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.

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.