Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.
Aude Fléchon, Rafael Morales-Barrera, Thomas Powles, Ajjai Alva, Mustafa Özgüroğlu, Tibor Csöszi, Yohann Loriot, Alejo Rodriguez-Vida, Lajos Géczi, Susanna Y Cheng, Yves Fradet, Stéphane Oudard, Christof Vulsteke, Seyda Gunduz, Ronac Mamtani, Evan Y Yu, Alvaro Montesa Pino, Urbano Anido, Mehmet A N Sendur, Gwenaelle Gravis, János Révész, Vladimir Kostorov, Olivier Huillard, Junshui Ma, Mohini Rajasagi, Amir Vajdi, Jared Lunceford, Razvan Cristescu, Kentaro Imai, Blanca Homet Moreno, Nobuaki Matsubara
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引用次数: 0
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.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.