In a study reported in The Lancet Oncology, Naranbhai et al found that the presence of HLA-A*03 was associated with poorer outcomes in patients receiving immune checkpoint inhibitors for advanced cancers.
As stated by the investigators, “Predictive biomarkers could allow more precise use of immune checkpoint inhibitors in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to immune checkpoint inhibitors. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy.”
Study Details
The study assessed the association of HLA-A*03 with clinical outcomes in eight cohorts, comprised of the following groups below.
Three observational cohorts of patients with various advanced tumors, consisting of:
- The Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) cohort (n = 1,166 treated with immune checkpoint inhibitors, 21.8% HLA-A*03 carriers, analyzed for overall survival)
- The Dana-Farber Cancer Institute (DFCI) Profile cohort (n = 1,326 treated with immune checkpoint inhibitors, 21.8% carriers, analyzed for overall survival)
- The Cancer Genome Atlas (TCGA) (n = 10,328 patients receiving non–immune checkpoint inhibitor therapy, analyzed for overall survival).
Five clinical trial cohorts from:
- The JAVELIN Solid Tumor trial in advanced bladder cancer (n = 168 treated with immune checkpoint inhibitors, 21.3% carriers, analyzed for overall survival)
- The pooled population of CheckMate-009, CheckMate-010, CheckMate-025 in advanced renal cell carcinoma (n = 324 treated with immune checkpoint inhibitors, 28.1% carriers, analyzed for objective response and progression-free survival)
- The JAVELIN Renal 101 trial in advanced renal cell carcinoma (n = 350 treated with immune checkpoint inhibitors, 23.4% carriers, analyzed for objective response and progression-free survival).
In total, the cohorts included 3,335 patients treated with immune checkpoint inhibitors (PD-1, PD-L1, or CTLA-4 inhibitors) and 10,917 patients treated with non–immune checkpoint inhibitor therapies.
Key Findings
HLA-A*03 was associated in an additive manner with poorer overall survival after immune checkpoint inhibitor treatment, with hazard ratios (HRs) per HLA-A*03 allele of 1.48 (95% confidence interval [CI] = 1.20–1.82, P = .00022) in the MSK-IMPACT cohort, 1.22 (95% CI = 1.05–1.42, P = .0097) in the DFCI Profile cohort, and 1.36 (95% CI = 1.01–1.85, P = .047) in the JAVELIN Solid Tumor trial.
HLA-A*03 was not associated with overall survival in patients receiving non–immune checkpoint inhibitor therapies in the TCGA cohort.
The effect of HLA-A*03 was observed across immune checkpoint inhibitor agents and tumor types but was not observed in patients receiving non–immune checkpoint inhibitor therapy. Presence of an HLA-A*03 allele was associated with poorer progression-free survival among patients receiving nivolumab in the three CheckMate trials (HR = 1.31, 95% CI = 1.01–1.71, P = .044) but not among patients receiving control everolimus therapy. Among patients receiving nivolumab, objective responses were observed in 0 (0%) of 8 HLA-A*03 homozygotes, 59 (26.6%) of 222 HLA-A*03 non-carriers, and 13 (17.1%) of 76 HLA-A*03 heterozygotes.
Similarly, HLA-A*03 was associated with poorer progression-free survival in patients receiving immune checkpoint inhibitors (avelumab plus axitinib) in the JAVELIN Renal 101 trial (HR = 1.59 per allele, 95% CI = 1.16–2.16, P = .0036) but not among in those receiving control sunitinib therapy. Among patients receiving avelumab plus axitinib, objective responses were observed in 1 (12.5%) of 8 HLA-A*03 homozygotes, 162 (63.8%) of 254 HLA-A*03 non-carriers, and 40 (55.6%) of 72 HLA-A*03 heterozygotes.
HLA-A*03 was associated with poorer overall or progression-free survival in a meta-analysis including all 3,335 patients receiving immune checkpoint inhibitors at genome-wide significance (P = 2.01 × 10-8) with no evidence of heterogeneity of effect (I² 0%, 95% CI = 0%–0.76%).
The investigators concluded, “HLA-A*03 is a predictive biomarker of poor response to immune checkpoint inhibitors. Further evaluation of HLA-A*03 is warranted in randomized trials. HLA-A*03 carriage could be considered in decisions to initiate immune checkpoint inhibitors in patients with cancer.”
Mary Carrington, PhD, of the Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Institutes of Health, Merck KGaA, and Pfizer. For full disclosures of the study authors, visit thelancet.com.
