First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)

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: antibodies, neoplasm; biomarkers, tumor; clinical trials as topic; costimulatory and inhibitory T-cell receptors; immunotherapy.

Figure 1

Pharmacokinetics and receptor occupancy of GSK3174998 during the first dosing cycle of GSK3174998 monotherapy. (A) Median plasma concentration-time profiles of GSK3174998 for cycle 1 displayed on a semi-logarithmic scale in Part 1. (B) Median receptor occupancy of GSK3174998 (%) on CD3+ T cells over time in Part 1. The highlighted dose level (0.3 mg/kg) was selected for further clinical evaluation in Part 2b expansion cohorts (GSK3174998+pembrolizumab). CD, cluster of differentiation; LLQ, lower limit of quantification.

Figure 2

Percentage change in sum of target lesion diameters from baseline in (A) Part 1 dose escalation (GSK3174998 alone), (B) Part 2 dose escalation (GSK3174998+pembrolizumab), and (C) Part 2 dose expansion (GSK3174998+pembrolizumab; one patient with soft tissue sarcoma was not evaluable) assessed using irRECIST. irRECIST, immune-related Response Evaluation Criteria in Solid Tumors; PD-1, programmed cell death 1 protein; PD-L1, programmed cell death 1 ligand.

Figure 3

Multiplexed immunofluorescence analysis of OX40 expression. (A) OX40 expression in baseline tumor biopsies (fresh and archival samples). Baseline tumor expression of OX40 is low (0% to 1.4% across all tested samples). (B) Dose dependence of fold changes in OX40+ cell subsets from baseline to on-treatment (week 6) paired fresh tumor biopsies. From left to right: Row 1: CD134+, PD-1+CD134+; Row 2: CD16−CD56+CD134+, CD16+CD56−CD134+, CD16+CD56+CD134+; Row 3: CD3+CD4+ FOXP3−CD134+, CD3+CD4+FOXP3+CD134+, CD3+CD4+FOXP3+PD-1+CD134+, CD3+CD4+FOXP3−PD-1+CD134+; Row 4: CD3+CD8+granzyme B−CD134+, CD3+CD8+granzymeB+CD134+, CD3+CD8+granzymeB−PD-1+CD134+, CD3+CD8+granzymeB+PD-1+CD134+. CD, cluster of differentiation; FOXP3, forkhead box protein 3; PD-1, programmed cell death 1 protein.

Figure 4

CT scans and multiplexed immunofluorescence analysis of immune cell infiltration in paired biopsies from responding patients. (A, B) GSK3174998 monotherapy (0.3 mg/kg dose)—dedifferentiated liposarcoma. (A) PD-(L)1-naive female patient in her mid-60s with dedifferentiated liposarcoma who remained on 0.3 mg/kg GSK3174998 monotherapy for 39 weeks. At the time her first scan was performed at week 12, her two target lesions (sum of diameters=167 mm) had decreased in size by 29% and further decreased by 38% at 24 weeks (baseline and week 24 scans are shown). The target lesion response was maintained; however, non-target lesion disease progression resulted in treatment discontinuation at week 39. Prior to receiving GSK3174998, the patient’s treatment was surgery, then metronomic doxorubicin (15 mg/kg weekly) ending 1 month before initiating treatment with GSK3174998. Multiplexed immunofluorescence analysis of baseline and week 6 paired tumor biopsy samples show decreased Treg and increased NK/NKT cell infiltration. (B) Changes in immune cell subsets in tumor tissue from baseline to week 6. Immune cells displaying >5-fold changes are highlighted. (C, D) GSK3174998 (0.1 mg/kg dose) + pembrolizumab (200 mg) – melanoma. (C) A male patient in his early 60s with melanoma treated with prior ipilimumab+nivolumab until disease progression after 14 months, ending treatment with nivolumab ≈2 months before initiating treatment with 0.1 mg/kg GSK3174998+pembrolizumab 200 mg. At week 4, the patient developed organizing pneumonia and treatment was held until week 9, when CT scans showed an 8% reduction in target lesions (sum of diameters=98); 12 weeks later, the target lesions had achieved CR, which was maintained for the duration the patient remained on study, completing the 2-year treatment period and remaining in follow-up until the study was closed (baseline and week 57 scans are shown). Multiplexed immunofluorescence analysis of baseline and week 6 paired tumor biopsy samples show decreased Treg and increased NK/NKT cell infiltration. (D) Changes in immune cell subsets in tumor tissue from baseline to week 6. Immune cells displaying >5-fold changes are highlighted. (E, F) GSK3174998 (0.3 mg/kg dose) + pembrolizumab (200 mg) – NSCLC. (E) PD-(L)1-naive female patient in her mid-50s with NSCLC (TPS=1%) with no activating mutations and who had received prior treatment with carboplatin, pemetrexed, and bevacizumab. She received 0.3 mg/kg GSK3174998+pembrolizumab 200 mg treatment for the maximum duration of 2 years. At her week-6 CT scan, the target lesion (54 mm) had decreased in size by 37% and continued to decrease to a maximum of 64%, maintaining a PR for the duration of the study (baseline and week 36 scans are shown). Multiplexed immunofluorescence analysis of baseline and week 6 paired tumor biopsy samples show increased infiltration of T helper cells, cytotoxic T cells, granzyme B–expressing CD8+ T cells, ICOS+ T cells, and proliferating cytotoxic T cells. (F) Changes in immune cell subsets in tumor tissue from baseline to week 6. Immune cells displaying >5-fold changes are highlighted. CD, cluster of differentiation; CR, complete response; FOXP3, forkhead box protein 3; H&E, hematoxylin and eosin; HLA-DR, human leukocyte antigen D related; ICOS, inducible T-cell costimulatory; NK, natural killer; NKT, natural killer T cell; NSCLC, non-small cell lung cancer; PanCK, pan cytokeratin; PD-1, programmed cell death 1 protein; PD-L1, programmed cell death 1 ligand; PR, partial response; Treg, regulatory T cell; TPS, tumor proportion score.