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.

Trial Registration: ClinicalTrials.gov identifier: NCT02598960.

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

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Tumor Necrosis Factor Receptors
Glucocorticoids
Clinical Trials
Safety
Neoplasms
Proteins
Therapeutics
Poisons
nivolumab
T-Lymphocytes
Death Domain Receptors
Regulatory T-Lymphocytes
Creatine Kinase
Human Activities
Natural Killer Cells
Pharmacokinetics
Immunoglobulin G
Biomarkers
Monoclonal Antibodies
Cell Proliferation

Cite this

Heinhuis, Kimberley M ; Carlino, Matteo ; Joerger, Markus ; Di Nicola, Massimo ; Meniawy, Tarek ; Rottey, Sylvie ; Moreno, Victor ; Gazzah, Anas ; Delord, Jean-Pierre ; Paz-Ares, Luis ; Britschgi, Christian ; Schilder, Russell J ; O'Byrne, Kenneth ; Curigliano, Giuseppe ; Romano, Emanuela ; Patah, Poliana ; Wang, Rui ; Liu, Yali ; Bajaj, Gaurav ; Siu, Lillian L. / 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. In: JAMA Oncology. 2020 ; Vol. 6, No. 1. pp. 100-107.
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title = "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",
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.",
author = "Heinhuis, {Kimberley M} and Matteo Carlino and Markus Joerger and {Di Nicola}, Massimo and Tarek Meniawy and Sylvie Rottey and Victor Moreno and Anas Gazzah and Jean-Pierre Delord and Luis Paz-Ares and Christian Britschgi and Schilder, {Russell J} and Kenneth O'Byrne and Giuseppe Curigliano and Emanuela Romano and Poliana Patah and Rui Wang and Yali Liu and Gaurav Bajaj and Siu, {Lillian L}",
year = "2020",
month = "1",
doi = "10.1001/jamaoncol.2019.3848",
language = "English",
volume = "6",
pages = "100--107",
journal = "JAMA Oncology",
issn = "2374-2437",
publisher = "American Medical Association",
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Heinhuis, KM, Carlino, M, Joerger, M, Di Nicola, M, Meniawy, T, Rottey, S, Moreno, V, Gazzah, A, Delord, J-P, Paz-Ares, L, Britschgi, C, Schilder, RJ, O'Byrne, K, Curigliano, G, Romano, E, Patah, P, Wang, R, Liu, Y, Bajaj, G & Siu, LL 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, vol. 6, no. 1, pp. 100-107. https://doi.org/10.1001/jamaoncol.2019.3848

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

In: JAMA Oncology, Vol. 6, No. 1, 01.2020, p. 100-107.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

T2 - A Phase 1/2a Dose-Escalation and Cohort-Expansion Clinical Trial

AU - Heinhuis, Kimberley M

AU - Carlino, Matteo

AU - Joerger, Markus

AU - Di Nicola, Massimo

AU - Meniawy, Tarek

AU - Rottey, Sylvie

AU - Moreno, Victor

AU - Gazzah, Anas

AU - Delord, Jean-Pierre

AU - Paz-Ares, Luis

AU - Britschgi, Christian

AU - Schilder, Russell J

AU - O'Byrne, Kenneth

AU - Curigliano, Giuseppe

AU - Romano, Emanuela

AU - Patah, Poliana

AU - Wang, Rui

AU - Liu, Yali

AU - Bajaj, Gaurav

AU - Siu, Lillian L

PY - 2020/1

Y1 - 2020/1

N2 - 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.

AB - 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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