帕博利珠单抗联合化疗与单纯化疗治疗转移性非小细胞肺癌时组织肿瘤突变负荷及突变状态与临床结局的相关性

Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC.

作者信息

Garassino Marina C, Gadgeel Shirish, Novello Silvia, Halmos Balazs, Felip Enriqueta, Speranza Giovanna, Hui Rina, Garon Edward B, Horinouchi Hidehito, Sugawara Shunichi, Rodriguez-Abreu Delvys, Reck Martin, Cristescu Razvan, Aurora-Garg Deepti, Loboda Andrey, Lunceford Jared, Kobie Julie, Ayers Mark, Piperdi Bilal, Pietanza M Catherine, Paz-Ares Luis

机构信息

Section of Hematology/Oncology, Thoracic Oncology program, University of Chicago, Chicago, Illinois, and IRCCS Istituto Nazionale dei Tumori, Milano.

Division of Hematology/Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, Michigan.

出版信息

JTO Clin Res Rep. 2022 Nov 8;4(1):100431. doi: 10.1016/j.jtocrr.2022.100431. eCollection 2023 Jan.

INTRODUCTION

We evaluated tissue tumor mutational burden (tTMB) and mutations in and as biomarkers for outcomes with pembrolizumab plus platinum-based chemotherapy (pembrolizumab-combination) for NSCLC among patients in the phase 3 KEYNOTE-189 (ClinicalTrials.gov, NCT02578680; nonsquamous) and KEYNOTE-407 (ClinicalTrials.gov, NCT02775435; squamous) trials.

METHODS

This retrospective exploratory analysis evaluated prevalence of high tTMB and , and mutations in patients enrolled in KEYNOTE-189 and KEYNOTE-407 and the relationship between these potential biomarkers and clinical outcomes. tTMB and , , and mutation status was assessed using whole-exome sequencing in patients with available tumor and matched normal DNA. The clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mutations/exome.

RESULTS

Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, = 293; KEYNOTE-407, = 312) and matched normal DNA, no association was found between continuous tTMB score and overall survival (OS) or progression-free survival for pembrolizumab-combination (Wald test, one-sided > 0.05) or placebo-combination (Wald test, two-sided > 0.05) in patients with squamous or nonsquamous histology. Pembrolizumab-combination improved outcomes for patients with tTMB greater than or equal to 175 compared with tTMB less than 175 mutations/exome in KEYNOTE-189 (OS, hazard ratio = 0.64 [95% confidence interval (CI): 0.38‒1.07] and 0.64 [95% CI: 0.42‒0.97], respectively) and KEYNOTE-407 (OS, hazard ratio = 0.74 [95% CI: 0.50‒1.08 and 0.86 [95% CI: 0.57‒1.28], respectively) versus placebo-combination. Treatment outcomes were similar regardless of , or mutation status.

CONCLUSIONS

These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB, or mutation status as a biomarker for this regimen.

引言

我们在3期KEYNOTE-189（ClinicalTrials.gov，NCT02578680；非鳞状）和KEYNOTE-407（ClinicalTrials.gov，NCT02775435；鳞状）试验中，评估了组织肿瘤突变负荷（tTMB）以及和基因的突变，将其作为帕博利珠单抗联合铂类化疗（帕博利珠单抗联合方案）用于非小细胞肺癌（NSCLC）患者疗效的生物标志物。

方法

这项回顾性探索性分析评估了KEYNOTE-189和KEYNOTE-407试验中入组患者的高tTMB以及、和基因突变的发生率，以及这些潜在生物标志物与临床结局之间的关系。在有可用肿瘤组织及匹配正常DNA的患者中，使用全外显子组测序评估tTMB以及、、基因突变状态。使用预先设定的175个突变/外显子的切点评估tTMB的临床效用。

结果

在有可评估全外显子组测序数据用于评估tTMB（KEYNOTE-189， = 293；KEYNOTE-407， = 312）及匹配正常DNA的患者中，对于鳞状或非鳞状组织学患者，连续tTMB评分与帕博利珠单抗联合方案（Wald检验，单侧＞ 0.05）或安慰剂联合方案（Wald检验，双侧＞ 0.05）的总生存期（OS）或无进展生存期之间均未发现关联。在KEYNOTE-189中，与tTMB低于175个突变/外显子相比，tTMB大于或等于175的患者接受帕博利珠单抗联合方案时，OS的风险比分别为0.64[95%置信区间（CI）：0.38‒1.07]和0.64[95%CI：0.42‒0.97]；在KEYNOTE-407中，与安慰剂联合方案相比，OS的风险比分别为0.74[95%CI：0.50‒1.08]和0.86[95%CI：0.57‒1.28]。无论、或基因突变状态如何，治疗结局相似。