Abstract CT150: A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1)

Background: OX40 is a costimulatory receptor transiently expressed on the surface of activated T cells and some innate immune cells (e.g. NK cells). OX40 agonists have been shown to increase antitumor immunity and improve tumor-free survival in preclinical models, demonstrating increased efficacy when given in combination with a PD-1 inhibitor. GSK998 is a humanized IgG1 agonistic OX40 monoclonal antibody. Methods: ENGAGE-1 (NCT02528357) is a Phase 1 dose escalation study evaluating safety, PK, PD, and clinical activity of GSK998 (0.003-10 mg/kg IV Q3W) alone (Part 1) and in combination with pembrolizumab 200 mg IV Q3W (Part 2) in pts with previously treated advanced solid tumors: non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma (MEL), bladder cancer, soft tissue sarcoma (STS), triple-negative breast cancer, and MSI-high colorectal carcinoma. Dose escalation used a continuous reassessment method and 4-week DLT period. Results: A total of 138 pts were enrolled (45 Part 1, 96 Part 2; 3 crossed over from Part 1). Two DLTs occurred in Part 2 only (G3 non-malignant pleural effusion 0.03 mg/kg; G1 myocarditis 10 mg/kg); MTD was not established. Most common (≥10%) treatment-related AEs (mostly G1-2) were diarrhea, fatigue (Part 1) and fatigue, nausea (Part 2). GSK998 demonstrated target engagement in the periphery as evidenced by PK and receptor occupancy (RO); a dose of 0.3 mg/kg was the threshold for linear PK & peripheral RO saturation over the 3-wk dose interval and was selected for further clinical evaluation in MEL, STS, and NSCLC in Part 2 expansion. Clinical responses and SD ≥24 weeks were observed in both PD-1/L1 naive and experienced pts: Part 1 (1 PR, 1 SD; both 0.3 mg/kg) and Part 2 (2 CR, 7 PR, 9 SD; 0.01-3 mg/kg); Part 2 clinical responses were not correlated with baseline tumor PD-L1 expression levels; including one MEL pt with PD-L1 TPS=0 who progressed on prior CTLA-4/PD-1 treatment and had a CR (>18mo). Overall, peripheral and tumor expression of OX40 was low ( Citation Format: Sophie Postel-Vinay, Vincent K. Lam, Willeke Ros, Todd M. Bauer, Aaron R. Hansen, Daniel C. Cho, F. Stephen Hodi, Jan H.M. Schellens, Jennifer K. Litton, Sandrine Aspeslagh, Karen A. Autio, Frans L. Opdam, Meredith McKean, Neeta Somaiah, Stephane Champiat, Mehmet Altan, Anna Spreafico, Osama Rahma, Elaine M. Paul, Christoph M. Ahlers, Helen Zhou, Herbert Struemper, Shelby A. Gorman, Maura Watmuff, Kaitlin M. Yablonski, Niranjan Yanamandra, Michael J. Chisamore, Emmett V. Schmidt, Axel Hoos, Aurelien Marabelle, Jeffrey S. Weber, John V. Heymach. A first-in-human phase I study of the OX40 agonist GSK3174998 (GSK998) +/- pembrolizumab in patients (Pts) with selected advanced solid tumors (ENGAGE-1) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT150.