Background: High polymorphic diversity in HLA class I (HLA-I) is essential for successful immunologic control of cancer. Lung cancer patients with maximal HLA-I heterozygosity treated with single-agent PD-L1 inhibitors as their second-line or beyond were reported with longer overall survival. However, the role of HLA heterozygosity for patients with NSCLC who received single-agent immunotherapy with or without chemotherapy as their first-line has not been reported.

Methods: Patients with unresectable stage III or IV NSCLC who underwent next-generation sequencing with HLA typing were enrolled in our study (N=27). HLA genotypes were determined using DNA sequencing data. They received either pembrolizumab (N=5) or pembrolizumab plus chemotherapy (N=22) as their first-line treatment. Kaplan-Meier curves were constructed to compare survival outcomes according to HLA (homozygous vs. heterozygous) and tumor mutation burden (TMB, above vs. below median) status. A log-rank test was applied to compare Kaplan-Meier curves between groups. Hazard ratios were derived from the Cox-proportional hazards model with adjustment for baseline characteristics including age, sex, and TMB.

Results: We determined HLA-I genotypes consisting of two alleles in 27 patients with NSCLC. Among these enrollees, 23 patients (85.2%) were heterozygous at every HLA-I locus and four patients (14.8%) were homozygous at more than one HLA-I locus. Response Evaluation Criteria in Solid Tumors (RECIST) evaluable patients were 19. In the HLA-heterozygous group (N=15), three patients (20%) had partial response (PR), eight patients (53.3%) had stable disease, and four patients (26.7%) had progressive disease (PD), whereas in the HLA-homozygous group (N=4), one (25%) had PR, one (25%) had SD, and two (50%) had PD. The disease control rates (CR, PR, and SD) were 73.3% in the HLA-heterozygous group and 50% in the HLA-homozygous group. Homozygosity at HLA-I genes seemed to be associated with shorter progression-free survival (PFS, HR=3.2, 95% CI=0.71-15, p=0.13) compared with heterozygosity at HLA-I genes. The HLA-heterozygous group had longer median PFS than the HLA-homozygous group (19 vs. 9.5 months, Log-rank p=0.11). When we controlled the effect of HLA homozygosity on PFS for age, sex, and TMB, the adjusted HRs were 4.4[0.82-23], 3.1[0.69-14] and 1.9[0.36-9.8] respectively.

Conclusion: No data exists on the effect of HLA homozygosity on clinical outcomes of patients treated with immunotherapy with or without chemotherapy as frontline treatment. We for the first time report that in such setting HLA homozygosity may be associated with worse outcomes.

Citation Format: Dongyup Lee, Jonghanne Park, Horyun Choi, Gahyun Gim, Sukjoo Cho, Leeseul Kim, Cyra Y. Kang, Pedro Viveiros, Young Kwang Chae. Association of human leukocyte antigen (HLA) homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer (NSCLC) treated with PD-L1 inhibitors as frontline therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6684.