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.
Original language | English |
---|---|
Pages (from-to) | 2849-2858 |
Number of pages | 10 |
Journal | Clinical Cancer Research |
Volume | 26 |
Issue number | 12 |
DOIs | |
State | Published - Jun 15 2020 |
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Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC. / Hellmann, Matthew D.; Nabet, Barzin Y.; Rizvi, Hira; Chaudhuri, Aadel A.; Wells, Daniel K.; Dunphy, Mark P.S.; Chabon, Jacob J.; Liu, Chih Long; Hui, Angela B.; Arbour, Kathryn C.; Luo, Jia; Preeshagul, Isabel R.; Moding, Everett J.; Almanza, Diego; Bonilla, Rene F.; Sauter, Jennifer L.; Choi, Hyejin; Tenet, Megan; Abu-Akeel, Mohsen; Plodkowski, Andrew J.; Johnston, Rocio Perez; Yoo, Christopher H.; Ko, Ryan B.; Stehr, Henning; Gojenola, Linda; Wakelee, Heather A.; Padda, Sukhmani K.; Neal, Joel W.; Chaft, Jamie E.; Kris, Mark G.; Rudin, Charles M.; Merghoub, Taha; Li, Bob T.; Alizadeh, Ash A.; Diehn, Maximilian.
In: Clinical Cancer Research, Vol. 26, No. 12, 15.06.2020, p. 2849-2858.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC
AU - Hellmann, Matthew D.
AU - Nabet, Barzin Y.
AU - Rizvi, Hira
AU - Chaudhuri, Aadel A.
AU - Wells, Daniel K.
AU - Dunphy, Mark P.S.
AU - Chabon, Jacob J.
AU - Liu, Chih Long
AU - Hui, Angela B.
AU - Arbour, Kathryn C.
AU - Luo, Jia
AU - Preeshagul, Isabel R.
AU - Moding, Everett J.
AU - Almanza, Diego
AU - Bonilla, Rene F.
AU - Sauter, Jennifer L.
AU - Choi, Hyejin
AU - Tenet, Megan
AU - Abu-Akeel, Mohsen
AU - Plodkowski, Andrew J.
AU - Johnston, Rocio Perez
AU - Yoo, Christopher H.
AU - Ko, Ryan B.
AU - Stehr, Henning
AU - Gojenola, Linda
AU - Wakelee, Heather A.
AU - Padda, Sukhmani K.
AU - Neal, Joel W.
AU - Chaft, Jamie E.
AU - Kris, Mark G.
AU - Rudin, Charles M.
AU - Merghoub, Taha
AU - Li, Bob T.
AU - Alizadeh, Ash A.
AU - Diehn, Maximilian
N1 - 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: M.D. Hellmann is an employee/paid consultant for Merck, AstraZeneca, Mirati, Genentech, BMS, Immunai, Shattuck Labs, Nektar, and Syndax, reports receiving other commercial research support from BMS, and holds ownership interest (including options) in Immunai, Shattuck Labs, and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. A.A. Chaud-huri is an employee/paid consultant for Roche Sequencing Solutions, Tempus Labs, and Fenix Group International, reports receiving other commercial research support from Roche Sequencing Solutions, reports receiving speakers bureau honoraria from Varian Medical Systems, Foundation Medicine, and Roche Sequencing Solutions, and is an advisory board member/unpaid consultant for Geneoscopy. D.K. Wells is an employee/paid consultant for and holds ownership interest (including patents) in Immuna. J.J. Chabon is an employee/paid consultant for Lexent Bio Inc. C.L. Liu holds ownership interest (including patents) in and is an advisory board member/unpaid consultant for CiberMed Inc. K.A. Arbour is an employee/paid consultant for AstraZeneca. J.L. Sauter holds ownership interest (including patents) in Merck. H.A. Wakelee is an employee/paid consultant for AstraZeneca, Janssen, Xcovery, Mirati, and Daiichi Sankyo, reports receiving commercial research grants from AstraZeneca/Medimmune, BMS, Genentech/Roche, Merck, Novartis, and Xcovery, and is an advisory board member/unpaid consultant for Merck and Genentech/ Roche. S.K. Padda reports receiving other commercial research support from 47 Inc., Epicentrx, Bayer, and Boehringer Ingelheim, and is an advisory board member/ unpaid consultant for Abbvie, AstraZeneca, G1 Therapeutic, and Pfizer. J.W. Neal reports receiving other commercial research support from Genentech/Roche, Merck, Novartis, Boehringer/Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, and GSK, and is an advisory board member/unpaid consultant for AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, and Calithera Biosciences. J.E. Chaft is an employee/ paid consultant for AstraZeneca, BMS, Merck, and Genentech. M.G. Kris is an employee/paid consultant for AstraZeneca, Pfizer, and Regeneron. C.M. Rudin is an employee/paid consultant for AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, Pharmamar, Vavotek, Harpoon, Bridge Medicines, and AstraZeneca, and reports receiving commercial research grants from Daiichi Sankyo. B.T. Li is an employee/paid consultant for Roche/Genentech, ThermoFisher Scientific, and Guardant Health, and reports receiving commercial research grants from Guardant Health, GRAIL, and Genentech. A.A. Alizadeh reports receiving commercial research grants from Celgene, holds ownership interest (including patents) in FortySeven and CiberMed, and is an advisory board member/unpaid consultant for Roche and Celgene. M. Diehn is an employee/paid consultant for Roche, AstraZeneca, BioNTech, Illumina, and RefleXion, reports receiving commercial research grants from Varian Medical Systems, holds ownership interest (including patents) in CiberMed Inc., and holds patents owned by Stanford, one (on circulating tumor DNA) is licensed to Roche. No potential conflicts of interest were disclosed by the other authors. 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: © 2020 American Association for Cancer Research.
PY - 2020/6/15
Y1 - 2020/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85082951564&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-3418
DO - 10.1158/1078-0432.CCR-19-3418
M3 - Article
C2 - 32046999
AN - SCOPUS:85082951564
VL - 26
SP - 2849
EP - 2858
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 12
ER -