Kimberley M Heinhuis1, Matteo Carlino2, Markus Joerger3, Massimo Di Nicola4, Tarek Meniawy5, Sylvie Rottey6, Victor Moreno7, Anas Gazzah8, Jean-Pierre Delord9, Luis Paz-Ares10, Christian Britschgi11, Russell J Schilder12, Kenneth O'Byrne13, Giuseppe Curigliano14, Emanuela Romano15, Poliana Patah16, Rui Wang16, Yali Liu16, Gaurav Bajaj16, Lillian L Siu17. 1. Division of Pharmacology, The Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, the Netherlands. 2. Department of Medical Oncology, Crown Princess Mary Cancer Centre Westmead Hospital, Westmead, Australia. 3. Department of Internal Medicine, Clinic for Medical Oncology and Hematology, Cantonal Hospital St Gallen, St Gallen, Switzerland. 4. Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori Milano, Milano, Italy. 5. Linear Clinical Research Ltd, Nedlands, Australia. 6. Department of Medical Oncology, Universitair Ziekenhuis Ghent, Ghent, Belgium. 7. South Texas Accelerated Research Therapeutics Madrid-Fundacion Jimenez Diaz, Fundacion Jimenez Diaz Hospital, Madrid, Spain. 8. Drug Development Department, Gustave Roussy, Villejuif, France. 9. Medical Oncology Departement, Institut Claudius Regaud and Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France. 10. Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. 11. Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. 12. Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. 13. Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia. 14. New Drugs Development Division for Innovative Therapies, University of Milano and Istituto Europeo Di Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Milano, Italy. 15. Department of Oncology, Center of Cancer Immunotherapy, U932, Institut Curie, Paris, France. 16. Bristol-Myers Squibb, Princeton, New Jersey. 17. Bras and Family Drug Development Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
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.
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.
Authors: Mara Cruellas; Alfonso Yubero; María Zapata; Eva M Galvez; Marta Gascón; Dolores Isla; Rodrigo Lastra; Luis Martínez-Lostao; Maitane Ocariz; Julián Pardo; Ariel Ramírez; Andrea Sesma; Irene Torres-Ramón; José Ramón Paño Journal: Infect Immun Date: 2021-08-16 Impact factor: 3.441