First-in-Human Phase I Study of the OX40 Agonist GSK3174998 With or Without Pembrolizumab in Patients With Selected Advanced Solid Tumors (Engage-1)

Authors

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

Publication Date

3-1-2023

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

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.

Keywords

Humans, Neoplasms, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Antibodies, Monoclonal, Tumor Microenvironment

Comments

Supplementary Materials

PMID: 36927527