Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung cancer

Abstract

Abstract Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (NSCLC). However, not all patients benefit from ICIs and can experience immune related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but human leukocyte antigen (HLA) has emerged as a potential predictive biomarker. We obtained HLA genotypes from 85 metastatic NSCLC patients on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 correlated with improved survival in both univariable (PFS 9.9 months, p = 0.040; OS 26.3 months, p = 0.0085) and multivariable analysis (PFS p = 0.0310, HR 0.55, 95% CI [0.31, 0.95]); OS p = 0.003, HR 0.40, 95% CI [0.21, 0.73]). 11 patients developed endocrine irAEs. HLA-DRB4 was expressed in 39/85 (45.9%) patients and was the predominant genotype for endocrine irAEs (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experienced improved survival outcomes. Additionally, we found a correlation between HLA-DRB4 and endocrine irAEs.