Association of tumor mutational burden and PD-L1 with the efficacy of pembrolizumab with or without chemotherapy versus chemotherapy in advanced urothelial carcinoma

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Fléchon, Aude
• dc.contributor.author Rodriguez-Vida, Alejo
• dc.contributor.author Matsubara, Nobuaki
• dc.date.accessioned 2025-10-27T16:09:48Z
• dc.date.available 2025-10-27T16:09:48Z
• dc.date.issued 2024
• dc.date.updated 2025-10-27T16:09:47Z
• dc.description.abstract Purpose: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes. Patients and methods: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1). Results: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone. Conclusions: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.
• dc.format.mimetype application/pdf
• dc.identifier.citation Fléchon A, Morales-Barrera R, Powles T, et al. Association of tumor mutational burden and PD-L1 with the efficacy of pembrolizumab with or without chemotherapy versus chemotherapy in advanced urothelial carcinoma. Clin Cancer Res. 2024 Dec 2;30(23):5353-64. DOI: 10.1158/1078-0432.CCR-23-3518
• dc.identifier.doi http://dx.doi.org/10.1158/1078-0432.CCR-23-3518
• dc.identifier.issn 1078-0432
• dc.identifier.uri http://hdl.handle.net/10230/71665
• dc.language.iso eng
• dc.publisher American Association for Cancer Research (AACR)
• dc.relation.ispartof Clinical Cancer Research. 2024;30(23):5353-64
• dc.rights © 2024 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.other Aparell urinari--Càncer
• dc.subject.other Quimioteràpia
• dc.title Association of tumor mutational burden and PD-L1 with the efficacy of pembrolizumab with or without chemotherapy versus chemotherapy in advanced urothelial carcinoma
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion