A human leukocyte antigen (HLA) variant is associated with poor outcomes in patients with cancer who receive immune checkpoint inhibitors (ICIs), according to research published in The Lancet Oncology.
The study showed that HLA-A*03 was associated with worse progression-free survival (PFS) and overall survival (OS) after ICI treatment.
The study included 8 cohorts of patients who received ICIs or other cancer therapies. The DFCI Profile cohort included patients with bladder cancer, glioma, melanoma, non-small cell lung cancer, and renal cell carcinoma (RCC).
The Cancer Genome Atlas cohort and the MSK-IMPACT cohort included patients with these 5 tumors types and others. The remaining 5 cohorts came from clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumor) or RCC (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101).
The cohorts included a total of 3335 patients treated with various ICIs (anti-PD-1, anti-PD-L1, and anti-CTLA-4) and 10,917 patients treated with non-ICI cancer therapies.
In the MSK-IMPACT cohort, which served as the discovery cohort, the presence of 1 or 2 HLA-A*03 alleles was significantly associated with shorter OS, when patients were stratified by tumor type (hazard ratio [HR], 1.54, 1.20-1.96; P =.00058).
This association was additive per HLA-A*03 allele (HR, 1.48; 95% CI, 1.20-1.82; P =.00022). Patients homozygous for HLA-A*03 (HR, 2.31; 95% CI, 1.23-4.33) or heterozygous for HLA-A*03 (HR, 1.47; 95% CI, 1.14-1.90) had an increased risk of death relative to patients without HLA-A*03.
HLA-A*03 was associated with reduced OS after ICI treatment in the validation cohorts as well. The researchers observed an increased risk of death for patients with HLA-A*03 in the DFCI Profile cohort (HR, 1.22; 95% CI, 1.05-1.42; P =.0097) and in the JAVELIN Solid Tumor trial (HR, 1.36; 95% CI, 1.01-1.85; P =.047).
However, HLA-A*03 was not associated with OS for patients in the Cancer Genome Atlas cohort who did not receive ICIs.
Across the 3 CheckMate trials, RCC patients with HLA-A*03 had shorter PFS if they received nivolumab (HR, 1.31; 1.01-1.71; P =.044) but not if they received the control treatment, everolimus. Among the patients who received nivolumab, 8 were HLA-A*03 homozygotes, and none of them achieved objective responses. However, responses were observed in 26.5% of HLA-A*03 non-carriers and 17.1% of HLA-A*03 heterozygotes (P =.059).
As in the CheckMate trials, HLA-A*03 was associated with shorter PFS in the JAVELIN Renal 101 trial for patients who received an ICI (avelumab plus axitinib) but not for those who received sunitinib. This effect was independent of PD-L1 status (HR, 1.58; 95% CI 1.16-2.15; P =.0039), the researchers noted.
The team also conducted a meta-analysis that included all 3335 patients treated with ICIs in the discovery and validation cohorts. The results showed an association between HLA-A*03 and poor outcomes at a genome-wide significant level (P =2.01×10–8).
Based on these results, the researchers concluded that HLA-A*03 is a biomarker of poor response to ICIs, and HLA-A*03 carriage could be considered in treatment decisions.
Disclosures: This research was supported by the National Institutes of Health, Merck KGaA, and Pfizer. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Naranbhai V, Viard M, Dean M, et al. HLA-A*03 and response to immune checkpoint blockade in cancer: An epidemiological biomarker study. Lancet Oncol. Published online December 9, 2021. doi:10.1016/S1470-2045(21)00582-9
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