HLA-A*03 alleles linked to poor ICI therapy response
By Lynda Williams, medwireNews Reporter
Carriage of a specific human leukocyte antigen (HLA) allele is associated with a poor response to immune checkpoint inhibitor (ICI) therapy in patients with a range of tumour types, suggests research published in The Lancet Oncology.
Mary Carrington (National Cancer Institute, Bethesda, Maryland, USA) and co-authors assessed the impact of one or two HLA-A*03 alleles on the overall survival (OS) of 3335 ICI-treated patients in three observational cohorts of advanced tumours and five clinical trials of patients with advanced bladder cancer or renal cell carcinoma (RCC).
Among 1166 participants of the MSK-IMPACT pan-cancer cohort, each HLA-A*03 allele conferred a significant increased risk of death after receipt of a PD-1, PD-L1 or CTLA-4 inhibitor (hazard ratio [HR]=1.48).
A similar significant relationship was also identified among 1326 patients in the pan-tumour DFCI Profile study (HR=1.22 per HLA-A*03 allele) and the researchers emphasize that HLA-A*03 alleles in these two studies had a negative impact on survival regardless of tumour type or class of ICI received.
By contrast, no relationship between HLA-A*03 carriage and outcome was found among participants of The Cancer Genome Atlas study who were given non-ICI treatments for bladder cancer, RCC, non-small-cell lung cancer, melanoma and other tumour types.
The JAVELIN Solid Tumor study of the PD-L1 inhibitor avelumab for bladder cancer patients showed a significant correlation between poor OS and HLA-A*03 (HR=1.36 per allele).
Among RCC patients participating in three CheckMate trials, individuals with an HLA-A*03 allele had significantly poorer OS than those without when they received the PD-1 inhibitor nivolumab (HR=1.31 per allele) but not if they were given the mTOR inhibitor everolimus.
And among patients in the JAVELIN Renal 101 trial, participants with a HLA-A*03 allele who received avelumab plus axitinib had significantly poorer progression-free survival than those who did not (HR for progression or death=1.59 per allele) but no such discrepancy by allele was found among patients given sunitinib.
Meta-analysis of data for all eight studies showed a significant genome-wide correlation between HLA-A*03 carriage and poor outcome from immunotherapy, without evidence of heterogeneity, the researchers emphasize.
Recommending further investigation into this association, the team suggests “[c]aution in treating patients who are HLA-A*03 carriers with immune checkpoint inhibitors” when other types of treatment are available.
“The magnitude of effect is such that HLA-A*03 homozygotes might even have potential harm from ICI therapy”, Carrington et al conclude.
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Lancet Oncol 2021; doi: 10.1016/S1470-2045(21)00582-9