@article{6e60cb8116894ba693e64c91632ddba1,
title = "PD-L1 Expression, Tumor Mutational Burden, and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non–Small Cell Lung Cancer",
abstract = "Introduction: Immune checkpoint blockade (ICB) has revolutionized the treatment of NSCLC, but only approximately 15% of patients achieve durable benefit. Understanding mechanisms of resistance to ICB is pivotal in developing more effective treatment strategies. Recent studies showed that human leukocyte antigen (HLA) class I heterozygosity might be important in mediating benefit from ICB. We aimed to investigate the impact of HLA class I genotype on outcomes of patients with NSCLC treated with ICB. Methods: We collected HLA typing, genomic, and clinical data from patients with advanced NSCLC treated with ICB at M. D. Anderson Cancer Center. We compared HLA class I–heterozygous and HLA class I–homozygous patients for progression-free survival (PFS) and overall survival (OS). HLA I supertype/alleles were also analyzed. To validate our findings, we also analyzed two previously published independent cohorts of patients with NSCLC (the CheckMate-012 and Chowell cohorts). Results: No significant correlations were observed for HLA class I zygosity and PFS or OS in the M. D. Anderson Cancer Center (n = 200), CheckMate-012 (n = 75), or Chowell (n = 371) cohorts. No HLA class I supertype/allele was consistently shown to be correlated with PFS or OS. Predictors of worse outcome across the three cohorts included presence of targetable driver mutation, serine/threonine kinase 11 gene (STK11) mutation, negative programmed death ligand 1 expression, and low tumor mutational burden. Conclusions: HLA class I genotype is not correlated with survival in advanced NSCLC treated with ICB. This suggests that the impact of HLA class I diversity may be disease specific and that tumor genomic and immune markers are more impactful in predicting benefit from ICB in NSCLC.",
keywords = "HLA class I, Immunotherapy, Lung cancer, PD-L1, Tumor mutational burden",
author = "Negrao, {Marcelo V.} and Lam, {Vincent K.} and Alexandre Reuben and Rubin, {Maria Laura} and Landry, {Lara Lacerda} and Roarty, {Emily B.} and Waree Rinsurongkawong and Jeff Lewis and Roth, {Jack A.} and Swisher, {Stephen G.} and Gibbons, {Don L.} and Wistuba, {Ignacio I.} and Vassiliki Papadimitrakopoulou and Glisson, {Bonnie S.} and Blumenschein, {George R.} and Lee, {J. Jack} and Heymach, {John V.} and Jianjun Zhang",
note = "Funding Information: This work was supported by: the generous philanthropic contributions to The University of Texas M. D. Anderson Cancer Center Lung Moon Shot Program; the M. D. Anderson Cancer Center Support Grant P30 CA01667; the MD Anderson Physician Scientist Program; the Thoracic/Head and Neck Medical Oncology Special Fellowship Program. We acknowledge the GEMINI Team for their work on this project. Funding Information: This work was supported by: the generous philanthropic contributions to The University of Texas M. D. Anderson Cancer Center Lung Moon Shot Program; the M. D. Anderson Cancer Center Support Grant P30 CA01667; the MD Anderson Physician Scientist Program; the Thoracic/Head and Neck Medical Oncology Special Fellowship Program. We acknowledge the GEMINI Team for their work on this project. Disclosure: Dr. Lam reports grants and personal fees from Takeda, personal fees from BMS, and grants from Guardant Health and Adaptimmune outside the submitted work. Dr. Swisher reports personal fees from Ethicon and Peter MacCallum Cancer Center outside the submitted work. Dr. Gibbons reports grants and personal fees from AstraZeneca and Janssen, personal fees from Sanofi and GSK, and grants from Takeda outside the submitted work. Dr. Wistuba reports grants and personal fees from Genentech/Roche, Bristol-Myers Squibb, Astra Zeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, and Merck; grants from EMD Serono, Oncoplex, DepArray, Adaptive, Adaptimmune, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, and 4D; and personal fees from GlaxoSmithKline and MSD outside the submitted work. Dr. Papadimitrakopoulou reports grants and personal fees from Nektar Therapeutics, AstraZeneca, Merck, F. Hoffman-La Roche, Bristol-Myers Squibb, Eli Lilly, and Novartis; personal fees from Arrys Therapeutics, LOXO Oncology, Araxes Pharma, Jannsen Research Foundation, Clovis Oncology, Takeda, Abbvie, TRM Oncology, Tesaro, Exelixis, and Gritstone, and grants from Janssen, Checkmate, and Incyte outside the submitted work. Dr. Glisson reports grants from Bristol Myers Squibb, Pfizer, and Medimmune outside the submitted work. Dr. Blumenschein reports personal fees from Abbvie, Adicet, Amgen, ARIAD, Clovis, and Genentech; grants and personal fees from Bayer, BMS, Celgene, Merck, Novartis, and Xcovery; and grants from Adaptimmune, Exelixis, Genentech, GlaxoSmithKline, Hoffman-La Roche, Immatics, Incyte, KITE, Macrogenetics, MedImmune, and Torque outside the submitted work. Dr. Heymach reports grants and personal fees from AstraZeneca, Spectrum, and GlaxoSmithKline; personal fees from Boehringer Ingelheim, Exelixis, Genentech, Guardant Health, Hengrui, Lilly, Novartis, EMD Serono, and Synta; and grants from Bayer outside the submitted work; in addition, Dr. Heymach has a patent held by Spectrum with royalties paid. Dr. Zhang reports personal fees from BMS, AstraZeneca, Geneplus, OrigMed, and Innovent outside the submitted work. The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2019 International Association for the Study of Lung Cancer",
year = "2019",
month = jun,
doi = "10.1016/j.jtho.2019.02.008",
language = "English (US)",
volume = "14",
pages = "1021--1031",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "6",
}