.76 (0.58–0.99)	9.5 (7.6–12.2)	0.73 (0.56–0.95)	72% (83)	—	—
C.N. Sternberg (2013)³⁶	CILAB	Multicenter, open-label, RCT	Feb. 2008 to Feb. 2010	Larotaxel plus cisplatin (166)	—	13.7 (11.2–17.1)	1.21 (0.83–1.76)	5.6 (4.1–6.2)	1.67 (1.24–2.25)	31%	98% (158)	—
				Gemcitabine–cisplatin (171)		14.3 (10.5–NR)	Ref.	7.6 (6.6–9.1)	Ref.	43%	99% (164)	—
M. S. van der Heijden (2023)¹⁷	CheckMate 901	Multicenter, open-label, RCT	Jan 30, 2018 to Sep 28, 2022	Nivolumab plus gemcitabine–cisplatin (304)	33.6 (range, 7.4–62.4)	21.7 (18.6–26.4)	0.78 (0.63–0.96)	7.9 (7.6–9.5)	0.72 (0.59–0.88)	57.6%	97% (296)	21%
				Gemcitabine–cisplatin (304)		18.9 (14.7–22.4)	Ref.	7.6 (6.1–7.8)	Ref.	43.1%	93% (267)	17%
J. T. Roberts (2006)³⁷	—	Multicenter, open-label, RCT	Nov 1996 to Sep 1998	MVAC (202)	—	15.2 (13.2–17.3)	Ref.	8.3 (7.3–9.7)	Ref.	—	—	—
				Gemcitabine–cisplatin (203)		14.0 (12.3–15.5)	1.09 (0.88–1.34)	7.7 (6.8–8.8)	1.09 (0.89–1.34)	—	—	—
H. von der Maase (2000)³⁸	—	Multicenter, open-label, RCT	Nov 1996 to Sep 1998	MVAC (202)	19	14.8 (13.2–16.8)	Ref.	—	—	49.4% (81)	—	—
				Gemcitabine–cisplatin (203)		13.8 (12.3–15.8)	1.04 (0.82–1.32)	—	—	45.7% (69)	—	—
Thomas Powles (2024)²²	EV-302	Multicenter, open-label, RCT		Enfortumab vedotin plus pembrolizumab (442)	17.2	31.5 (25.4–NR)	0.47 (0.38–0.58)	12.5 (10.4–16.6)	0.45 (0.38–0.54)	67.7% (296)	99.8% (439)	97.0% (427)
				Platinum-based chemotherapy (444)		16.1 (13.9–18.3)	Ref.	6.3 (6.2–6.5)	Ref.	44.1% (196)	98.6% (427)	95.6% (414)

AEs and TRAEs in the KEYNOTE-361 trial were all grade 3 or higher.

The OS, PFS, ORR, and AE outcomes in the JAVELIN Bladder 100 trial were all evaluated based on post-chemotherapy (between the start of randomization and the end of follow-up) data.

The median follow-up time for PFS in the CALGB 90601 trial was 46.0 (95% CI 29.2–68.1) months.

AEs, adverse events; BPC, best supportive care; CI, confidence interval; HD-MVAC, high-dose intensity MVAC; HR, hazard ratio; mOS, median overall survival; MVAC, methotrexate, vinblatine, adriamycin, and cisplatin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCT, randomized controlled trial; Ref, reference; TRAEs, treatment-related adverse events.

Table 2.

The summary of baseline characteristics included trails.

Trial	Regimen (no.)	Median age (range)	Age ⩾65, no. (%)	Male, no. (%)	White, no. (%)	mUC, no. (%)	LTUC, no. (%)	Visceral metastases, no. (%)	Liver metastasis, no. (%)	Cisplatin ineligibility, no. (%)	ECOG = 0, no. (%)	PD-L1 positive, no. (%)
EORTC 30987^a	PAX + GemPlat (312)	61 (27–81)	—	256 (82)	—	275 (88)	265 (85)	145 (47)	41 (13)	0	171 (55)	—
	GemPlat (314)	61 (32–79)	—	252 (81)	—	276 (88)	267 (85)	155 (49)	51 (16)	0	171 (54)	—
IMvigor130	ATEZO + GemPlat (451)	69 (62–75)	298 (66)	338 (75)	346 (77)	401 (89)	322 (71)	259 (57)	95 (21)	263 (58)	182 (40)	303 (67)
	ATEZO (362)	67 (62–74)	220 (61)	280 (77)	260 (72)	319 (88)	271 (75)	201 (56)	85 (23)	192 (53)	157 (43)	248 (68)
	GemPlat (400)	67 (61–73)	247 (62)	298 (75)	304 (76)	366 (92)	298 (74)	239 (60)	91 (23)	222 (56)	173 (43)	270 (68)
KEYNOTE-361	PEMBRO + GemPlat (351)	69 (62–75)	233 (66)	272 (78)	—	327 (93)	287 (82)	259 (74)	78 (22)	195 (56)	150 (43)	159 (45)
	PEMBRO (307)	68 (61–74)	198 (64)	228 (74)	—	291 (95)	242 (79)	239 (78)	65 (21)	170 (55)	134 (44)	160 (52)
	GemPlat (352)	69 (61–75)	333 (66)	262 (74)	—	328 (93)	270 (77)	252 (72)	74 (21)	196 (56)	168 (48)	158 (45)
JAVELIN Bladder 100	AVE + GemPlat (350)	68 (37–90)	221 (63)	266 (76)	232 (66)	—	244 (70)	191 (55)	43 (13)	147 (42)	213 (61)	189 (54)
	GemPlat (350)	69 (32–89)	243 (69)	275 (79)	238 (68)	—	269 (77)	191 (55)	44 (13)	122 (35)	211 (60)	169 (48)
DANUBE	DURVA (346)	67 (60–73)	209 (60)	249 (72)	278 (80)	334 (97)	284 (83)	285 (82)	—	149 (43)	170 (49)	209 (60)
	DURVA + TREME (342)	68 (60–73)	205 (60)	256 (75)	253 (74)	329 (96)	268 (78)	268 (78)	80 (23)	148 (43)	189 (55)	205 (60)
	GemPlat (344)	68 (60–73)	211 (61)	274 (80)	260 (76)	323 (94)	258 (75)	266 (77)	93 (27)	151 (44)	189 (55)	207 (60)
CALGB 90601^b	BEV + GemPlat (252)	—	62 (25)	199 (79)	229 (91)	—	183 (73)	174 (69)	0	0	145 (58)	—
	GemPlat (254)	—	69 (27)	198 (78)	235 (93)	—	192 (76)	174 (69)	0	0	130 (51)	—
C.N. Sternberg (2006)^a	MVAC (129)	62 (32–81)	—	107 (83)	—	—	108 (84)	47 (36)	13 (10)	0	52 (40)	—
	HD-MVAC (134)	61 (36–76)	—	105 (78)	—	—	120 (90)	37 (28)	14 (10)	0	51 (38)	—
CILAB	LTX + Cis (166)	64 (42–82)	—	139 (84)	—	151 (91)	124 (75)	—	30 (18)	0	71 (45)	—
	GemPlat (171)	64 (35–85)	—	138 (81)	—	151 (89)	131 (77)	—	35 (20)	0	70 (44)	—
CheckMate 901	NIVO + GemPlat (304)	65 (32–86)	154 (51)	236 (78)	211 (69)	261 (86)	235 (77)	—	64 (21)	0	162 (53)	111 (37)
	GemPlat (304)	65 (35–85)	156 (51)	234 (77)	225 (74%)	269 (89)	219 (72)	—	64 (21)	0	162 (53)	110 (36)
J. T. Roberts (2006)	MVAC (202)	63	—	160 (79)	197 (98)	141 (70)	—	99 (49)	—	0	—	—
	GemPlat (203)	63	—	160 (79)	197 (98)	127 (63)	—	93 (46)	—	0	—	—
EV-302	EV + PEMBRO (442)	69 (37–87)	298 (67)	344 (78)	308 (70)	421 (95)	305 (69)	318 (72)	100 (23)	198 (45)	223 (51)	254 (58)
	GemPlat (444)	69 (22–91)	309 (70)	336 (76)	290 (65)	420 (95)	339 (76)	318 (72)	99 (22)	210 (47)	215 (48)	254 (58)

The performance status of participants in the two trails was assessed using the WHO Performance Status.

The age stratification was divided at the threshold of 70 years in the CALGB 90601 trail.

ATEZO, atezolizumab; ATEZO + GemPlat, atezolizumab plus platinum-based chemotherapy; AVE + GemPlat, platinum-based chemotherapy plus avelumab maintenance; BEV + GemCis, bevacizumab plus gemcitabine–cisplatin; DURVA, durvalumab; DURVA + TREME, durvalumab plus tremelimumab; ECOG, Eastern Cooperative Oncology Group; EV + PEMBRO, enfortumab vedotin plus pembrolizumab; GemCis, gemcitabine–cisplatin; GemPlat, platinum-based chemotherapy (gemcitabine–cisplatin or gemcitabine-carboplatin); HD-MVAC, high-dose intensity MVAC; LTUC, lower-tract urothelial carcinoma; LTX + Cis, larotaxel plus cisplatin; mUC, metastatic urothelial carcinoma; MVAC, methotrexate, vinblatine, Adriamycin, and cisplatin; NIVO + GemPlat, nivolumab plus gemcitabine–cisplatin; PAX + GemPlat, paclitaxel plus gemcitabine–cisplatin; PD-L1, programmed death ligand 1; PEMBRO, pembrolizumab; PEMBRO + GemPlat, pembrolizumab plus platinum-based chemotherapy.

These studies were published between 2000 and 2024, with 9 RCTs being open-label. The median follow-up durations ranged from 11.8 months to 7.3 years, and the median age of the participants ranged from 61 to 69 years. A total of 2363 patients (31.1%) were either cisplatin-ineligible or cisplatin-eligible but received carboplatin due to investigator choice. Six trials (n = 5368) reported the PD-L1 expression status, with 3006 (56%) patients being PD-L1 positive.

The risk of bias assessment for each RCT was independently assessed using the RoB 2 tool (Supplemental Table 1). The quality assessment of the 17 RCTs indicated that all studies demonstrated a low risk of bias in domains regarding outcome measurement and the selection of reported results. Nonetheless, some concerns were identified in the randomization process and deviations from intended interventions in 14 trials, which contributed to a slightly elevated overall bias rating in these areas. One RCT was evaluated as high risk of bias due to the deviations from intended interventions.

Overall survival

Overall population

The NMA evaluated OS across 15 various treatment regimens and generated a corresponding network diagram (Supplemental Figure 1(a)). Compared to platinum-based chemotherapy, EV plus pembrolizumab (HR 0.47, 95% CrI 0.38–0.58), platinum-based chemotherapy plus avelumab maintenance (HR 0.76, 95% CrI 0.63–0.91), nivolumab plus gemcitabine–cisplatin (HR 0.78, 95% CrI 0.63–0.96), and atezolizumab plus platinum-based chemotherapy (HR 0.85, 95% CrI 0.73–0.99) were associated with significantly improved OS (Figure 2(a)). Although atezolizumab plus platinum-based chemotherapy showed an HR of 0.85, it did not surpass the prespecified final efficacy boundary for statistical significance in the final analysis, indicating no survival benefit in OS.²⁸ The league table further showed that EV plus pembrolizumab demonstrated a significantly better OS compared to platinum-based chemotherapy plus avelumab maintenance (HR 0.62, 95% CrI 0.47–0.82), and nivolumab plus gemcitabine–cisplatin (HR 0.60, 95% CrI 0.45–0.81; Supplemental Figure 2). According to the treatment ranking analysis, EV plus pembrolizumab had the highest likelihood of providing the maximal OS (SUCRA, 0.9999), followed by platinum-based chemotherapy plus avelumab maintenance, nivolumab plus gemcitabine–cisplatin (SUCRA: 0.8173 and 0.7681, respectively; Figure 2(b)).

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.

Subgroups based on cisplatin eligibility

Within the cisplatin-eligible setting, the NMA evaluated OS across 14 various treatment regimens. EV plus pembrolizumab (HR 0.53, 95% CrI 0.39–0.72) and nivolumab plus gemcitabine–cisplatin (HR 0.78, 95% CrI 0.63–0.96) demonstrated significantly more favorable OS compared to gemcitabine plus cisplatin (Figure 3(a)). The league table further indicated that EV plus pembrolizumab showed superior efficacy over nivolumab plus gemcitabine–cisplatin (HR 0.68, 95% CrI 0.47–0.99; Supplemental Figure 3). According to the treatment ranking analysis, EV plus pembrolizumab emerged as the most effective regimen (SUCRA, 0.9881).

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).

Within the cisplatin-ineligible setting, the NMA assessed OS across nine different treatment regimens. EV plus pembrolizumab (HR 0.43, 95% CrI 0.31–0.59) and gemcitabine–carboplatin plus avelumab maintenance (HR 0.70, 95% CrI 0.52–0.94) showed superior efficacy compared to gemcitabine plus carboplatin (Figure 3(b)). The league table showed that EV plus pembrolizumab demonstrated a significantly better OS compared to gemcitabine–carboplatin plus avelumab maintenance (HR 0.61, 95% CrI 0.40–0.95; Supplemental Figure 4). Treatment ranking analysis confirmed that EV plus pembrolizumab was the most effective option (SUCRA, 0.9880).

Subgroups based on PD-L1 status

For PD-L1-positive patients, the NMA evaluated OS across 10 treatment regimens. Among them, EV plus pembrolizumab (HR 0.49, 95% CrI 0.37–0.66), platinum-based chemotherapy plus avelumab maintenance (HR 0.69, 95% CrI 0.53–0.90), and durvalumab plus tremelimumab (HR 0.75, 95% CrI 0.60–0.94) were associated with more favorable OS compared to platinum-based chemotherapy (Figure 3(c)). The league table indicated that EV plus pembrolizumab significantly outperformed durvalumab plus tremelimumab (HR 0.65, 95% CrI 0.45–0.94; Supplemental Figure 5). According to the treatment ranking analysis, EV plus pembrolizumab was the most effective regimen in this setting (SUCRA, 0.9896).

In the PD-L1-negative population, the NMA assessed OS across 10 treatment regimens. Only EV plus pembrolizumab (HR 0.44, 95% CrI 0.31–0.62) was associated with a more favorable OS compared to platinum-based chemotherapy (Figure 3(d)). The league table showed that EV plus pembrolizumab outperformed any other regimens and ranked as the most effective option (SUCRA, 0.9990) in this population (Supplemental Figure 6).

Other subgroups

The NMA results for OS in additional subgroup analyses based on age, gender, race, primary tumor location, performance status, and metastatic organs are presented in Supplemental Table 2. Across all subgroups, EV plus pembrolizumab consistently emerged as the most effective option.

Progression-free survival

The NMA evaluated PFS across 12 treatment regimens and generated a corresponding network diagram (Supplemental Figure 1(b)). Compared to platinum-based chemotherapy, EV plus pembrolizumab (HR 0.45, 95% CrI 0.38–0.54), platinum-based chemotherapy plus avelumab maintenance (HR 0.54, 95% CrI 0.46–0.64), nivolumab plus gemcitabine–cisplatin (HR 0.72, 95% CrI 0.59–0.88), bevacizumab plus gemcitabine–cisplatin (HR 0.77, 95% CrI 0.63–0.95), pembrolizumab plus platinum-based chemotherapy (HR 0.78, 95% CrI 0.65–0.93), and atezolizumab plus platinum-based chemotherapy (HR 0.82, 95% CrI 0.70–0.96) were associated with significantly improved PFS (Figure 4(a)). The league table showed that EV plus pembrolizumab demonstrated a significantly better PFS compared to other regimens, except platinum-based chemotherapy plus avelumab maintenance (Supplemental Figure 7). According to the treatment ranking analysis, EV plus pembrolizumab had the highest likelihood of providing the maximal PFS (SUCRA, 0.9936), followed by platinum-based chemotherapy plus avelumab maintenance (SUCRA, 0.9136), nivolumab plus gemcitabine–cisplatin (SUCRA, 0.7377), and others (Figure 4(b)). The subgroup analysis indicated that EV plus pembrolizumab remained the best choice for improving PFS across different subgroups (Supplemental Table 3).

Figure 4.

The NMA results of PFS. (a) The forest plot and (b) the cumulative probability ranking plot of the overall population.

Overall response rate

The NMA evaluated ORR across 15 treatment regimens. Compared to platinum-based chemotherapy, platinum-based chemotherapy plus avelumab maintenance (OR 4.29, 95% CrI 2.25–7.73), EV plus pembrolizumab (OR 2.60, 95% CrI 1.96–3.38), nivolumab plus gemcitabine–cisplatin (OR 1.82, 95% CrI 1.30–2.48), pembrolizumab plus platinum-based chemotherapy (OR 1.50, 95% CrI 1.10–2.00), and paclitaxel plus gemcitabine–cisplatin (OR 1.63, 95% CrI 1.17–2.20) were associated with a significantly higher ORR (Supplemental Figure 8(a)). According to the treatment ranking analysis, platinum-based chemotherapy plus avelumab maintenance was most likely to achieve the best ORR (SUCRA, 0.9927), followed by EV plus pembrolizumab (SUCRA, 0.9294), nivolumab plus gemcitabine–cisplatin (SUCRA, 0.8138), and others (Supplemental Figure 8(b)).

Adverse events

The NMA evaluated the TRAEs (Supplemental Figure 9) across 8 treatment regimens and TRAEs with grade ⩾3 (Supplemental Figure 10) across 10 treatment regimens. Based on the ranking results, atezolizumab monotherapy was likely to be the safest treatment option in terms of both all-grade TRAEs (SUCRA, 0.9969; Supplemental Figure 9(b)) and grade 3 or higher TRAEs (SUCRA, 0.9993; Supplemental Figure 10(b)). To note, the JAVELIN Bladder 100 trial did not account for the impact of chemotherapy prior to maintenance therapy, and the ranking results should be interpreted with caution. Among the other regimens, EV plus pembrolizumab had the highest incidence of all-grade TRAEs (SUCRA, 0.1681; Supplemental Figure 9(b)). However, this combination therapy was associated with a significantly lower toxicity in terms of grade 3 or higher TRAEs compared to platinum-based chemotherapy (OR 0.60, 95% CrI 0.45–0.78; Supplemental Figure 10(a)). Among the treatments with OS benefit in the overall population, nivolumab plus gemcitabine–cisplatin showed a trend of better safety than EV plus pembrolizumab in terms of all-grade TRAEs (OR 0.66, 95% CrI 0.28–1.29; Supplemental Figure 9(a)). However, EV plus pembrolizumab showed significantly reduced grade 3 or higher TRAEs than nivolumab plus gemcitabine–cisplatin (OR 0.41, 95% CrI 0.21–0.72; Supplemental Figure 10(a)). The results of pairwise comparisons of all-grade TRAEs and grade 3 or higher TRAEs among different treatment regimens are provided in Supplemental Figures 9 and 10.

Discussion

The development of ICIs and ADCs has revolutionized the first-line treatment paradigm for patients with la/mUC. Recently, landmark clinical trials, such as IMvigor 130,^28,29 JAVELIN Bladder 100,^30–32 CheckMate-901,¹⁷ and EV-302,²² have reported their findings, providing more potent treatment options for this setting. Given the lack of direct head-to-head comparisons of existing treatment strategies, it is essential to conduct an NMA to evaluate the efficacy and safety of different regimens. In this study, we systematically reviewed 17 articles, including 11 phase III RCTs with 8770 participants, and indirectly compared the safety and efficacy of different options through NMA. Our findings indicated that the combination of EV plus pembrolizumab represented the most effective first-line treatment for la/mUC across various patient subgroups, with an acceptable safety profile.

The observed effectiveness of EV plus pembrolizumab combination therapy likely stems from its action on two distinct pathways: EV targets Nectin-4, while pembrolizumab, as an ICI, blocks PD-1. Previous studies indicated that Nectin-4 expression in bladder cancer tissue is approximately 30%–60%, and it is generally associated with poor prognosis, and UC patients with high Nectin-4 expression face higher risks of progression and cancer-specific mortality.^39–42 However, response to combination therapy does not appear to differ based on Nectin-4 expression levels.⁴³ The potential mechanism contributing to the synergistic antitumor effect may be that EV enhances the efficacy of ICIs by modulating the tumor microenvironment. ADCs exhibited immunomodulatory properties by promoting dendritic cell activation and inducing immunogenic cell death, thereby enhancing T-cell infiltration into the tumor microenvironment and amplifying the overall immune response.⁴⁴ The presence of tumor-infiltrating lymphocytes within the tumor microenvironment was also considered a robust predictor of response to immunotherapy, and enabled the reactivation of suppressed antitumor T cells, facilitating an effective immune response against cancer cells.⁴⁵ Taken together, these results highlight the synergistic potential of ADCs in combination with ICIs, reinforcing their value as a promising adjunct to immunotherapy.

Although EV plus pembrolizumab showed promising efficacy and safety as a first-line treatment for la/mUC, it is not suitable for all patients. Clinical practice should account for individual baseline conditions and comorbidities. Several specific toxicities were reported to be associated with EV, including rash, peripheral neuropathy, ocular disorders, and hyperglycemia. For pembrolizumab, severe dermatologic reactions, pneumonia, and hepatitis were the most common grade 3 or higher AEs of concern. Therefore, caution is advised when administering EV in combination with pembrolizumab, especially for patients with uncontrolled diabetes, grade ⩾2 peripheral neuropathy, or severe pre-existing dermatologic conditions.^22,46 Although cost-effectiveness was not assessed in this study, it represents an essential dimension of treatment selection and warrants further investigation in future research.

For patients unable to receive EV, platinum-based chemotherapy plus avelumab maintenance and nivolumab plus gemcitabine–cisplatin are effective alternatives. However, these options also have limitations. Avelumab is only suitable for patients without disease progression following first-line chemotherapy. It is estimated that approximately half of the patients with la/mUC may not receive maintenance due to ineligibility or physician/patient choice.¹⁶ Similarly, Nivolumab is limited to cisplatin-eligible patients, yet more than 50% of la/mUC patients were cisplatin-ineligible.⁶ Such limitations point to an urgent need for the development of precision medicine approaches to optimize first-line therapy in la/mUC.

The role of PD-L1 as a predictive biomarker in first-line treatments for la/mUC patients remains uncertain. Many studies have shown its association with treatment response, but large phase III trials have yet to validate its predictive power.^12,14,33 Our meta-analysis showed that multiple ICI-based combination therapies had superior efficacy compared to platinum-based chemotherapy in the PD-L1-positive population, while only EV plus pembrolizumab was associated with significantly improved OS compared to platinum-based chemotherapy in the PD-L1-negative population. These findings indicated that PD-L1 might have a role in treatment selection in previously untreated la/mUC patients. However, variability in PD-L1 scoring systems and antibodies used across the included studies increases the complexity of integration. Excluding patients from potentially beneficial treatments based solely on PD-L1 expression might result in some patients being deprived of effective therapy. Combining novel biomarkers, such as circulating tumor DNA status, may help optimize patient selection for first-line treatments.^47,48

It is important to acknowledge the heterogeneity in patient populations across different clinical trials. For instance, the IMvigor130 trial focused on cisplatin-ineligible patients who received carboplatin-based chemotherapy, whereas the CheckMate 901 trial enrolled only cisplatin-eligible patients.^17,29 By contrast, the EV302 trial included both cisplatin-eligible and cisplatin-ineligible patients. In addition, the JAVELIN Bladder 100 trial exclusively enrolled patients who had achieved at least stable disease following platinum-based chemotherapy, which sets it apart from other studies.^15,22 These variations in inclusion criteria may impact treatment outcomes and affect the generalizability of the results. Cisplatin-ineligible patients, in particular, may present distinct prognostic features and therapeutic responses compared to cisplatin-eligible populations, influencing overall treatment efficacy. To address this concern, we conducted subgroup analyses based on the clinical context of different patient populations to minimize the impact of population heterogeneity on our analytical results. Using platinum-based chemotherapy as the reference group for ranking, the results demonstrated that EV combined with pembrolizumab remained the optimal choice across various subgroups. However, when applying these findings in clinical practice, it is crucial to consider the inherent differences among patient populations. This heterogeneity across different clinical trials further underscores the importance of conducting head-to-head randomized clinical trials with more comprehensive inclusion criteria.

This study has several limitations. First, our assessment of various treatment options relied on indirect comparisons, which introduce a degree of uncertainty. Direct head-to-head trials are needed to provide more definitive conclusions. In addition, the included studies spanned a broad time period, during which advancements in technology and changes in care standards may have influenced patient outcomes. Heterogeneity in baseline characteristics and study designs also poses challenges, as we have mentioned above. Moreover, some trials had immature OS data, which could evolve with further analysis. Despite these limitations, this study offers a comprehensive evaluation of first-line treatment options for la/mUC patients and highlights the need for ongoing research to refine these strategies.

Conclusion

To the best of our knowledge, this NMA provides the most up-to-date comparison of first-line treatment options for la/mUC and its subgroups, with EV plus pembrolizumab emerging as the optimal regimen for most patients. The ongoing integration of novel therapies like ADCs with ICIs offers hope for improved outcomes, though individualized treatment strategies based on patient characteristics and biomarker profiles remain crucial to maximize the benefits of these advances.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251357527 – Supplemental material for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials

Supplemental material, sj-docx-1-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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sj-docx-2-tam-10.1177_17588359251357527 – Supplemental material for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials

Supplemental material, sj-docx-2-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-10-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-11-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-12-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-3-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-4-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-5-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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Supplemental material, sj-eps-7-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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sj-eps-8-tam-10.1177_17588359251357527 – Supplemental material for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials

Supplemental material, sj-eps-8-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

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sj-eps-9-tam-10.1177_17588359251357527 – Supplemental material for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials

Supplemental material, sj-eps-9-tam-10.1177_17588359251357527 for First-line systemic therapy in patients with metastatic or locally advanced urothelial carcinoma: a systematic review and network meta-analysis of randomized controlled trials by Yandong Xie, Haoyang Liu, Yanfeng Tang, Yaowen Zhang, Nanwei Xu, Fengnian Zhao, Jinge Zhao, Guangxi Sun, Zhenhua Liu, Pengfei Shen, Hao Zeng and Junru Chen in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Hao Zeng

Junru Chen

Supplemental material

Supplemental material for this article is available online.

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