Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
JAMA Oncol. 2022 Aug 1;8(8):1160-1168. doi: 10.1001/jamaoncol.2022.1981.
Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC).
To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022.
Treatment with PD-1/PD-L1 inhibition without chemotherapy.
Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.
These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.
虽然肿瘤突变负担（TMB）已被探索作为实体瘤免疫治疗疗效的潜在生物标志物，但在非小细胞肺癌（NSCLC）患者中，哪种最佳 TMB 阈值能最好地区分免疫检查点抑制剂治疗的改善结局，仍缺乏共识。
确定在 NSCLC 患者中，随着临床相关程序性死亡配体 1（PD-L1）水平的升高，TMB 水平与免疫治疗疗效之间的关联。
设计、地点和参与者：这项多中心队列研究纳入了在丹娜-法伯癌症研究所（DFCI）、纪念斯隆凯特琳癌症中心（MSKCC）和 Stand Up To Cancer（SU2C）/马克基金会数据集中接受免疫治疗的晚期 NSCLC 患者，这些患者接受了 PD-1 或 PD-L1 抑制治疗。从 2013 年 9 月至 2020 年 9 月，收集了患者的临床病理和基因组数据。数据分析于 2021 年 11 月至 2022 年 2 月进行。
接受 PD-1/PD-L1 抑制治疗，不接受化疗。
TMB 水平与客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）的关系。
在接受 PD-1/PD-L1 阻断治疗的 1552 例晚期 NSCLC 患者的整个队列中，中位（范围）年龄为 66（22-92）岁，830 例（53.5%）为女性，1347 例（86.8%）患有非鳞状组织学特征的癌症。作为 TMB 的函数对 ORR 进行回归树建模，在发现队列（MSKCC）中确定了 2 个 TMB 分组，定义为低 TMB（≤19.0 个突变/兆碱基）和高 TMB（>19.0 个突变/兆碱基），这与发现队列和 2 个独立队列（DFCI 和 SU2C/马克基金会）中的 ORR、PFS 和 OS 的改善有关。这些 TMB 水平也与 PD-L1 肿瘤比例评分亚组中免疫治疗结局的显著改善相关，亚组为<1%、1%至 49%和 50%或更高。在高 TMB 且 PD-L1 表达为 50%或更高的患者中，PD-1/PD-L1 抑制的 ORR 高达 57%，而在低 TMB 且 PD-L1 表达<1%的患者中，ORR 低至 8.7%。多重免疫荧光和转录组谱分析显示，高 TMB 水平与 CD8 阳性、PD-L1 阳性 T 细胞浸润增加、肿瘤和免疫细胞上 PD-L1 表达增加以及先天和适应性免疫反应特征的上调有关。
这些发现表明，TMB 水平的升高与免疫细胞浸润和炎症性 T 细胞介导的反应有关，导致 NSCLC 患者在 PD-L1 表达亚组中对 PD-1/PD-L1 阻断的敏感性增加。
