Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing

作者：Hira A. Rizvi, Francisco Sánchez-Vega, Konnor La, Walid Khaled Chatila, Philip Jonsson, Darragh F. Halpenny, Andrew J. Plodkowski, Niamh M. Long, Jennifer L. Sauter, Natasha Rekhtman, Travis J. Hollmann, Kurt Alex Schalper, Justin F. Gainor, Ronglai Shen, Ai Ni, Kathryn Cecilia Arbour, Taha Merghoub, Jedd D. Wolchok, Alexandra Snyder, 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 D. Schultz, Matthew David Hellmann · 发表于：Journal of Clinical Oncology · 年份：2018 · DOI：10.1200/jco.2017.75.3384 · 被引用次数：1436 · 研究领域：Cancer Genomics and Diagnostics、Lung Cancer Treatments and Mutations、Cancer Immunotherapy and Biomarkers

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 ...