GSK609 an agonist IgG4 monoclonal 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) head and neck squamous cell carcinoma (HNSCC).
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 were evaluated for PK and PD effects on lymphocytes and ICOS receptor occupancy (RO). Tumor biopsies at screening and week 6 were evaluated for changes in tumor immune infiltrates (TIL) by a multiplexed immuno-fluorescence and gene expression platforms.
The GSK609 PK disposition showed 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 demonstrated non-linear, dose-dependent changes in select immune activation markers. Exposure-response assessments revealed 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 demonstrated similar safety outcomes across the exposures/doses. Additionally, population PK modeling suggests comparable exposures can be maintained by fixed dosing as well.
The current data provide preliminary evidence of GSK609 target engagement and biological activity at clinically tolerable doses and support further exploration of the 0.3 mg/kg or 24mg fixed dose.
NCT02723955.
Chloe Stevenson of Fishawack Indicia Ltd, UK.
GlaxoSmithKline.
GlaxoSmithKline (GSK) in collaboration with Merck Sharp & Dohme Corp.
E. Angevin: Advisory/Consultancy, Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: MSD; Advisory/Consultancy, Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: GSK; Advisory/Consultancy: Celgene Research; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: MedImmune; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: AbbVie; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Aduro; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Agios; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Amgen; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Argen-x; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Astex; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: AstraZeneca; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: Roche; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: Sanofi; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: Innate Pharma; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: Celgene; Research grant/Funding (institution), Travel/Accommodation/Expenses, principal/sub-investigator of Clinical Trials: BMS; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Aveo pharmaceuticals; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Beigene; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Blueprint; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Boehringer Ingelheim; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Chugai; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Clovis; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Daiichi Sankyo; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Debiopharm; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Eisai; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials Eos; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Bayer; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Exelixis; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Forma; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Gamamabs; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Genentech; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Gortec; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: H3 Biomedicine; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Incyte; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Janssen; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Kura Oncology; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Kyowa; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Lilly; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Loxo; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Lysarc; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Lytix Biopharma; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Menarini; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Merus; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Nanobiotix; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Nektar Therapeutics; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Novartis; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Octimet; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Oncoethix; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Oncopeptides AB; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Orion; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Pharmamar; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Pierre Fabre; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Servier; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Sierra Oncology; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Taiho; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Takeda; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Tesoro; Research grant/Funding (institution), principal/sub-investigator of Clinical Trials: Xencor. T. Bauer: Advisory/Consultancy: Ignyta; Advisory/Consultancy: Guardant Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Loxo; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Moderna Therapeutics; Speaker Bureau/Expert testimony: Bayer; Speaker Bureau/Expert testimony: Daiichi Sankyo; Speaker Bureau/Expert testimony: Medpacto Inc; Speaker Bureau/Expert testimony: Incyte; Speaker Bureau/Expert testimony: Mirati Therapeutics; Speaker Bureau/Expert testimony: MedImmune; Speaker Bureau/Expert testimony: AbbVie; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Speaker Bureau/Expert testimony: Leap Therapeutics; Speaker Bureau/Expert testimony: MabVax; Speaker Bureau/Expert testimony: Stemline Therapeutics; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Lilly; Speaker Bureau/Expert testimony: GSK; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Genentech/Roche; Speaker Bureau/Expert testimony: Deciphera; Speaker Bureau/Expert testimony: Merrimack; Speaker Bureau/Expert testimony: Immunogen; Speaker Bureau/Expert testimony: Millennium; Speaker Bureau/Expert testimony: Ignyta; Speaker Bureau/Expert testimony: Calithera Biosciences; Speaker Bureau/Expert testimony: Peleton; Speaker Bureau/Expert testimony: Kolltan Pharmaceuticals; Speaker Bureau/Expert testimony: Principia Biopharma; Speaker Bureau/Expert testimony: Immunocore; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Aileron Therapeutics; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Moderna Therapeutics; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Boehringer Ingelheim; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Astellas Pharma; Speaker Bureau/Expert testimony: Five Prime Therapeutics; Speaker Bureau/Expert testimony: Jacobio; Speaker Bureau/Expert testimony: Top Alliance BioScience; Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Clovis Oncology; Speaker Bureau/Expert testimony: Takeda; Speaker Bureau/Expert testimony: Karyopharm Therapeutics; Speaker Bureau/Expert testimony: Onyx; Speaker Bureau/Expert testimony: Phosplatin Therapeutics; Speaker Bureau/Expert testimony: Foundation Medicine; Speaker Bureau/Expert testimony: ARMO BioSciences; Travel/Accommodation/Expenses: Celgene; Travel/Accommodation/Expenses: EMD Serono; Travel/Accommodation/Expenses: Pharmacyclics; Travel/Accommodation/Expenses: Sysmex. D. Rischin: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Research grant/Funding (institution): GSK; Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution): Roche. V. Moreno: Advisory/Consultancy: Merck; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Regeneron/Sanofi; Research grant/Funding (institution): Medscape/Bayer. J.M. Trigo: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD. M. Chisamore: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. J. Shaik, F. Rigat, C. Ellis, H. Chen, R. Gagnon, S.J. Scherer, D. Turner, S. Yadavilli, A. Hoos: Shareholder/Stockholder/Stock options, Full/Part-time employment: GSK. M. Ballas: Shareholder/Stockholder/Stock options, Full/Part-time employment: GSK; Shareholder/Stockholder/Stock options: BMS; Shareholder/Stockholder/Stock options: Abbott; Shareholder/Stockholder/Stock options: Novartis. M. Maio: Advisory/Consultancy, Travel/Accommodation/Expenses: GSK; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: Incyte. All other authors have declared no conflicts of interest.