HLA-I homozygosity as a protective biomarker for developing immune related adverse events ( irAE) among non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy in the first- or second-line setting

Abstract Background: Biomarkers that predict risk of immune-mediated adverse events (irAEs) among non-small cell lung cancer (NSCLC) patients may reduce morbidity and mortality associated with these treatments. While it has been suggested that human leukocyte antigen (HLA-I) homozygosity is associated with short survival among these patients, its association with toxicity has not been examined. Method: We carried out high resolution HLA typing on 193 NSCLC patients treated with anti-PD1/PDL1. Toxicity data was collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We investigated the correlation between HLA-I/II homozygosity, different supertypes and alleles with irAE. In addition, we investigated the relationship between irAE, clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results: We recorded 103 irAE among 179 (58%) patients suitable for analysis. Homozygosity at one or more HLA-I loci, but not HLA-II was associated with increased risk of irAE with relative risk RR=0.57 (95%CI 0.31-0.96, P=0.025). None of the patients with homozygosity at one or more HLA-I loci developed pneumonitis of any grade (P=0.037) or grade 3 toxicity (P=0.023). The presence of HLA-A03 (N=49) supertype or HLA-DRB1*0401 (N=22) genotype was correlated with increased risk of developing irAE, (RR=1.40, 95%CI 0.99-2.01, P=0.039) and (RR=1.51, 95%CI 1.05-2.06, P=0.023) respectively. In contrast, none of the patients with HLA-DQB1*0301 (N=5) experienced gastrointestinal toxicity (P=0.048) and HLA-DRB1*15:01 (N=16) seems to be protective against developing arthralgia (RR=0.19, 95%CI 0.03-1.0, P=0.041). The occurrence of any irAE was associated with improved ORR, PFS and OS (RR=1.94, 95%CI 1.57-2.47, P less than 0.0001), (HR=0.37, 95%CI 0.25-0.54, P less than 0.0001) and (HR=0.26, 95%CI 0.16-0.41, P less than 0.0001) respectively. The usage of steroid to treat irAE did not diminish the positive clinical outcome. Conclusions: Homozygosity at one or more HLA-I loci can be a useful biomarker to predict irAE among NSCLC patients treated with anti-PD1/PD-L1 in the first- or second-line setting. This is more important among patients who developed pneumonitis or Grade 3 toxicities. However, the occurrence of any irAE is correlated with favourable clinical outcome. Citation Format: Afaf Abed, Ngie Law, Leslie Calapre, Johnny Lo, Vikas Bhat, Samantha Bowyer, Michael Millward, Elin Gray. HLA-I homozygosity as a protective biomarker for developing immune related adverse events (irAE) among non-small cell lung cancer (NSCLC) patients treated with single agent immunotherapy in the first- or second-line setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5132.