Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma
Fléchon, Aude (Centre Léon Bérard (França))
Morales-Barrera, Rafael (Vall d'Hebron Institut d'Oncologia)
Powles, Thomas (Queen Mary University of London)
Alva, Ajjai (University of Michigan Health System)
Özgüroğlu, Mustafa (Istanbul University-Cerrahpaşa)
Csoszi, Tibor (Hetényi Géza Hospital (Szolnok, Hongria))
Loriot, Yohann (Université Paris-Saclay)
Rodriguez-Vida, Alejo (Institut Hospital del Mar d'Investigacions Mèdiques)
Géczi, Lajos (Medical Oncology Center and the National Tumor Biology Laboratory (Budapest, Hongria))
Cheng, Susanna Y. (Odette Cancer Centre (Toronto, Canadà))
Fradet, Yves (CHU de Québec-Université Laval)
Oudard, Stephane (University Paris Cité)
Vulsteke, Christof (University of Antwerp)
Gunduz, Seyda (Mayo Clinic (Scottsdale, Estats Units d'Amèrica))
Mamtani, Ronac (University of Pennsylvania)
Yu, Evan Y. (Fred Hutchinson Cancer Center (Seattle, Washington))
Montesa Pino, Alvaro (Universitario Virgen de la Victoria (Màlaga, Andalusia))
Anido, Urbano (Complejo Hospitalario Universitario de Santiago de Compostela)
Sendur, Mehmet A.N. (Ankara Yıldırım Beyazıt University Faculty of Medicine)
Gravis, Gwenaelle (Paoli-Calmettes Institute (Marseille, França))
Révész, János (Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital (Miskolc, Hongria))
Kostorov, Vladimir (Ulitsa Savushkina (Saint Petersburg, Russia))
Huillard, Olivier (Université de Paris Cité)
Ma, Junshui (Merck & Co., Inc. (Rahway, New Jersey))
Rajasagi, Mohini (Merck & Co., Inc. (Rahway, New Jersey))
Vajdi, Amir (Merck & Co., Inc. (Rahway, New Jersey))
Lunceford, Jared (Merck & Co., Inc. (Rahway, New Jersey))
Cristescu, Razvan (Merck & Co., Inc. (Rahway, New Jersey))
Imai, Kentaro (Merck & Co., Inc. (Rahway, New Jersey))
Homet Moreno, Blanca (Merck & Co., Inc. (Rahway, New Jersey))
Matsubara, Nobuaki (National Cancer Center Hospital East (Chiba, Japó))
Universitat Autònoma de Barcelona

Data:	2024
Resum:	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. 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). 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. These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Clinical cancer research, Vol. 30 (october 2024) , p. 5353-5364, ISSN 1557-3265

DOI: 10.1158/1078-0432.CCR-23-3518
PMID: 39475359

12 p, 1.5 MB

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