First in human study with GSK3359609 [GSK609], inducible T cell co-stimulator (ICOS) receptor agonist in patients [Pts] with advanced, solid tumors: Preliminary results from INDUCE-1

Background: ICOS, a member of CD28/B7 superfamily, is expressed on T cells (TC) after TC receptor engagement with cognate antigen. ICOS provides a costimulatory signal augmenting TC expansion, function and survival. GSK609 is a humanized, IgG4 antibody engineered to reduce Fc-mediated depleting effects yet retain cross-linking for potent agonist activity against human ICOS. GSK609's unique profile as a pure TC agonist void of TC depleting effects offers antitumor potential as monotherapy and in rational combinations with agents that modulate key immune pathways. Methods: INDUCE-1 evaluates safety, PK, PD, and antitumor activity of GSK609 given as an intravenous (IV) infusion every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab [P] Q3W (Part 2). Modified toxicity probability interval informed dose escalation [DE] decisions (≥ 3 pts/dose level [DL]). Eligible pts must have relapsed disease, adequate organ function, no active autoimmune disease requiring treatment; prior immunotherapy was allowed. Pts remained on treatment until progression or unacceptable toxicity. Blood was collected for safety, PK, PD; tumor biopsies collected for PD. Results: To date, 79 pts enrolled, Part 1: 22 in DE and 30 in PK/PD cohort; Part 2: 27 in DE. In Part 1, 45 pts (87%) had adverse events (AEs); most frequent (≥20%) regardless of cause were fatigue (29%) and pain (19%). Fatigue was the most frequent treatment-related (TR) event (15%); liver enzyme increases in 1 pt were the only TR AEs leading to discontinuation. In Part 2, 25 pts (93%) had AEs; most frequent were nausea (33%), fatigue (26%), arthralgia (22%), decreased appetite (22%) and vomiting (22%). Pyrexia was the most frequent TR AE (7%); no TR AE led to discontinuation. No DLTs were reported in DE with Part 2 ongoing at planned, top DL. In Part 1, GSK609 showed approximate dose proportional increases in systemic exposures over the 0.01 – 3 mg/kg DLs. Clinical activity was seen in Part 1 and Part 2. Conclusions: GSK609 +/- P was well tolerated; MTD was not reached. AEs were manageable and most were unrelated to study treatment. Complete safety, PD and clinical activity data from DE and PK/PD will be presented. Clinical trial identification: NCT02723955, first posted date: March 31, 2016. Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: A. Hansen: Research support: Genentech/Roche, Merck, GlaxoSmithKline, Bristol Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim. T.M. Bauer: Consulting/advisory: Ignyta, Guardant Health, Loxo, Pfizer, Moderna Therapeutics; Research funding: Daiichi Sankyo, Medpacto, Inc, Incyte, Mirati Therapeutics, Medimmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Peleton, Immunocore, Roche, Aileron Therapeutics, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio. M. Maio: Patient's fee for subjects enrolled in clinical trials: BMS, GSK, AZ, Roche, MSD, Incyte, Novartis; Advisor/Board member: BMS, GSK, AZ, Roche, MSD, Incyte; Honorarium, compensation for Advisory Boards: BMS, GSK, AZ, Roche, MSD, Incyte; Travel expenses related to participation to Ad Boards/Scientific meetings: BMS, GSK, AZ, Roche, MSD, Incyte. H. Gan: Consulting/advisory: Abbvie, Merck Serono; Speakers' bureau: Abbvie, Bristol Myers Squibb, Ignyta; Research funding: Abbvie; Travel/accommodation expenses: Abbvie, Ignyta, MSD. D. Rischin: Research funding: Genentech/Roche, Merck, Amgen, Regeneron, Bristol-Myers Squibb, GSK. M. Millward: Consulting/advisory: Bristol-Meyers Squibb, Roche, Merck, Sharp & Dohme, Novartis, AstraZeneca. A.J. Olszanski: Consulting/advisory: Array, Bristol-Meyers Squibb, Merck, Takeda; Research funding: Amgen, Bristol-Meyers Squibb, EMD Serono, Immunocore, Incyte, Kura, Kyowa Hakko Kirin, Lilly, Pfizer, GSK, Takeda, Checkmate, Boston Biomedical, Astellas, Targovax. D.C. Cho: Honoraria: Bristol-Myers Squibb, Exelixis, Genentech; Consulting/advisory: Pfizer, Prometheus E. Paul, S. Yadavilli, J. Sadik Shaik, C. Ellis, H. Zhou: Employee and shareholder: GSK. M. Ballas: Employee and shareholder: GSK; Stockholder: BMS. E.V. Schmidt: Employment and stock holder: Merck. A. Hoos: Employee and shareholder: GSK; Non-Executive Director and stockholder: Imugene. E. Angevin: Consulting/advisory: GSK, MSD; Research funding: Abbvie, Roche, Sanofi. All other authors have declared no conflicts of interest.