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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Carlino reported receiving personal fees for serving as an advisory board member and receiving honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme and for serving as an advisory board member for Novartis, and Pierre Fabre outside the submitted work. Dr Meniawy reported receiving research funding for this sponsored study from Bristol-Myers Squibb; and serving on the advisory board for Bristol-Myers Squibb Australia. Dr Rottey reported receiving honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche; serving in a consulting or advisory role (institutional) for Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche; receiving research funding (institutional) from Roche; and receiving travel and accommodations expenses from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche. Dr Moreno reported receiving consulting fees from Merck; receiving travel support from Regeneron/Sanofi; delivering presentations to Nanobiotix; and receiving an educational grant from Medscape/Bayer. Dr Gazzah reported receiving travel, accommodation, and congress registration expenses from Boehringer Ingelheim, Novartis, Pfizer, and Roche; serving as a consultant or in an expert role for Novartis; and receiving research funding from AbbVie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Daiichi Sankyo, Debiopharm SA, Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech Inc, GlaxoSmithKline, H3 Biomedicine Inc, Hoffmann La Roche Ag, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharm Dev Inc, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc, and Xencor. Dr Delord reported serving in a consulting or advisory role for Novartis, Roche/Genentech, Bristol-Myers Squibb, and MSD Oncology; and receiving research funding (institutional) from Genentech, Bristol-Myers Squibb, MSD Oncology, and AstraZeneca. Dr Paz-Ares reported receiving personal fees for serving as a medical advisor for Roche, Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Amgen, Pharmamar, Takeda, Pfizer, Merck, Celgene, and Sanofi outside the submitted work. Dr Britschgi reported receiving personal fees for serving as a consultant for Roche, AstraZeneca, Takeda, Boehringer Ingelheim, and Pfizer outside the submitted work. Dr Schilder reported receiving a grant from Bristol-Myers Squibb; and personal fees from Incyte, Immunogen, Celsion, and FlatIron outside the submitted work. Dr O’Byrne reported having stock and other ownership interests in CARP Pharmaceuticals; receiving honoraria from Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Teva, Boehringer Ingelheim, AstraZeneca, Pfizer/EMD Serono, Novartis, Janssen-Cilag, and Mundipharma; serving in a consulting or advisory role for Merck Sharp & Dohme, Boehringer Ingelheim, Roche/Genentech, Janssen-Cilag, Pfizer, AstraZeneca/MedImmune, Bristol-Myers Squibb, Novartis, Teva, and Natera; serving on the speakers’ bureau for Merck Sharp & Dohme, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Janssen-Cilag, Pfizer, Mundipharma, Novartis, and Foundation Medicine; receiving research funding from AstraZeneca/MedImmune, and Bristol-Myers Squibb; holding 4 patents held by University of Queensland; and receiving travel and accommodations expenses from Boehringer Ingelheim, Bristol-Myers Squibb, and Roche. Dr Curigliano reported being an expert advisory board member for Bristol-Myers Squibb, Roche, Novartis, Lilly, Pfizer, Seattle Genetics, and Samsung; and serving on the scientific advisory board for Ellipsis. Dr Romano reported receiving research funding from Bristol-Myers Squibb; and serving as a consultant for Roche. Dr Patah reported being an employee of Bristol-Myers Squibb. Dr Wang reported being an employee of Bristol-Myers Squibb. Dr Liu reported being an employee of Bristol-Myers Squibb. Dr Bajaj reported being an employee of Bristol-Myers Squibb. Dr Siu reported serving as a consultant for Merck, Pfizer, Celgene, AstraZeneca/MedImmune, Morphosys, Roche, GeneSeeq, Loxo, Oncorus, and Symphogen; and receiving clinical trial support (institution) from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Regeneron, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/MedImmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, and Agios.

Figures

Figure 1.. CONSORT Diagram

aThis was not a randomized trial and the monotherapy and combination therapy arms were not comparator arms. CONSORT indicates Consolidated Standards of Reporting Trials.

Figure 2.. Intratumoral T-Cell and Regulatory T-Cell Modulation After BMS-986156 Plus Nivolumab Therapy

Tumor-infiltrating CD8+ T cells (P = .72) (A) and FoxP3+ regulatory T cells (P = .44) (B) by immunohistochemistry biopsies before treatment and while receiving treatment for 53 matched pairs of patients receiving BMS-986156 plus nivolumab combination therapy (all patients included in this analysis received 240 mg of nivolumab every 2 weeks). The Wilcoxon signed rank test was performed for all the comparisons. The horizontal line in each box plot denotes the median level. C1 D15 indicates cycle 1, day 15.