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Importance
Multiple immunostimulatory agonist antibodies have been clinically
tested in solid tumors to evaluate the role of targeting
glucocorticoid-induced tumor necrosis factor (TNF) receptor-related
protein in anticancer treatments.
Objective
To evaluate the safety and activity of the fully human
glucocorticoid-induced TNF receptor-related protein agonist IgG1
monoclonal antibody BMS-986156 with or without nivolumab in patients
with advanced solid tumors.
Design, Setting, and Participants
This global, open-label, phase 1/2a study of BMS-986156 with or
without nivolumab enrolled 292 patients 18 years or older with
advanced solid tumors and an Eastern Cooperative Oncology Group
performance status of 1 or less. Prior checkpoint inhibitor therapy
was allowed. Monotherapy and combination dose-escalation cohorts ran
concurrently to guide expansion doses beginning October 16, 2015;
the study is ongoing.
Interventions
The protein agonist BMS-986156 was administered intravenously at a
dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy,
and in the combination group 30, 100, 240, or 800 mg plus 240 mg of
nivolumab every 2 weeks; same-dose cohorts were pooled for analysis.
One cohort also received 480 mg of BMS-986156 plus 480 mg of
nivolumab every 4 weeks.
Main Outcomes and Measures
The primary end points were safety, tolerability, and dose-limiting
toxic effects. Additional end points included antitumor activity per
Response Evaluation Criteria in Solid Tumors, version 1.1, and
exploratory biomarker analyses.
Results
With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34
patients (16 women and 18 men; median age, 56.6 years [range, 28-75
years]) received monotherapy (4 patients completed initial
treatment), and 258 patients (140 women and 118 men; median age, 60
years [range, 21-87 years]) received combination therapy (65
patients completed initial treatment). No grade 3 to 5
treatment-related adverse events occurred with BMS-986156
monotherapy; grade 3 to 4 treatment-related adverse events occurred
in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no
grade 5 treatment-related adverse events. One dose-limiting toxic
effect (grade 4 elevated creatine phosphokinase levels) occurred in
a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab
every 2 weeks; BMS-986156 with or without nivolumab exhibited linear
pharmacokinetics with dose-related increase after a single dose.
Peripheral T-cell and natural killer-cell proliferation increased
after administration of BMS-986156 with or without nivolumab. No
consistent and significant modulation of intratumoral CD8+ T cells
and FoxP3+ regulatory T cells was observed. No responses were seen
with BMS-986156 alone; objective response rates ranged from 0% to
11.1% (1 of 9) across combination therapy cohorts, with a few
responses observed in patients previously treated with
anti-programmed death receptor (ligand) 1 therapy.
Conclusions and Relevance
Based on this cohort, BMS-986156 appears to have had a manageable
safety profile, and BMS-986156 plus nivolumab demonstrated safety
and efficacy comparable to historical data reported for nivolumab
monotherapy.
Trial Registration
ClinicalTrials.gov identifier: NCT02598960.
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