SNPs of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T cell priming, are associated with auto- and allo-immunity. Previously, studies implied a role for these SNPs as surrogate markers for outcome in melanoma patients treated with immune checkpoint inhibitors. However, no predictive SNPs are defined to date. The primary aim of this study was to analyze different CTLA-4 SNPs in a large real-world cohort of melanoma patients treated with ipilimumab and to correlate these SNPs with toxicity and survival.
Archival blood and/or tumor-tissue samples were collected from 317 advanced stage melanoma patients treated with ipilimumab (+/- nivolumab) in 5 Swiss and Dutch hospitals. DNA was extracted and used for MALDI-TOF MS based genotyping for 11 different SNPs. Associations between different allele genotypes and occurrence of grade ≥3 toxicity, treatment response and survival outcomes were tested using univariable logistic regressions or Cox proportional hazard models.
DNA of 216/317 patients could be analyzed. The cohort was representative of a real-life population of metastatic melanoma patients receiving ipilimumab (+/- nivolumab): among the remaining 216/317 evaluable patients, 65.3% were male, median age at diagnosis was 59 years, 37% of patients had partial or complete response and 59% had ≥1 immune-related adverse events. A TT-genotype in the -1722 C/T SNP (rs733618, T=0.8345 (1000Genomes)), located in the promoter region of CTLA-4, was significantly associated with a decreased rate of ≥ grade 3 toxicity [odds ratio=0.40; CI95=0.16 - 1.00; p=0.049]. The TT-genotype in the Jo27 T/C SNP (rs11571297, T=0.5575 (1000Genomes)) [hazard ratio (HR)=0.54; CI95=0.28-1.02, p=0.056] and the GG-genotype in the Jo31 SNP (rs11571302, G=0.5713 (1000Genomes) [HR=0.54; CI95 = 0.29-0.99, p=0.046], both located at the 3’ untranslated region, were associated with increased overall survival.
CTLA-4 SNPs might be predictive of toxicity and/or survival in melanoma patients receiving ipilimumab. Confirmatory studies are needed to exploit findings of this exploratory study and to investigate the exact role of CTLA-4 SNPs as possible biomarkers.
The authors.
BMS.
K.D. Joode: Financial Interests, Personal, Other, Travel expenses congress: Ipsen. A.A.M. Van der Veldt: Financial Interests, Institutional, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi. R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Licensing Fees, Patent pending: Pamgene; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. Y. Metaxas: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb. All other authors have declared no conflicts of interest.