Pharmacokinetic/ pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study

Abstract

Background: GSK609 an agonist non-T cell depleting IgG4monoclonal antibody (mAb) against inducible co-stimulatory receptor (ICOS) exhibits T cell mediated immune stimulating and anti-tumor activity. INDUCE-1 is the first in human study investigating GSK609 alone and in combinations which include pembrolizumab in select tumor types including recurrent/metastatic (R/M) HNSCC. Methods: Safety, PK, PD, and preliminary antitumor activity of GSK609 are being evaluated at doses from 0.001 to 10 mg/kg every 3 weeks (Q3W). Blood samples collected prior to dosing and on-study are evaluated for PK and PD effects on lymphocytes and ICOS receptor occupancy (RO). Tumor biopsies at Screening and Week 6 are evaluated for changes in tumor immune infiltrates (TIL) by a multiplexed immuno-fluorescence and gene expression platforms. Results: The GSK609 PK disposition shows low clearance, limited central volume of distribution, and mean systemic half-life of 19 days which is consistent with other humanized mAbs. Evidence of target engagement and tumor size reduction are observed in a R/M HNSCC expansion cohort (EC) at 0.3 mg/kg with 200 mg pembrolizumab. Dose and concentration-RO analyses suggest ≥0.1 mg/kg GSK609 maintains ≥ 70% RO on peripheral CD4+ and CD8+ T cells. Quantitative TIL evaluation of paired tumor biopsies demonstrates favorable immune microenvironment in the tumor at exposures observed in patients treated with 0.3mg/kg. TIL and tumor-based gene expression data demonstrate non-linear, dose-dependent changes in select immune activation markers. Exposure-response assessments reveal no difference in baseline-to- Week 9 target lesion change across exposures in the EC. Furthermore, cross-cohort pooled exposure-response analysis of ≥Grade 2 AEs demonstrates similar safety outcomes across the exposures/doses. Additionally, population PK modeling suggests comparable exposures can be maintained by fixed dosing as well. Conclusions: The current data provide preliminary evidence of GSK609 target engagement and biological activity at clinically tolerable doses and support further exploration of the 0.3mg/kg or 24mg fixed dose.