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    Original Investigation
    November 7, 2019

    Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor–Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors: A Phase 1/2a Dose-Escalation and Cohort-Expansion Clinical Trial

    Author Affiliations
    • 1Division of Pharmacology, The Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, the Netherlands
    • 2Department of Medical Oncology, Crown Princess Mary Cancer Centre Westmead Hospital, Westmead, Australia
    • 3Department of Internal Medicine, Clinic for Medical Oncology and Hematology, Cantonal Hospital St Gallen, St Gallen, Switzerland
    • 4Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori Milano, Milano, Italy
    • 5Linear Clinical Research Ltd, Nedlands, Australia
    • 6Department of Medical Oncology, Universitair Ziekenhuis Ghent, Ghent, Belgium
    • 7South Texas Accelerated Research Therapeutics Madrid-Fundacion Jimenez Diaz, Fundacion Jimenez Diaz Hospital, Madrid, Spain
    • 8Drug Development Department, Gustave Roussy, Villejuif, France
    • 9Medical Oncology Departement, Institut Claudius Regaud and Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
    • 10Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
    • 11Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
    • 12Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
    • 13Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia
    • 14New Drugs Development Division for Innovative Therapies, University of Milano and Istituto Europeo Di Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy
    • 15Department of Oncology, Center of Cancer Immunotherapy, U932, Institut Curie, Paris, France
    • 16Bristol-Myers Squibb, Princeton, New Jersey
    • 17Bras and Family Drug Development Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
    JAMA Oncol. Published online November 7, 2019. doi:https://doi.org/10.1001/jamaoncol.2019.3848
    Key Points

    Question  Is the glucocorticoid-induced tumor necrosis factor receptor–related protein agonist BMS-986156 treatment with or without nivolumab tolerable and clinically active in patients with advanced solid tumors?

    Findings  In this open-label, phase 1/2a study of 292 treated patients with advanced solid tumors (69 completed initial treatment), BMS-986156 therapy had a tolerable safety profile; combination therapy had a similar safety profile to that of nivolumab. No responses were seen with monotherapy; however, in combination therapy, response rates were comparable to those historically observed with nivolumab (<15% across tumor types).

    Meaning  This study represents the largest data set on glucocorticoid-induced tumor necrosis factor receptor–related protein agonism with or without nivolumab to our knowledge; a clear signal has not emerged demonstrating that glucocorticoid-induced tumor necrosis factor receptor–related protein agonism may be an effective therapeutic strategy in a broad patient population.

    Abstract

    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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