4514 - Pharmacokinetic/ pharmacodynamic (PK/PD) exposure-response characterization of GSK3359609 (GSK609) from INDUCE-1, a phase I open-label study

Background

GSK609 an agonist non-T cell depleting 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) 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.

Clinical trial identification

NCT02723955 (Rel. 31March2016).

Editorial acknowledgement

Legal entity responsible for the study

GlaxoSmithKline.

Funding

GlaxoSmithKline.

Disclosure

M. Maio: Honoraria (self): BMS, MSD, Roche, Merck, Eli Lilly; Honoraria (institution), Patients’ fee to the University Hospital of Siena: BMS, MSD, AZ, Roche, Merck; Advisory / Consultancy: BMS, MSD, Roche, Merck, Eli Lilly; Travel / Accommodation / Expenses: BMS, MSD, Roche, Merck, Eli Lilly; Non-remunerated activity/ies, Press conferences: Merck, BMS. T. Bauer: Advisory / Consultancy, Self: Guardant Health; Loxo; Pfizer; Advisory / Consultancy, Institution: Ignyta; Moderna Therapeutics; Pfizer; Speaker Bureau / Expert testimony, Self: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Medpacto, Inc.; Incyte; Mirati Therapeutics; MedImmune; Abbvie; AstraZeneca; Leap Therapeutics; MabVax; Stemline Therapeutics; Merck; Lilly; GlaxoSmithKline; Novartis, Pfizer; Genentech/Roche; Deciphera; Merrimack; Immunogen; Millennium; I; Travel / Accommodation / Expenses: Astellas Pharma; AstraZeneca; Celgene; Clovis Oncology; EMD Serono; Genentech; Lilly; Merck; Novartis; Pharmacyclics; Sysmex. D. Rischin: Advisory / Consultancy, All uncompensated : MSD, Regeneron, GSK, BMS; Research grant / Funding (institution): Regeneron, Roche, MSD, GSK, BMS; Travel / Accommodation / Expenses: MSD. V. Moreno: Advisory / Consultancy: Merck, BMS; Travel / Accommodation / Expenses: Regeneron/Sanofi, BMS. J.M. Trigo Perez: Advisory / Consultancy: Regeneron/Sanofi, BMS; Speaker Bureau / Expert testimony: Regeneron/Sanofi, BMS; Travel / Accommodation / Expenses: Regeneron/Sanofi, BMS. M. Chisamore: Full / Part-time employment: Merck & Co. Inc; Shareholder / Stockholder / Stock options: Merck & Co. Inc. J. Sadik Shaik: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. F. Rigat: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. C. Ellis: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. H. Chen: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. R. Gagnon: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. S. Scherer: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. D. Turner: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. S. Yadavilli: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. M. Ballas: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. A. Hoos: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. E. Angevin: Advisory / Consultancy: Merck Sharp & Dohme, GlaxoSmithKline, Celgene Research, MedImmune; Travel / Accommodation / Expenses: AbbVie, Roche, Sanofi, Pfizer, MedImmune, Innate Pharma, Celgene, BMS; Research grant / Funding (institution): Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio. All other authors have declared no conflicts of interest.