Abstract 4514
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.
Resources from the same session
5877 - Efficacy of anti-PD(L)1 treatment in patients with metastatic urothelial cancer based on mRNA- and protein- based PD-L1 determination: Results from the multicentric, retrospective FOsMIC trial
Presenter: Jonas Jarczyk
Session: Poster Display session 3
Resources:
Abstract
5204 - A differential bladder microbiota composition is associated with tumor grade in bladder cancer.
Presenter: Monica Parra-Grande
Session: Poster Display session 3
Resources:
Abstract
4904 - Molecular characterization of metastatic urothelial carcinoma (mUC) in prior or current smokers (PCS) vs non-smokers (NS)
Presenter: Victor Sacristan Santos
Session: Poster Display session 3
Resources:
Abstract
5370 - Evaluation of different diagnostic methods for identification of FGFR alteration in advanced urothelial carcinomas: Proficiency Results based on multiple RNA extraction kits and mutation detection methods
Presenter: Veronika Weyerer
Session: Poster Display session 3
Resources:
Abstract
2579 - Title: Genomic characterization of non-schistosomiasis-related squamous cell carcinoma (NSR-SCC) of the urinary bladder: a retrospective study of potential prognostic and predictive biomarkers
Presenter: Esmail Al-ezzi
Session: Poster Display session 3
Resources:
Abstract
2203 - TiNivo: Tivozanib combined with nivolumab results in prolonged progression free survival in patients with metastatic renal cell carcinoma (mRCC). Final Results.
Presenter: Philippe Barthelemy
Session: Poster Display session 3
Resources:
Abstract
4712 - First-Line Pembrolizumab (pembro) Monotherapy for Advanced Non‒Clear Cell Renal Cell Carcinoma (nccRCC): Updated Follow-Up for KEYNOTE-427 Cohort B
Presenter: Cristina Suárez
Session: Poster Display session 3
Resources:
Abstract
2091 - First-Line Pembrolizumab (pembro) Monotherapy in Advanced Clear Cell Renal Cell Carcinoma (ccRCC): Updated Follow-Up For KEYNOTE-427 Cohort A
Presenter: James Larkin
Session: Poster Display session 3
Resources:
Abstract
2368 - Association Between Depth of Response and Overall Survival: Exploratory Analysis in Patients With Previously Untreated Advanced Renal Cell Carcinoma (aRCC) in CheckMate 214
Presenter: Viktor Grünwald
Session: Poster Display session 3
Resources:
Abstract
6008 - Quality of life in previously untreated patients with advanced renal cell carcinoma (aRCC) in CheckMate 214: updated results
Presenter: David Cella
Session: Poster Display session 3
Resources:
Abstract