TY - JOUR
T1 - HLA-A*03 and response to immune checkpoint blockade in cancer
T2 - an epidemiological biomarker study
AU - Naranbhai, Vivek
AU - Viard, Mathias
AU - Dean, Michael
AU - Groha, Stefan
AU - Braun, David A.
AU - Labaki, Chris
AU - Shukla, Sachet A.
AU - Yuki, Yuko
AU - Shah, Parantu
AU - Chin, Kevin
AU - Wind-Rotolo, Megan
AU - Mu, Xinmeng Jasmine
AU - Robbins, Paul B.
AU - Gusev, Alexander
AU - Choueiri, Toni K.
AU - Gulley, James L.
AU - Carrington, Mary
N1 - Funding Information:
VN and MC conceived the study. VN, MV, MD, SG, DAB, CL, SAS, PS, XJM, PBR, and AG curated data and did data analyses. VN and MC wrote the first draft of the manuscript. YY did HLA typing. MC, MW-R, KC, AG, TKC, and JLG supervised the analyses. MC, JLG, and TKC were responsible for funding acquisition. PBR and XJM did the analyses of the JAVELIN Renal 101 randomised controlled trial for which TKC was the Principal Investigator. MW-R supervised analyses of the CheckMate suite of studies. All authors reviewed and edited the final manuscript. The underlying data was accessed and verified by VN, MV, DAB, SG, and AG (academic authors) and XJM, PR, MW-R, and PS (industry authors).
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 number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Research was supported in part by the Intramural Research Program of the National Institutes of Health through an National Cancer Institute FLEX award to JLG and MC, the Frederick National Lab, and the Center for Cancer Research. JLG and MD are employees of the National Institutes of Health The results published here are in whole or part based upon data generated by the TCGA Research Network (https://www.cancer.gov/tcga), the DFCI Oncology Data Retrieval System, and the Dana-Farber Cancer Institute, Brigham Women's Hospital Data Sharing Group. DAB was supported by the Dana-Farber, Harvard Cancer Center Kidney Cancer SPORE Career Enhancement Programme (P50CA101942-15), the Department of Defense CDMRP (KC170216 and KC190130), and the DOD Academy of Kidney Cancer Investigators (KC190128T). TKC is supported in part by the Dana-Farber, Harvard Cancer Center Kidney SPORE Programme, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Cohorts included in this research were financially supported by Merck and Pfizer.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/1
Y1 - 2022/1
N2 - Background: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. Methods: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). Findings: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20–1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05–1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01–1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01–1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16–2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 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 impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10−8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0–0·76) Interpretation: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. Funding: National Institutes of Health, Merck KGaA, and Pfizer.
AB - Background: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. Methods: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). Findings: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20–1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05–1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01–1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01–1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16–2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 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 impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10−8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0–0·76) Interpretation: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. Funding: National Institutes of Health, Merck KGaA, and Pfizer.
UR - http://www.scopus.com/inward/record.url?scp=85121932095&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(21)00582-9
DO - 10.1016/S1470-2045(21)00582-9
M3 - Article
C2 - 34895481
AN - SCOPUS:85121932095
SN - 1470-2045
VL - 23
SP - 172
EP - 184
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 1
ER -
