Abstract LB-127:  From bench to bedside: Exploring OX40 receptor modulation in a phase 1/2a study of the OX40 costimulatory agonist BMS-986178 ± nivolumab (NIVO) or ipilimumab (IPI) in patients with advanced solid tumors

Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-inhuman study evaluated MEDI0562 in adults with advanced solid tumors.Patients and Methods: In this phase I, multicenter, openlabel, single-arm, dose-escalation (3þ3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2-48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67 þ CD4 þ and CD8 þ memory T-cell proliferation in the periphery and decreased intratumoral OX40 þ FOXP3 þ cells.Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.

Section: Discussionmentioning

confidence: 99%

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors

Glisson

Leidner

Ferris

et al. 2020

“…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).…”

Section: Translational Relevancementioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Gutierrez

Moreno

Heinhuis

et al. 2021

Self Cite

This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, AE nivolumab and/or ipilimumab in patients with advanced solid tumors. Patients and Methods: Patients (with non-small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20-320 mg) AE nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1. Results: Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a followup of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3-4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts. Conclusions: In this study, BMS-986178 AE nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.

“…A population pharmacokinetic model was developed by nonlinear mixed-effects modeling using data from 90 participants from monotherapy and combination cohorts in the first-inhuman clinical study of BMS-986178. The pharmacokinetics and pharmacodynamics of BMS-986178 was linear, and was described by a two-compartment, zero-order intravenous infusion with first-order elimination (17). Subsequently, a pharmacokineticpharmacodynamic analysis (E max model) was conducted to characterize the relationship between BMS-986178 concentrations and blood receptor occupancy using data from 19 patients treated with 20-320 mg BMS-986178 in the clinical study.…”

Section: Statistical Analysis and Pharmacokinetic-pharmacodynamic Analysismentioning

confidence: 99%

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

Wang

Gao

Raymond

et al. 2019

Self Cite

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.