Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis

Abstract

Background: Human leukocyte antigen class 1 (HLA-1)-dependent immune activity is linked to autoimmune diseases. HLA-1-dependent CD8⁺ T cells are required for immune checkpoint blockade antitumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to immune checkpoint blockade.

Methods: Patients with advanced solid tumors stratified into 5 cohorts received single agent pembrolizumab (anti-programmed cell death-1) 200 mg intravenously every 3 weeks in an investigator-initiated phase II trial (Investigator-Initiated Phase II Study of Pembrolizumab Immunological Response Evaluation study, NCT02644369). Germline whole-exome sequencing of peripheral blood mononuclear cells was performed using the Illumina HiSeq2500 platform. HLA-1 haplotypes were predicted from whole-exome sequencing using HLAminer and HLAVBSeq. Heterozygosity of HLA-A, -B, and -C, individual HLA-1 alleles, and HLA haplotype dimorphism at positions -21 M and -21 T of the HLA-A and -B leader sequence were analyzed as predictors of toxicity defined as grade 2 or greater immune-related adverse events and clinical benefit defined as complete or partial response, or stable disease for 6 or more cycles of pembrolizumab. Statistical significance tests were 2-sided.

Results: In the overall cohort of 101 patients, the frequency of toxicity and clinical benefit from pembrolizumab was 22.8% and 25.7%, respectively. There was no association between any of the HLA-1 loci or alleles with toxicity. HLA-C heterozygosity had an association with decreased clinical benefit relative to HLA-C homozygosity when controlling for cohort (odds ratio = 0.28, 95% confidence interval = 0.09 to 0.91, P = .04). HLA-A and -B haplotype -21 M/T dimorphism and heterozygosity of HLA-A, -B, and -C were not predictive of outcomes.

Conclusions: HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram of patient allocation and outcomes. CONSORT diagram displaying all relevant details regarding the 101 patients used in this human leukocyte antigen class 1 (HLA-1) analysis from the Investigator-Initiated Phase II Study of Pembrolizumab Immunological Response Evaluation (INSPIRE) study. Note that patients can develop more than 1 type of toxicity event. CB = clinical benefit; CR = complete response; HGSOC = high-grade serous ovarian carcinoma; HNSCC = head and neck squamous cell carcinoma; NE = nonevaluable; PD = progressive disease; PR = partial response; SD = stable disease; TNBC = triple-negative breast cancer.

Figure 2.

Survival and progression outcomes. Kaplan-Meier curves of (A) overall survival (OS) and (B) progression-free survival (PFS) after dichotomizing patients with germline heterozygosity of human leukocyte antigen (HLA)-A, -B, and -C compared with homozygosity of at least 1 HLA loci. P values are adjusted for cohort and calculated using the Wald test. CI = confidence interval; HR = hazard ratio.