Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition
Barzin Y Nabet, Mohammad S Esfahani, Everett J Moding, Emily G Hamilton, Jacob J Chabon, Hira Rizvi, Chloe B Steen, Aadel A Chaudhuri, Chih Long Liu, Angela B Hui, Diego Almanza, Henning Stehr, Linda Gojenola, Rene F Bonilla, Michael C Jin, Young-Jun Jeon, Diane Tseng, Cailian Liu, Taha Merghoub, Joel W Neal, Heather A Wakelee, Sukhmani K Padda, Kavitha J Ramchandran, Millie Das, Andrew J Plodkowski, Christopher Yoo, Emily L Chen, Ryan B Ko, Aaron M Newman, Matthew D Hellmann, Ash A Alizadeh, Maximilian Diehn, Barzin Y Nabet, Mohammad S Esfahani, Everett J Moding, Emily G Hamilton, Jacob J Chabon, Hira Rizvi, Chloe B Steen, Aadel A Chaudhuri, Chih Long Liu, Angela B Hui, Diego Almanza, Henning Stehr, Linda Gojenola, Rene F Bonilla, Michael C Jin, Young-Jun Jeon, Diane Tseng, Cailian Liu, Taha Merghoub, Joel W Neal, Heather A Wakelee, Sukhmani K Padda, Kavitha J Ramchandran, Millie Das, Andrew J Plodkowski, Christopher Yoo, Emily L Chen, Ryan B Ko, Aaron M Newman, Matthew D Hellmann, Ash A Alizadeh, Maximilian Diehn
Abstract
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
Keywords: circulating tumor DNA; immune checkpoint inhibition; immunotherapy; liquid biopsy; non-small cell lung cancer; response classification.
Conflict of interest statement
Declaration of Interests J.J.C. reports paid consultancy from Lexent Bio Inc. A.A.C. reports speaker honoraria and travel support from Roche Sequencing Solutions (RSS), Varian, and Foundation Medicine; a research grant from RSS; and has served as a paid consultant for Oscar Health. T.M. is a co-founder of Imvaq. J.W.N. reports research support from Genentech (GNE)/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Takeda Pharmaceuticals, Nektar Therapeutics, Adaptimmune, and GSK, and has served in a consulting or advisory role for AstraZeneca (AZ), GNE/Roche, Exelixis Inc., Jounce Therapeutics, Takeda Pharmaceuticals, and Eli Lilly. H.A.W. has received honoraria from Novartis and AZ and has participated on the advisory boards of Xcovery, Janssen, and Mirati. S.K.P. reports grant support from EpicentRx, Forty Seven, Bayer, and Boehringer Ingelheim and serves in a consulting or advisory role for AZ, AbbVie, G1 Therapeutics, and Pfizer. M. Das reports grant support from AbbVie, United Therapeutics, Varian, and Celgene and serves in a consulting role for AZ and Bristol-Myers Squibb (BMS). A.M.N. has patent filings related to expression deconvolution and cancer biomarkers and has served as a consultant for Roche, Merck, and CiberMed. M.D.H. reports paid consultancy from BMS, Merck, GNE, AZ/MedImmune, Nektar, Syndax, Janssen, Mirati Therapeutics, Shattuck Labs, and Blueprint Medicines; travel/honoraria from BMS and AZ; research funding from BMS; 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 Personal Genome Diagnostics. A.A.A. reports ownership interest in CiberMed and FortySeven, patent filings related to cancer biomarkers, and paid consultancy from GNE, Roche, Chugai, Gilead, and Celgene. M. Diehn reports research funding from Varian, ownership interest in CiberMed, patent filings related to cancer biomarkers, paid consultancy from Roche, AZ, and BioNTech, and travel/honoraria from Reflexion. M.Diehn, A.A.A., B.Y.N., and M.S.E. are co-inventors on a provisional patent application filed by Stanford University relating to this manuscript.
Copyright © 2020 Elsevier Inc. All rights reserved.
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Source: PubMed