@article{3d502e07c813494580654f2c38135bb2,
title = "Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC",
abstract = "Purpose: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non–small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. Experimental Design: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). Results: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P < 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51–1; negative predictive value = 0.93 (95% CI, 0.80–0.99)]. Conclusions: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.",
author = "Hellmann, {Matthew D.} and Nabet, {Barzin Y.} and Hira Rizvi and Chaudhuri, {Aadel A.} and Wells, {Daniel K.} and Dunphy, {Mark P.S.} and Chabon, {Jacob J.} and Liu, {Chih Long} and Hui, {Angela B.} and Arbour, {Kathryn C.} and Jia Luo and Preeshagul, {Isabel R.} and Moding, {Everett J.} and Diego Almanza and Bonilla, {Rene F.} and Sauter, {Jennifer L.} and Hyejin Choi and Megan Tenet and Mohsen Abu-Akeel and Plodkowski, {Andrew J.} and Johnston, {Rocio Perez} and Yoo, {Christopher H.} and Ko, {Ryan B.} and Henning Stehr and Linda Gojenola and Wakelee, {Heather A.} and Padda, {Sukhmani K.} and Neal, {Joel W.} and Chaft, {Jamie E.} and Kris, {Mark G.} and Rudin, {Charles M.} and Taha Merghoub and Li, {Bob T.} and Alizadeh, {Ash A.} and Maximilian Diehn",
note = "Funding Information: M. Diehn), V-Foundation (to A.A. Alizadeh), the Damon Runyon Cancer Research Foundation (to M.D. Hellmann), Ludwig Trust, Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748), Parker Institute for Cancer Immunotherapy, Druckenmiller Center for Lung Cancer Research at MSKCC, Swim Across America, and Stand Up to Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. Four investigators (M.D. Hellmann, D.K. Wells, T. Merghoub, A.A. Alizadeh) are members of the Parker Institute for Cancer Immunotherapy. M.D. Hellmann is a Damon Runyon Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-98-18). B.Y. Nabet is a Stanford Cancer Systems Biology Scholar and supported by the NIH (5R25CA180993). Funding Information: This work was supported by grants from the NCI (R01CA188298, to M. Diehn and A.A. Alizadeh), the NIH Director's New Innovator Award Program (1-DP2-CA186569, to M. Diehn), the Virginia and D.K. Ludwig Fund for Cancer Research (to M. Diehn and A.A. Alizadeh), the CRK Faculty Scholar Fund (to M. Diehn), V-Foundation (to A.A. Alizadeh), the Damon Runyon Cancer Research Foundation (to M.D. Hellmann), Ludwig Trust, Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748), Parker Institute for Cancer Immunotherapy, Druckenmiller Center for Lung Cancer Research at MSKCC, Swim Across America, and Stand Up to Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. Four investigators (M.D. Hellmann, D.K. Wells, T. Merghoub, A.A. Alizadeh) are members of the Parker Institute for Cancer Immunotherapy. M.D. Hellmann is a Damon Runyon Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-98-18). B.Y. Nabet is a Stanford Cancer Systems Biology Scholar and supported by the NIH (5R25CA180993). Funding Information: This work was supported by grants from the NCI (R01CA188298, to M. Diehn and A.A. Alizadeh), the NIH Director's New Innovator Award Program (1-DP2-CA186569, to M. Diehn), the Virginia and D.K. Ludwig Fund for Cancer Research (to M. Diehn and A.A. Alizadeh), the CRK Faculty Scholar Fund (to Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = jun,
day = "15",
doi = "10.1158/1078-0432.CCR-19-3418",
language = "English",
volume = "26",
pages = "2849--2858",
journal = "Clinical Cancer Research",
issn = "1078-0432",
number = "12",
}