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First In-Human Study with GSK3359609, an Inducible T cell Costimulator Receptor Agonist in Patients with Advanced, Solid Tumours: Preliminary Results from INDUCE-1

| Oncology
Authors:
*Aaron R. Hansen,1 Todd M. Bauer,2 Victor Moreno,3 Michele Maio,4 Stefanie Groenland,5 Juan Martin-Liberal,6 Hui Gan,7 Danny Rischin,8 Michael Millward,9 Anthony J. Olszanski,10 Daniel C. Cho,11 Elaine Paul,12 Marc Ballas,13 Catherine Ellis,13 Helen Zhou,14 Sapna Yadavilli,13 Jafar Sadik Shaik,15 Emmett V. Schmidt,16 Axel Hoos,13 Eric Angevin17
Disclosure:

Dr Hansen has received fees for providing advisory and consulting services and research support for Genentech/Roche, Merck, GSK, Bristol-Myers Squibb, Novartis, Boston Biomedical, and Boehringer-Ingelheim. Dr Bauer has received fees for consulting or acting in an advisory role for Ignyta, Guardant Health, Loxo, Pfizer, and Moderna Therapeutics; and has received research funding from Daiichi Sankyo, Medpacto, Inc., Incyte, Mirati Therapeutics, Medimmune, AbbVie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Pfizer, Novartis, Genentech/Roche, Deciphera, Merrimack, Immunogene, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharm., Principa Biopharma, Peleton, Immunocore, Aileron Therapeutics, Roche, BMS, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Loxo, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, and Foundation Medicine. Dr Maio has received fees related to advisory boards and travel from GSK, Bristol-Myers Squibb, AstraZeneca, Roche, Merck Sharp & Dohme, and Incyte. Dr Gan has received fees for consulting or acting in an advisory role from Abbvie and Merck Serono; has received fees for being on a speaker’s bureau for Abbvie, Bristol Myers Squibb, Ignyta, Merck, Serono, and Eisai; has received research funding from Abbvie; and has received money for travel, accommodation, and expenses from Abbvie, Ignyta, and Merck Sharp & Dohme. Dr Rischin has sat on advisory boards/steering committees (uncompensated) for Merck, Amgen, Regeneron, and Bristol-Myers Squibb. Dr Millward has received fees for sitting on advisory boards for Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, and AstraZeneca. Dr Olszanski has received fees for consulting or acting in an advisory role for Bristol-Myers Squibb, G1 Therapeutics, Kyowa Hakko Kirin, Merck, Takeda, Array, Pfizer, EMD Serono, and Iovance. Dr Cho has received honoraria from Bristol-Myers Squibb, Exelixis, and Genentech; and has received fees for consulting or acting in an advisory role from Pfizer and Prometheus. Dr Angevin has received fees for consulting or acting in an advisory role from Merck Sharp & Dohme, GlaxoSmithKline, Celgene Research; has received money for travel, accommodations, and expenses from AbbVie, Roche, Sanofi, and Pfizer; and has been a principal or sub-investigator for 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 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, Merck Sharp & Dohme, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor. Dr Paul, Dr Ballas, Dr Ellis, Dr Zhou, Dr Yadavilli, and Dr Shaik are employees of and hold stocks/shares in GlaxoSmithKline. Dr Hoos is employee of and holds stocks/shares in GlaxoSmithKline; and is a Non-executive Director: Shareholder of Imugene. Dr Schmidt is an employee of and holds stocks/shares in Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. The remaining authors have declared no conflicts of interest.

Acknowledgements:

The authors thank the patients and families, as well as site staff and the GlaxoSmithKline 204691 study team.

Support:

Funding for this study (NCT02723955) was provided by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA.

Citation
EMJ Oncol. ;6[1]:68-71. Abstract Review No. AR1.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND

Inducible T cell costimulator (ICOS), a member of the CD28/B7 receptor superfamily, is expressed on T cells after T cell receptor engagement with cognate antigen.1 ICOS provides a costimulatory signal augmenting T cell expansion, function, and survival, and is involved in B cell function.2-4 GSK335609 is a humanised IgG4 antibody engineered to reduce Fc-mediated depleting effects yet retain cross-linking for potent agonist activity.5 Engagement of ICOS to stimulate agonist function is hypothesised to translate into an optimal therapeutic effect.4,6 GSK3359609’s unique mechanism offers an opportunity to investigate the antitumour potential of targeting a T cell costimulator alone and in combination.

METHODS

INDUCE-1 is a dose escalation (DE) and ongoing expansion phase study of GSK3359609 alone (Part 1) and in combination with pembrolizumab (Part 2).7 The modified toxicity probability interval informed DE decisions with three or more patients enrolled per dose level (DL). GSK3359609 was administered as an intravenous infusion every 3 weeks (Q3W) with or without 200 mg pembrolizumab Q3W; treatment continued up to 2 years or until progression or unacceptable toxicity. To be included in the study, patients needed to have metastatic or relapsed invasive malignancy, measurable disease, received five or fewer lines of prior therapy in the advanced setting, adequate organ function, and no active autoimmune disease requiring treatment; the PK/PD cohorts required pre-treatment and Day 43 on-treatment tumour biopsies. The primary objective was to determine safety, tolerability, and maximum tolerated (MTD) GSK3359609 dose.

RESULTS

In the DE phase and the PK/PD cohort, 98 patients enrolled. In Part 1, 22 patients enrolled in the DE cohort and 40 patients enrolled in the PK/PD cohort. In Part 2, 36 patients enrolled in the DE cohort. Most patients had microsatellite stable colorectal carcinoma (26%) and ≥2 baseline target lesions (57%); 37% had received ≥3 prior lines of therapy in the advanced setting and 31% prior anti-programmed cell death protein 1/ligand-1 therapy. In Part 1 (n=62), 22 patients (35%) had at least one treatment-related adverse event (TR-AE). The most frequent TR-AE (≥3 patients) were fatigue (15%), aspartate transaminase (AST) elevations (5%), and diarrhoea (3%); AST elevations were the most frequent Grade 3 or 4 TR-AE (n=2 [3%]). In Part 2, 15 patients (42%) had at least one TR-AE; the most frequent TR-AE were AST elevations (8%) and pyrexia (8%); no Grade 3 or 4 TR-AE occurred in >1 patient. One DLT occurred in DE: Grade 3 pneumonitis in a Part 2 patient treated at the top GSK3359609 DL of 3 mg/kg, which led to discontinuation of both drugs. In the PK/PD cohort, liver enzyme increases in one patient (GSK3359609 3 mg/kg) were DLT and the only TR-AE leading to treatment discontinuation. Disease progression was the primary reason for treatment discontinuation (92%). Approximate dose proportional increases in systemic GSK3359609 concentrations over 0.01–3.00 mg/kg DL were observed. At DL ≥0.3 mg/kg, ICOS receptor occupancy was ≥75% across the dosing interval. On-target PD effects in tumour infiltrating lymphocytes and clinical activity were observed in Part 1 and 2, including in anti-programmed cell death protein 1/ligand-1 therapy experienced patients (Figure 1).

Figure 1: Axial CT images of left upper lobe lung lesion and subcutaneous left bicep lesion.
Fifty-three-year-old male diagnosed with Stage IIIc, BRAF/cKIT mutation-negative nodular melanoma; previous regimens included treatment with the combination of ipilimumab and nivolumab for approximately 2 months (BoR was SD); nivolumab alone for approximately 1 year (BoR was SD). At baseline, total disease burden was five target lesions (sum of diameters was 225 mm) and multiple non-target lesions. In this study, the patient received GSK3359609 monotherapy in three 0.1 mg/kg doses until Week 48. After Week 48, the dose was 1 mg/kg; the BoR was PR.
BoR: best overall response; PR: partial response; SD: stable disease.

CONCLUSION

GSK3359609 alone and in combination with pembrolizumab was well-tolerated across the 0.001–3.000 mg/kg dose range. MTD was not reached; the maximum administered dose was 3 mg/kg. A range of doses (≥0.1–1.0 mg/kg) showed biological and clinical activity. These doses are under investigation in expansion cohorts to establish the GSK3359609 dose and assess clinical activity across different patient groups. Preliminary biological and clinical data support the mechanism of action of a non-depleting ICOS agonist as a clinical target.

References
Hutloff A et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 1999;397(6716):263-6. Simpson TR et al. Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr Opin Immunol. 2010;22(3):326-32. Mak TW et al. Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat Immunol. 2003;4(8):765-72. Fan X et al. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med. 2014;211(4):715-25. Mayes P et al. The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Disc. 2018;17(7):509-27. Brett S et al. Nonclinical evaluation of a non-depleting, first-in-class humanized IgG4 agonist anti-ICOS antibody. Abstract 1840P. ESMO Congress, 19-23 October, 2018. GlaxoSmithKline. Dose Escalation and Expansion Study of GSK3359609 in Subjects With Selected Advanced Solid Tumors (INDUCE-1). NCT02723955. https://clinicaltrials.gov/ct2/show/NCT02723955.