The association of human leukocyte antigen variants in immune-related toxicity and efficacy in Chinese lung cancer patients treated with immune checkpoint inhibitors

BackgroundPrevious studies in European populations have indicated an association between Human Leukocyte Antigen (HLA) allelic variations and efficacy as well as the risk of immune-related adverse events (irAEs) during immune checkpoint inhibitor (ICI) use in lung cancer patients (pts). Limited exploration of these relationships has been done in pts of Asian ancestry.MethodsA case-control study was conducted with 1807 subjects from 3261 lung cancer pts who received at least one cycle of ICI, any regimen, between January 2018 and December 2023 at Hunan Cancer Hospital. 248 pts with immune-related pneumonitis (IRP) and 380 pts with immune-related hepatitis (IRH) were identified and control cohorts without those irAEs were randomly selected at a 1:3 ratio (744 pts for IRP, 1140 pts for IRH). Illumina Asian Screening Arrays and CookHLA was used for HLA genotyping. Multivariable logistic regression models adjusting for baseline factors were used for HLA-irAE analysis, while multivariable Cox proportional hazards models were used for the association between HLA and overall survival (OS) (allele frequency >2%).ResultsThe median onset time for IRP and IRH was 5.9 and 2.1 months, respectively. Analysis of baseline characteristics revealed significant differences in the line of ICI and treatment strategy for the IRH cohorts. No HLA alleles were found to be associated with either of the irAEs or OS at an FDR of <0.05. However, at FDR < 0.1, HLA-A*02:07 (OR:3.19, 95%CI: 1.61-6.36, p<0.001, FDR:0.06) and HLA-DQB1*05:01 (OR:3.45, 95%CI: 1.47-7.39, p=0.002, FDR:0.09) were suggestive of higher risk of developing severe (grade ≥3) IRH (n=62). Furthermore, HLA-DQB1*06:01 (HR:1.35, 95%CI: 1.13-1.62, p<0.001, FDR:0.07) was suggestive of poor OS, while HLA-DQB1*03:01 (HR:0.79, 95%CI: 0.68-0.92, p=0.003, FDR:0.09) was suggestive of improved OS.ConclusionsThis case-controlled real-world study, the largest of its kind in the Chinese population, suggested that certain HLA alleles might be linked to the incidence of severe IRH and overall survival in Chinese lung cancer pts treated with ICI. Further research is needed to confirm the findings.Legal entity responsible for the studyThe authors.FundingThis research was supported by F. Hoffmann-La Roche Ltd., which provided grant support mainly on the sample sequencing and study operation according to local laws and regulations.DisclosureAll authors have declared no conflicts of interest.