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)

Abstract

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 naïve 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 (<2% total cells in tumor were OX40 +ve). MultiOmyxTM data from tumor biopsies suggested increased NK/decreased Treg involvement in some responders. Conclusions: GSK998 +/- pembrolizumab was well tolerated, with evidence of target engagement; monotherapy clinical activity was limited. While combination responses may not be significantly greater than expected for pembrolizumab alone, responses were observed in some PD-1/L1 experienced pts and some with low PD-L1 expression. Given the low OX40 expression observed and preclinical evidence that increased expression improves activity of OX40 agonism, ongoing clinical evaluation of GSK998 will assess whether concurrent immune-stimulation or immunogenic cell death impacts OX40 expression and increases the efficacy of this agent. Combinations with TLR4 and ICOS agonists and an anti-BCMA antibody-drug conjugate are ongoing. 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, Aurélien 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.

Immunotherapies targeting stimulatory pathways and beyond

“…GSK3174998 (GSK998), a humanized IgG1 mAb that targets and stimulates OX40 on T cells, is being investigated as monotherapy or in combination with pembrolizumab in a phase I clinical trial in patients with previously treated, advanced solid malignancies (NCT02528357). Results for 138 patients including 45 on monotherapy and 96 on combination therapy were published in an abstract [ 35 ]. The ORR was 7% and the DCR was 14%.…”

“…Two patients achieved a CR in the combination cohort. Eight patients achieved a PR (1 monotherapy and 7 combination) and 10 achieved SD (1 monotherapy and 9 combination) [ 35 ]. In the dose-escalation phase, there were 2 DLTs reported in the combination group including 1 grade 3 pleural effusion and 1 grade 1 myocarditis.…”

Update of early phase clinical trials in cancer immunotherapy

“…GSK3174998 was studied with or without pembrolizumab. There was one PR out of 45 patients enrolled in the monotherapy part, and 2 CRs and 7 PRs out of 96 patients enrolled in the combination part ( 26 ). GSK3174998 is now being explored in combination with other agents, such as pembrolizumab or GSK1795091, a toll-like receptor 4 agonist (TLR4).…”

Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma

“…Co-stimulatory receptors are present on T cells and counter-act the negative regulation of inhibitory receptors such as PD-1 and CTLA-4 ( 51 ). Phase I studies of anti-OX40 agonists have yielded disappointing results, with a single partial response noted in the trial of MEDI0562 in advanced solid tumors, and best response of stable disease with GSK998 ( 52 , 53 ). When combined with pembrolizumab in a trial enrolling 96 patients, anti-OX40, gave 2 CRs and 7PRs ( 53 ).…”

“…Phase I studies of anti-OX40 agonists have yielded disappointing results, with a single partial response noted in the trial of MEDI0562 in advanced solid tumors, and best response of stable disease with GSK998 ( 52 , 53 ). When combined with pembrolizumab in a trial enrolling 96 patients, anti-OX40, gave 2 CRs and 7PRs ( 53 ). 4-1BB targeted therapy was complicated by hepatic toxicity that was mitigated at lower doses ( 54 ).…”