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.

中文翻译：

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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在晚期尿路上皮癌中的疗效的相关性


目的：三臂 III 期 KEYNOTE-361 研究未达到一线帕博利珠单抗联合化疗与化疗治疗晚期尿路上皮癌的无进展生存期 （PFS） 或总生存期 （OS） 的双重主要终点。这项预先指定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） 与临床结果的相关性。患者和方法： 分别通过全外显子组测序和 PD-L1 IHC 22C3 pharmDx 测定 TMB 和 PD-L1 CPS。使用 logistic 回归 [客观缓解率 （ORR）] 和 Cox 比例风险回归模型 （PFS 和 OS） 评估每个治疗组的相关性;计算单侧 （pembrolizumab 单药治疗;pembrolizumab 加化疗） 和双侧 （化疗） 名义 P 值。显着性预先指定为 α = 0.05，无需调整多重性。通过 175 个突变/外显子组 （TMB） 和 CPS 10 （PD-L1） 的预先设定临界值评估疗效。结果： 在 993 例接受治疗的患者中，820 例 （82.6%） 和 993 例 （100%） 分别有可评估的 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 和 P = 0.007）;帕博利珠单抗联合化疗的 PFS 和 OS （单侧 P = 0.007 和 P = 0.010）;和单独化疗的 OS （双侧 P = 0.040）。连续 PD-L1 CPS 显示 pembrolizumab 单药治疗的预期 ORR 和 PFS 相关证据。与单独化疗相比，TMB ≥175 突变/外显子组和 PD-L1 CPS ≥10 亚组单独使用帕博利珠单抗或化疗的 PFS 和 OS 改善最高。 结论： 这些数据表明，TMB 可能预测晚期尿路上皮癌患者对单独使用 pembrolizumab 或联合化疗的反应。