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. 2019 Jun;14(6):1021-1031.
doi: 10.1016/j.jtho.2019.02.008. Epub 2019 Feb 16.

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

Marcelo V Negrao  1 , Vincent K Lam  1 , Alexandre Reuben  1 , Maria Laura Rubin  2 , Lara Lacerda Landry  1 , Emily B Roarty  1 , Waree Rinsurongkawong  1 , Jeff Lewis  2 , Jack A Roth  3 , Stephen G Swisher  3 , Don L Gibbons  1 , Ignacio I Wistuba  4 , Vassiliki Papadimitrakopoulou  1 , Bonnie S Glisson  1 , George R Blumenschein Jr  1 , J Jack Lee  2 , John V Heymach  1 , Jianjun Zhang  5
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Free article

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

Marcelo V Negrao et al. J Thorac Oncol. 2019 Jun.
Free article

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.

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