Clinical StudiesApplicability of Routine Targeted Next-generation Sequencing to Estimate Tumor Mutational Burden (TMB) in Patients Treated With Immune Checkpoint Inhibitor TherapyPinato, David J.*,†; Urus, Heather*,†; Newsom-Davis, Thomas‡; Du Parcq, Persephone§; Belessiotis, Katherine†; Mapara, Leah†; Gupta, Nandita∥; Power, Danielle†; Weir, Justin∥; Wong, Ching Ngar*; Ratnakumaran, Ragu P.†; Dominy, Kathy§; Khorashad, Jamshid§; Bower, Mark‡Author Information *Department of Surgery & Cancer, Imperial College London †Department of Oncology, Imperial College NHS Trust, Charing Cross Hospital ‡Department of Oncology, Chelsea & Westminster Hospital §Molecular Pathology Laboratory, Hammersmith Hospital ∥Department of Histopathology, Imperial College NHS Trust, Hammersmith Hospital, London, UK D.J.P. and H.U. contributed equally. Primary research data are presented in a summative manner in the manuscript. No publicly available dataset has been generated as part of this work. D.J.P.: study concepts, study design, statistical analysis, manuscript preparation, and manuscript editing. H.U., T.N.-D., P.D.P., K.B., L.M., N.G., D.P., J.W., C.N.W., R.P.R., K.D., J.K., M.B.: data acquisition. D.J.P., J.K., P.D.P., K.D.: quality control of data and algorithms. D.J.P., J.K., M.B.: data analysis and interpretation. All the authors: manuscript review. Reprints: David J. Pinato, Department of Medical Oncology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0HS, UK (e-mail: firstname.lastname@example.org). Received May 8, 2019 Accepted July 30, 2019 Online date: September 24, 2019 Journal of Immunotherapy: February/March 2020 - Volume 43 - Issue 2 - p 53-56 doi: 10.1097/CJI.0000000000000295 Buy Metrics Abstract It remains unclear whether targeted next-generation sequencing (tNGS) conveys a reliable estimate of tumor mutational burden (TMB). We sequenced 79 archival samples of immune checkpoint inhibitors (ICPIs) recipients (57% lung cancer, 43% melanoma) using Ion Ampliseq Cancer Hotspot Panel. Employing multiple cutoff values, we verified that TMB by tNGS did not correlate with response or survival following ICPI. We found enrichment of ATM mutations in ICPI-refractory tumors (P=0.01) to correlate with worse survival (4.2 vs. 10 mo, P=0.03). Limited-coverage tNGS delivers an imprecise estimate of patients’ TMB but may aid identification of candidate somatic variants of predictive/prognostic significance. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.