An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors

Abstract

Purpose: The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study.Experimental Design: We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade.Results: Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4 þ and CD8 þ T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy > 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing.Conclusions: Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.

OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors

“…In addition, BMS-986178 treatment increased the proliferation of CD4 þ /CD8 þ effector memory cells that was enhanced when BMS-986178 was combined with nivolumab (anti-PD-1) or ipilimumab (anti-CTLA-4; ref. 28). Although increases in exposure corresponded with pharmacodynamic effects, as previously reported, the optimal dose of OX40 agonism may not be the highest dose possible.…”

“…The rationale for selection of these doses has been described previously and was based on pharmacokinetic and pharmacodynamic modeling of the relationship between RO, pharmacodynamic modulation, and efficacy (28)(29)(30)(31). On the basis of preclinical data, available RO data from the every 2 weeks cohort receiving monotherapy, and C min (minimum plasma concentration after dosing) data at day 14 (trough sample), a mathematical model was developed to predict RO at various dosing regimens (e.g., every 4 weeks, every 6 weeks, and every 12 weeks), taking into account interpatient variability in both pharmacokinetics and pharmacodynamics (RO), to maximize the potentiation of T-cell responses (28,31).…”

“…BMS-986178 is a fully human IgG1 agonist mAb that binds with high affinity to the OX40 receptor (28). Preclinical studies with the murine analogue OX40.23 as monotherapy demonstrated antitumor activity that was further enhanced when it was combined with checkpoint inhibitors (29).…”

“…In the phase I clinical trial, the combination of BMS-986178 and nivolumab or ipilimumab demonstrated linear pharmacokinetics with dose-related increases in exposure (30). BMS-986178 monotherapy increased proinflammatory cytokines, such as IFNg and the IFNg-induced cytokines CXCL9 and CXCL10, in patients with advanced solid tumors, with greater effects observed after combination therapy (28). In addition, BMS-986178 treatment increased the proliferation of CD4 þ /CD8 þ effector memory cells that was enhanced when BMS-986178 was combined with nivolumab (anti-PD-1) or ipilimumab (anti-CTLA-4; ref.…”

“…Although increases in exposure corresponded with pharmacodynamic effects, as previously reported, the optimal dose of OX40 agonism may not be the highest dose possible. Dose-optimization studies demonstrated that OX40 receptor occupancy (RO) between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a RO >40% led to a profound loss in OX40 receptor expression (28). Here we describe results of a phase I/IIa dose-escalation and -expansion study of BMS-986178 with or without nivolumab and/or ipilimumab in patients with advanced solid tumors (NCT02737475).…”