Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
J Thorac Oncol. 2023 Jun;18(6):731-743. doi: 10.1016/j.jtho.2023.01.091. Epub 2023 Feb 10.
Although programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized.
In this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT.
Among 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38).
In advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT.
尽管程序性死亡蛋白 1 和程序性死亡配体 1（PD-L1）阻断联合铂类双重化疗已成为晚期 NSCLC 一线治疗的主要方法，但与化疗免疫治疗（CIT）疗效相关的因素尚未得到很好的描述。
在这项多中心回顾性分析中，从晚期 NSCLC 患者（缺乏 EGFR 和 ALK 敏感基因改变）中收集临床病理和基因组数据，并结合临床结果进行评估。
在接受 CIT 治疗的 1285 例患者中，较差的表现状态和血液中中性粒细胞与淋巴细胞比值的增加与客观缓解率（ORR）、中位无进展生存期（mPFS）和中位总生存期（mOS）的显著降低相关。随着 PD-L1 肿瘤比例评分从低于 1%、1%至 49%、50%至 89%和大于或等于 90%，ORR（32.7%比 37.5%比 51.6%比 61.7%，p<0.001）、mPFS（5.0 比 6.1 比 6.8 比 13.0 个月，p<0.001）和一般 mOS（12.9 比 14.6 比 34.7 比 23.1 个月，p=0.009）均逐渐改善。在具有全面基因组数据的 789 例 NSCLC 中，肿瘤突变负担（TMB）大于或等于第 90 百分位数的 NSCLC 患者的 ORR（53.5%比 36.4%，p=0.004）、mPFS（10.8 比 5.5 个月，p<0.001）和 mOS（29.2 比 13.1 个月，p<0.001）得到改善，与 TMB 小于第 90 百分位数的患者相比。在所有非鳞状 NSCLC 患者中，STK11、KEAP1 或 SMARCA4 突变的存在与 CIT 的 ORR、mPFS 和 mOS 显著降低相关（均 p<0.05）；在同时存在 STK11、KEAP1 或 SMARCA4 突变的 KRAS 突变 NSCLC 亚组中也观察到了这一点（均 p<0.05）。在 KRAS 野生型 NSCLC 中，KEAP1 和 SMARCA4 突变与 CIT 的 mPFS 和 mOS 明显缩短相关（均 p<0.05），但 STK11 突变状态对 mPFS（p=0.16）或 mOS（p=0.38）没有显著影响。
在晚期 NSCLC 中，更好的患者表现状态、较低的衍生中性粒细胞与淋巴细胞比值、增加的 PD-L1 表达、极高的 TMB 和 STK11/KEAP1/SMARCA4 野生型状态与 CIT 一线治疗的临床结局改善相关。
