TY - JOUR T1 - First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1) JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2022-005301 VL - 11 IS - 3 SP - e005301 AU - Sophie Postel-Vinay AU - Vincent K Lam AU - Willeke Ros AU - Todd M Bauer AU - Aaron R Hansen AU - Daniel C Cho AU - F Stephen Hodi AU - Jan H M Schellens AU - Jennifer K Litton AU - Sandrine Aspeslagh AU - Karen A Autio AU - Frans L Opdam AU - Meredith McKean AU - Neeta Somaiah AU - Stephane Champiat AU - Mehmet Altan AU - Anna Spreafico AU - Osama Rahma AU - Elaine M Paul AU - Christoph M Ahlers AU - Helen Zhou AU - Herbert Struemper AU - Shelby A Gorman AU - Maura Watmuff AU - Kaitlin M Yablonski AU - Niranjan Yanamandra AU - Michael J Chisamore AU - Emmett V Schmidt AU - Axel Hoos AU - Aurelien Marabelle AU - Jeffrey S Weber AU - John V Heymach Y1 - 2023/03/01 UR - http://jitc.bmj.com/content/11/3/e005301.abstract N2 - Background The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.Methods GSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.Conclusions GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration number NCT02528357.Data are available upon reasonable request. Information about GlaxoSmithKline’s data sharing commitments and access requests to anonymized individual participant data and associated documents can be requested for further research from ClinicalStudyDataRequest.com. ER -