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

Kimberley M. Heinhuis, Matteo Carlino, Markus Joerger, Massimo Di Nicola, Tarek Meniawy, Sylvie Rottey, Victor Moreno, Anas Gazzah, Jean Pierre Delord, Luis Paz-Ares, Christian Britschgi, Russell J. Schilder, Kenneth O'Byrne, Giuseppe Curigliano, Emanuela Romano, Poliana Patah, Rui Wang, Yali Liu, Gaurav Bajaj, Lillian L. Siu

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)100-107
Number of pages8
JournalJAMA oncology
Volume6
Issue number1
DOIs
Publication statusPublished - Jan 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Heinhuis, K. M., Carlino, M., Joerger, M., Di Nicola, M., Meniawy, T., Rottey, S., Moreno, V., Gazzah, A., Delord, J. P., Paz-Ares, L., Britschgi, C., Schilder, R. J., O'Byrne, K., Curigliano, G., Romano, E., Patah, P., Wang, R., Liu, Y., Bajaj, G., & Siu, L. L. (2020). 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. JAMA oncology, 6(1), 100-107. https://doi.org/10.1001/jamaoncol.2019.3848