Hira Rizvi, Francisco Sanchez-Vega, Konnor La, Walid Chatila, Philip Jonsson, Darragh Halpenny, Andrew Plodkowski, Niamh Long, Jennifer L. Sauter, Natasha Rekhtman, Travis Hollmann, Ronglai Shen, Ai Ni, Kathryn C. Arbour, Taha Merghoub, Jedd Wolchok, Jamie E. Chaft, Mark G. Kris, Charles M. Rudin, Nicholas D. Socci, Michael F. Berger, Barry S. Taylor, Ahmet Zehir, David B. Solit, Maria E. Arcila, Marc Ladanyi, Gregory J. Riely, Nikolaus Schultz, and Matthew D. Hellmann, Memorial Sloan Kettering Cancer Center; Taha Merghoub, Jedd Wolchok, Alexandra Snyder, Jamie E. Chaft, Mark G. Kris, Charles M. Rudin, Gregory J. Riely, and Matthew D. Hellmann, Weill Cornell Medical College, New York, NY; Kurt A. Schalper, Yale School of Medicine, New Haven, CT; Justin F. Gainor, Massachusetts General Hospital, Boston, MA; and Alexandra Snyder, Adaptive Biotechnologies, Seattle, WA.
J Clin Oncol. 2018 Mar 1;36(7):633-641. doi: 10.1200/JCO.2017.75.3384. Epub 2018 Jan 16.
Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number-altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P < .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number-altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.
免疫检查点抑制剂（ICI）治疗晚期非小细胞肺癌的特点是在一部分患者中具有持久的反应和改善的生存。需要临床可用的工具来优化 ICI 的使用，并了解反应的分子决定因素。靶向下一代测序（NGS）越来越常规，但它在确定对 ICI 反应的预测因子方面的作用尚不清楚。
为接受抗程序性死亡-1 或抗程序性死亡配体 1 [抗程序性细胞死亡（PD）-1]治疗并通过靶向 NGS（MSK-IMPACT；n = 240）进行分析的晚期非小细胞肺癌患者收集详细的临床注释和反应数据。通过实体瘤反应评估标准（RECIST）版本 1.1 评估疗效，持久的临床获益（DCB）定义为持续> 6 个月的部分缓解/稳定疾病。比较 DCB 患者和无持久获益（NDB）患者的肿瘤突变负担（TMB）、基因组拷贝数改变分数和基因改变。对 49 例患者进行全外显子组测序（WES），比较靶向 NGS 与 WES 定量 TMB。
靶向 NGS 估计的 TMB 与 WES 相关性良好（ρ = 0.86；P <.001）。TMB 在 DCB 患者中高于 NDB 患者（P =.006）。在 TMB 高于或低于第 50 百分位的递增阈值以上的患者中，DCB 更为常见，无进展生存期更长（38.6% v 25.1%；P <.001；风险比，1.38；P =.024）。NDB 患者的基因组拷贝数改变分数最高。EGFR 和 STK11 的变异与缺乏获益相关。TMB 和 PD-L1 表达是独立变量，TMB 加 PD-L1 的组合进一步增强了对 ICI 的获益。
靶向 NGS 准确估计 TMB，升高的 TMB 进一步提高了对 ICI 的获益可能性。TMB 与 PD-L1 表达不相关；两者都具有相似的预测能力。将 TMB 和 PD-L1 表达纳入多变量预测模型应会提高预测能力。
