@article{9dfc6fb1e96448af8c712a7123fd7913,
title = "HLA-corrected tumor mutation burden and homologous recombination deficiency for the prediction of response to PD-(L)1 blockade in advanced non-small-cell lung cancer patients",
abstract = "Background: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. Patients and methods: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. Results: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved. Conclusion: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.",
keywords = "PD-L1, homology-dependent recombination deficiency, human leukocyte antigen, immunotherapy, non-small-cell lung cancer, tumor mutation burden",
author = "Shim, {J. H.} and Kim, {H. S.} and H. Cha and S. Kim and Kim, {T. M.} and V. Anagnostou and Choi, {Y. L.} and Jung, {H. A.} and Sun, {J. M.} and Ahn, {J. S.} and Ahn, {M. J.} and K. Park and Park, {W. Y.} and Lee, {S. H.}",
note = "Funding Information: JSA reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb-Ono, personal fees from Merck Sharp & Dohme (MSD), personal fees from Janssen, personal fees from Samsung Bioepis, outside the submitted work. S-HL reports grants and personal fees from MSD, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Roche, outside the submitted work. KP reports personal fees from Astellas, Astra Zeneca, AMGEN, Boehringer Ingelheim, Clovis, Eli Lilly, Hanmi, KHK, Merck, MSD, Novartis, ONO, Roche, BluePrint, outside the submitted work. VA receives research funding from Bristol-Myers Squibb. All remaining authors have declared no conflicts of interest. Funding Information: This work was supported by the Post-Genome Technology Development Program (Business model development driven by the clinico-genomic database for precision immuno-oncology) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea) [grant number 10067758 ]; and a grant from the National Research Foundation of Korea funded by the Korean Government (NRF-2018-Global PhD Fellowship Program) [grant number 2018H1A2A1062330 ] to JHS. This work was supported in part by US National Institutes of Health grants [grant number CA121113 ] (VA), the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (VA), the V Foundation (VA), Swim Across America (VA), the Allegheny Health Network — Johns Hopkins Research Fund (VA), and the LUNGevity Foundation (VA) (no grant numbers). Funding Information: We would like to acknowledge all of the patients and their families for their contributions to this study. We thank Matthew L. Meyerson, Sam Freeman, and Tao Zou at the Dana-Farber Cancer Institute for their critical review of the manuscript. We are grateful to Sang Ha Shin and Tae Hee Hong at Samsung Genome Institute who provided engaging discussions and critical review of our manuscript. This work was supported by the Post-Genome Technology Development Program (Business model development driven by the clinico-genomic database for precision immuno-oncology) funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea) [grant number 10067758]; and a grant from the National Research Foundation of Korea funded by the Korean Government (NRF-2018-Global PhD Fellowship Program) [grant number 2018H1A2A1062330] to JHS. This work was supported in part by US National Institutes of Health grants [grant number CA121113] (VA), the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (VA), the V Foundation (VA), Swim Across America (VA), the Allegheny Health Network?Johns Hopkins Research Fund (VA), and the LUNGevity Foundation (VA) (no grant numbers). JSA reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb-Ono, personal fees from Merck Sharp & Dohme (MSD), personal fees from Janssen, personal fees from Samsung Bioepis, outside the submitted work. S-HL reports grants and personal fees from MSD, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Roche, outside the submitted work. KP reports personal fees from Astellas, Astra Zeneca, AMGEN, Boehringer Ingelheim, Clovis, Eli Lilly, Hanmi, KHK, Merck, MSD, Novartis, ONO, Roche, BluePrint, outside the submitted work. VA receives research funding from Bristol-Myers Squibb. All remaining authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jul,
doi = "10.1016/j.annonc.2020.04.004",
language = "English (US)",
volume = "31",
pages = "902--911",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "7",
}