medwireNews: The risk for disease progression or death increases with HLA-A*03 allele count in people undergoing immune checkpoint inhibitor (ICI) therapy for cancer, irrespective of tumor type and agent used, research suggests.
Writing in The Lancet Oncology, Mary Carrington (National Cancer Institute, Bethesda, Maryland, USA) and co-authors say: “The magnitude of effect is such that HLA-A*03 homozygotes might even have potential harm from ICI therapy.”
They therefore believe: “Caution in treating patients who are HLA-A*03 carriers with [ICIs] should be considered when alternative therapeutic options exist.”
Carrington and team began their study by investigating the relationship between HLA amino-acid variation and overall survival in the MSK-IMPACT pan-cancer observational cohort (n=1166). They identified 71 polymorphic amino acid sites among HLA-A allotypes, 76 among HLA-B allotypes, and 69 among HLA-C allotypes. Of these, a variation at position 161 of HLA-A, which corresponds to HLA-A*03, was the most strongly associated with overall survival (OS).
Specifically, each HLA-A*03 allele was associated with a significant 1.48-fold increased risk for death after use of various ICI treatments (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors).
These findings were validated in the observational DFCI Profile cohort (n=1326), where each HLA-A*03 allele was associated with a significant 1.22-fold increased risk for death after ICI treatment.
In both cohorts, the effect of HLA-A*03 on survival was observed across the five main tumor types evaluated (bladder cancer, glioma, melanoma, non-small-cell lung cancer, and renal cell carcinoma [RCC]), and regardless of the type of ICI agent used.
The researchers performed further validation using data from 169 participants of the JAVELIN Solid Tumour clinical trial for bladder cancer with similar results. In this case, the hazard ratio (HR) for death was 1.36 per HLA-A*03 allele.
Conversely, HLA-A*03 was not associated with OS in 10,328 patients treated with non-ICI therapies in The Cancer Genome Atlas trial.
Carrington et al then focused on RCC using pooled data from the three CheckMate clinical trials of nivolumab, as a large proportion of the effect of HLA-A*03 on OS in MSK-IMPACT occurred in people with RCC.
These analyses showed that HLA-A*03 carriers who received nivolumab had a significant 1.31-fold higher risk for disease progression or death than noncarriers, but there was no such association among people who received everolimus.
Furthermore, there were no objective responses among the eight people homozygous for HLA-A*03 in the nivolumab group, compared with a rate of 17.1% among the 76 HLA-A*03 heterozygotes and 26.6% among the 222 HLA-A*03 noncarriers.
And a similar pattern was observed for the 720 participants of the JAVELIN Renal 101 trial that compared avelumab plus axitinib with sunitinib.
Finally, the researchers performed a meta-analysis of all 3335 patients treated with ICI across the eight trials. This showed that “HLA-A*03 was associated with poor outcomes at a genome-wide significant level and there was no evidence of heterogeneity in effect,” they say.
Carrington et al conclude: “Given the frequency distributions of HLA-A*03, our findings might have relevance to a substantial population of patients treated globally with ICIs for a variety of indications, but further validation, ideally in trial settings in different populations with different tumour types and varying therapies, is needed.”
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