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. 2023 Mar 26;30(4):3637-3647.
doi: 10.3390/curroncol30040277.

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC)

Lisa Bloudek  1 , Phoebe Wright  2 , Caroline McKay  3 , Christina Louise Derleth  2 , Jennifer Susan Lill  2 , Enrique Lenero  3 , Zsolt Hepp  2 , Scott David Ramsey  1   4   5 , Sean D Sullivan  1   4   5 , Beth Devine  4
Affiliations

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC)

Lisa Bloudek et al. Curr Oncol. .

Abstract

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

Keywords: bladder cancer; network meta-analysis; oncology; overall survival; standard of care; systematic literature review.

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Conflict of interest statement

This study was sponsored by Seagen Inc. P.W., C.L.D., J.S.L. and Z.H. are employees of, and hold stock/stock options in, Seagen Inc. L.B. is an employee of Curta Inc. C.M. and E.L. are employees of Astellas Pharma Global Development, Inc. C.M. also holds stock/stock options in J&J and Merck. L.B., S.D.R., S.D.S. and B.D. received support from Seagen for this research. S.D.R. has previously performed paid consulting work for AstraZeneca, Bayer, Biovica, Flatiron Health, Genentech, GRAIL, Merck, and Seagen Inc.; has received institutional research funding from Bayer and Genentech/Roche; and travel expenses from Bayer. Curta Inc. and Astellas Pharma Global Development, Inc. received funding from Seagen Inc. for this research.

Figures

Figure 1
Figure 1
Network diagram and HR for OS by treatment network for the cis-eligible/mixed network. Abbreviations: Atezo, atezolizumab; cis, cisplatin; CrI, credible interval; ddGemCis, dose-dense gemcitabine + cisplatin; ddMVAC, dose-dense methotrexate + vinblastine + doxorubicin + cisplatin; DUR, durvalumab; DXT, docetaxel; GemPlat, gemcitabine + platinum (cisplatin or carboplatin); HR, hazard ratio; MVAC, methotrexate + vinblastine + doxorubicin + cisplatin; OS, overall survival; PAX, paclitaxel; Pembro, pembrolizumab; TREME, tremelimumab.
Figure 2
Figure 2
Network diagram and HR for OS by treatment network for the cis-ineligible (wide) network. Abbreviations: Atezo, atezolizumab; cis, cisplatin; CrI, credible interval; Gem, gemcitabine; GemCarbo, gemcitabine + carboplatin; HR, hazard ratio; OS, overall survival; OXP, oxaliplatin; Pembro, pembrolizumab; VFL, vinflunine.
Figure 3
Figure 3
Network diagram and HR for OS by treatment network for the cis-ineligible (strict) network. Abbreviations: Cis, cisplatin; CrI, credible interval; DUR, durvalumab; Gem, gemcitabine; GemCarbo, gemcitabine + carboplatin; HR, hazard ratio; OXP, oxaliplatin; OS, overall survival; TREME, tremelimumab; VFL, vinflunine.
Figure 4
Figure 4
Network diagram and HR for PFS by treatment network for the cis-eligible/mixed network. Abbreviations: Cis, cisplatin; CrI, credible interval; ddGemCis, dose-dense gemcitabine + cisplatin; ddMVAC, dose-dense methotrexate + vinblastine + doxorubicin + cisplatin; DUR, durvalumab; DXT, docetaxel; GemPlat, gemcitabine + platinum (cisplatin or carboplatin); HR, hazard ratio; MVAC, methotrexate + vinblastine + doxorubicin + cisplatin; PAX, paclitaxel; Pembro, pembrolizumab; PFS, progression-free survival; TREME, tremelimumab.
Figure 5
Figure 5
Network diagram and HR for PFS by treatment network for the cis-ineligible (wide) network. Abbreviations: Atezo, atezolizumab; cis, cisplatin; CrI, credible interval; Gem, gemcitabine; GemCarbo, gemcitabine + carboplatin; HR, hazard ratio; M-CAVI, methotrexate + carboplatin + vinblastine; OXP, oxaliplatin; Pembro, pembrolizumab; PFS, progression-free survival; VFL, vinflunine.
Figure 6
Figure 6
Network diagram and HR for PFS by treatment network for the cis-ineligible (strict) network. Abbreviations: CrI, credible interval; Gem, gemcitabine; GemCarbo, gemcitabine + carboplatin; HR, hazard ratio; M-CAVI, methotrexate + carboplatin + vinblastine; OXP, oxaliplatin; PFS, progression-free survival; VFL, vinflunine.
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