Exploratory PGx analysis of germline genetic variants in candidate genes and clinical response in study 204691

Trial description: GSK3359609 is a humanized anti-ICOS monoclonal antibody (mAb) selected for binding to and agonist activity in ICOS-expressing CD4+ and CD8+ effector T cells, which is specifically engineered with two amino acid changes from the native human immunoglobulin 4 (IgG4), referred to as IgG4PE. It is in development for the treatment of cancers as monotherapy and/or combination with agents that prime or modulate tumor immunity. GSK3359609 binds to the Fcγ receptors, e.g. FcγRIIb (main) and FcγRIIa, to modulate antibody agonist activity, which also may be essential for optimal ICOS agonist activity and associated antitumor effects in humans. Genetic variation in FCGRs, e.g. FCGR2B I231T, FCGR2A H131R, and FCGR3A V158F, have been reported to affect the receptors’ function, and would potentially impact target engagement and therapeutic effects of treatment with agonistic mAbs. Germline genetic variants in ICOS and ICOSLG were reported to disrupt the regulatory role of miRNAs in the expression of ICOS/CD28, which might contribute to the occurrence and progress of colorectal cancers. Interim cuts of the clinical data may be assessed on an ongoing basis as well as a final assessment at the completion of study 204961. The initial interim analysis is an exploratory evaluation of the effects of genetic variants in FCGRs and ICOS/ICOSLG on clinical response to GSK3359609 in subjects from Study 204691, who provided written informed consent for genetic research, DNA samples, were successfully genotyped, and have valid clinical endpoint data available. Analysis will assess whether candidate genetic variants in FCGRs and ICOS/ICOSLG are associated with efficacy, overall response rate (ORR), lesion change from baseline, and progression-free survival (PFS), in the analysis population using appropriate models. In addition, relationships between the ICOS/ICOSLG variants and tissue mRNA, and between HLA genotypes and efficacy will be explored, respectively. Based on numbers of subjects being included for these exploratory analyses, power to detect genetic effects is likely limited. For each endpoint evaluated, statistical significance will be considered at the p-value ≤0.05, adjusted for the number of candidate variants tested.A final assessment will be conducted after the completion of study 204691. The analysis of additional efficacy or safety endpoints may be conducted if of clinical relevance. Analysis of genome wide variation (GWAS) may be included and appropriate significance thresholds applied. Additional interim analyses may be conducted if warranted based on the findings in clinical interim analyses.