Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2024-10-30 DOI:10.1158/1078-0432.CCR-23-3518

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.

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肿瘤突变负荷和PD-L1与Pembrolizumab联合或不联合化疗与化疗对晚期尿路上皮癌疗效的关系

目的：三臂III期KEYNOTE-361研究未达到无进展生存期（PFS）或总生存期（OS）的双重主要终点。这项预设的探索性分析评估了肿瘤突变负荷（TMB）和PD-L1联合阳性评分（CPS）与临床结果的关系：TMB和PD-L1 CPS分别通过全外显子组测序和PD-L1 IHC 22C3 pharmDx测定。使用逻辑回归[客观反应率(ORR)]和Cox比例危险度回归模型（PFS和OS）评估各治疗组的相关性；计算单侧（pembrolizumab单药治疗；pembrolizumab加化疗）和双侧（化疗）名义P值。显著性预设为α = 0.05，不进行多重性调整。疗效按照预设的175个突变/外显子组（TMB）和CPS 10（PD-L1）临界值进行评估：在993名接受治疗的患者中，分别有820人（82.6%）和993人（100%）拥有可评估的TMB和CPS数据。连续 TMB 与 Pembrolizumab 单药治疗的 ORR、PFS 和 OS 呈正相关（单侧 P <0.001、P <0.001、P = 0.007）；Pembrolizumab 加化疗的 PFS 和 OS 呈正相关（单侧 P = 0.007、P = 0.010）；单独化疗的 OS 呈正相关（双侧 P = 0.040）。连续PD-L1 CPS显示了pembrolizumab单药治疗与ORR和PFS预期相关的证据。TMB≥175个突变/外显子组和PD-L1 CPS≥10的亚组与单用pembrolizumab或单用化疗相比，PFS和OS改善幅度最大：这些数据表明，TMB可预测晚期尿路上皮癌患者对pembrolizumab单药或联合化疗的反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

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.