HLA-A*03 is a Predictive Biomarker of Poor Response to Immune Checkpoint Blockade in Cancer

Background: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICI) in treating advanced cancers. Methods: We measured the effect of HLA variation on overall and progression-free survival in eight cohorts, including 3,339 patients with advanced cancer treated with various ICI agents and 10,867 treated with alternative therapies. Findings: HLA-A*03 associated in an additive fashion with reduced survival after ICI treatment in a discovery cohort (hazard ratio, 1·54 per HLA-A*03 allele; 95% confidence interval [CI] 1·20-1·96, p<0·001), validation cohort (hazard ratio, 1·22 per HLA-A*03 allele; 95% CI 1·05-1·42, p=0·009) and clinical trial for bladder cancer (hazard ratio, 1·36 per HLA-A*03 allele; CI 1·005-1·851, p=0·05). The HLA-A*03 effect was observed across ICI agents and tumor types, but not in patients treated with alternative therapies. HLA-A*03+ patients had shorter progression-free survival in three clinical trials of nivolumab for renal cell cancer (RCC, hazard ratio, 1·31; 95% CI 1·0-1·71, p=0·04), but not in the control arm. Objective responses were observed in 0% (0/8) of HLA-A*03 homozygotes in the ICI arm. HLA-A*03 associated with shorter progression-free survival in patients receiving ICI in another randomized clinical trial for RCC (avelumab/axitinib; hazard ratio, 1·59 per HLA-A*03 allele; 95%CI 1·16-2·16, p=0·004), but not those receiving control therapy. Objective responses rate was 12·5% (1/8) among HLA-A*03 homozygotes in the ICI arm. HLA-A*03 associated with impaired outcome in meta-analysis of all 3,339 ICI treated patients at genome-wide significance (p=2·01x10-8, I2=0%, 95% CI 0%-0·76%). Interpretation: HLA-A*03 is a predictive biomarker of poor response to ICI and should be considered in decisions regarding cancer therapy. Clinical Trial Registration Details: This study included data from several registered clinical trials: 1. JAVELIN Solid Tumor urothelial carcinoma cohort ClinicalTrials.gov NCT01772004 2. CheckMate 009, 010, 025, ClinicalTrials.gov NCT01358721, NCT01354431, NCT01668784 3. JAVELIN Renal 101, ClinicalTrials.gov NCT02684006 Funding Information: This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. This research was financially supported by Merck KGaA, Darmstadt, Germany and Pfizer. Declaration of Interests: D.A.B. acknowledges support by the DF/HCC Kidney Cancer SPORE Career Enhancement Program (P50CA101942-15), DOD CDMRP (KC170216, KC190130), and the DOD Academy of Kidney Cancer Investigators (KC190128T). TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. K.C. and P.S. are employees of EMD Serono Research & Development Institute, Inc.; an affiliate of Merck KGaA, Darmstadt, Germany. P.B.R. and X.J.M. are employees of Pfizer. All other authors have nothing to declare. Ethics Approval Statement: This study was performed with IRB approvals form the DFCI MGH and NCI.