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)
AU - Postel-Vinay, Sophie
AU - Lam, Vincent K.
AU - Ros, Willeke
AU - Bauer, Todd M.
AU - Hansen, Aaron R.
AU - Cho, Daniel C.
AU - Stephen Hodi, F.
AU - Schellens, Jan H.M.
AU - Litton, Jennifer K.
AU - Aspeslagh, Sandrine
AU - Autio, Karen A.
AU - Opdam, Frans L.
AU - McKean, Meredith
AU - Somaiah, Neeta
AU - Champiat, Stephane
AU - Altan, Mehmet
AU - Spreafico, Anna
AU - Rahma, Osama
AU - Paul, Elaine M.
AU - Ahlers, Christoph M.
AU - Zhou, Helen
AU - Struemper, Herbert
AU - Gorman, Shelby A.
AU - Watmuff, Maura
AU - Yablonski, Kaitlin M.
AU - Yanamandra, Niranjan
AU - Chisamore, Michael J.
AU - Schmidt, Emmett V.
AU - Hoos, Axel
AU - Marabelle, Aurelien
AU - Weber, Jeffrey S.
AU - Heymach, John V.
N1 - Funding Information:
The authors acknowledge the following individuals for their contributions and critical review during the development of this manuscript: Yolanda Alvarez, Sara Brett, Bob Gagnon, and Hoang Tran, and Vinod Kumar from GlaxoSmithKline (GSK). The authors also wish to acknowledge the patients who participated in this study, their families and caregivers, site personnel, and the GSK, Merck, ICON, and Neogenomics teams. Editorial support was provided by Brittany Woodby, PhD, at MediTech Media and was funded by GSK.
Publisher Copyright:
© 2023 BioMed Central Ltd.. All rights reserved.
PY - 2023/3/16
Y1 - 2023/3/16
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.
AB - 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.
KW - antibodies, neoplasm
KW - biomarkers, tumor
KW - clinical trials as topic
KW - costimulatory and inhibitory T-cell receptors
KW - immunotherapy
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U2 - 10.1136/jitc-2022-005301
DO - 10.1136/jitc-2022-005301
M3 - Article
C2 - 36927527
AN - SCOPUS:85150313762
SN - 2051-1426
VL - 11
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 3
M1 - e005301
ER -