JAMA Netw Open. 2026 Jun 1;9(6):e2614764. doi: 10.1001/jamanetworkopen.2026.14764.
ABSTRACT
IMPORTANCE: Antibody-drug conjugates (ADCs), including enfortumab vedotin, disitamab vedotin, and sacituzumab govitecan, are altering the therapeutic landscape for locally advanced or metastatic urothelial carcinoma (la/mUC). Comprehensive comparative evidence evaluating their translation in the clinical setting and modifying clinical covariates is required.
OBJECTIVE: To synthesize multidimensional evidence from interventional and observational settings to evaluate clinical outcomes, define the evolving therapeutic positioning of enfortumab vedotin, disitamab vedotin, and sacituzumab govitecan, and identify drivers of heterogeneity through meta-regression.
DATA SOURCES: PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar were searched from database inception to October 23, 2025.
STUDY SELECTION: Interventional and observational studies of adults with la/mUC treated with enfortumab vedotin, disitamab vedotin, or sacituzumab govitecan.
DATA EXTRACTION AND SYNTHESIS: Independent reviewers extracted data following PRISMA guidelines. A rigorous metadata deduplication algorithm prevented patient double-counting. Random-effects models pooled data. Bayesian network meta-analysis (NMA) used reconstructed individual patient data. Inverse-variance weighted meta-regression assessed clinical covariates.
MAIN OUTCOMES AND MEASURES: Primary outcomes were disease control rate, objective response rate (ORR), and clinical complete response.
RESULTS: Forty independent studies involving 6085 patients were included. For enfortumab vedotin monotherapy, the pooled ORR was 43.9% (95% CI, 40.4%-47.5%) in interventional studies and 44.6% (95% CI, 41.0%-48.2%) in observational cohorts. For enfortumab vedotin plus pembrolizumab, interventional cohorts were associated with a pooled ORR of 67.5% (95% CI, 63.5%-71.3%) overall and 65.4% (95% CI, 60.0%-70.5%) in cisplatin-ineligible patients. Furthermore, disitamab vedotin plus programmed cell death protein 1 (PD-1) inhibitors was associated with an ORR of 74.7% (95% CI, 69.4%-79.4%) in interventional trials and 61.7% (95% CI, 52.6%-70.1%) observationally. Meta-regression identified prior PD-1/L1 exposure (β = -0.071; P = .003) and treatment regimen (β = -0.890; P < .001) as factors associated with primary response. Notably, the pure randomized clinical trial network meta-analysis of first-line treatments for cisplatin-ineligible patients revealed that enfortumab vedotin monotherapy was associated with a statistically significant overall survival advantage over chemotherapy (HR, 0.50; 95% CI, 0.29-0.86; posterior probability >99%).
CONCLUSIONS AND RELEVANCE: In this meta-analysis of ADCs for la/mUC, enfortumab vedotin-based regimens were associated with robust outcomes across clinical settings, and disitamab vedotin combined with immunotherapy was associated with potent clinical activity. Meta-regression indicated that prior immunotherapy exposure and hepatic tumor burden were associated with attenuated treatment responses.
PMID:42223943 | DOI:10.1001/jamanetworkopen.2026.14764
