Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors.

Background: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.
Methods: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m ² (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments.
Results: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab.
Conclusions: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer.
Trial Registration Numbers: NCT02110082; NCT02253992.
Competing Interests: Competing interests: NIK reports consulting fees from Bristol Myers Squibb, Merck, Jounce, Novartis, Regeneron, Genzyme, Iovance, Castle Biosciences, Nektar, Replimune, and Instil Bio; research funding (to institute) from Bristol Myers Squibb, Merck, Celgene, Novartis, GSK, HUYA, Regeneron, Replimune, Modulation Therapeutics; participation on a data safety monitoring board with Incyte, AstraZeneca; participation in a study steering committee with Bristol Myers Squibb, Nektar, Regerenon, Replimune; and ownership of common stock in Bellicum, Amarin, and Asensus Surgical. PAO reports grants from Bristol Myers Squibb, Neon Therapeutics, Merck, Pfizer, Novartis, Celldex, Xencor, Roche/Genentech, Oncorus; consulting fees from Bristol Myers Squibb, Evaxion, Merck, Roche/Genentech, Novartis, Immunetune, LG Chem; leadership or fiduciary role with NCCN. RF reports grants or contracts from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Novasenta, Tesaro; consulting fees with Adagene, Aduro Biotech, Bicara Therapeutics, Brooklyn ImmunoTherapeutics, Catenion, EMD Serono, Everest Clinical Research Corporation, F. Hoffman-La Roche Ltd., Federation Bio, Genocea Biosciences, Kowa Research Institute, Mirati Therapeutics, Nanobiotix, Novartis, Novasenta, PPD Development, Sanofi, Zymeworks; participation on a data safety monitoring or advisory board with Coherus BioSciences, Eisai Europe Ltd., Genmab, Hookipa, Instil Bio, Lifescience Dynamics, MacroGenics, MeiraGtx, Merck, Mirror Biologics, Numab Therapeutics AG, OncoCyte, Pfizer, Rakuten Medical, Seagen, SIRPant Immunotherapeutics, Vir Biotechnology, stock or stock options with Novasenta. TC reports speaker fees/honoraria from AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; advisory role/consulting fees from Arrowhead Pharmaceuticals, Bristol Myers Squibb, Genentech, MedImmune/AstraZeneca, Merck, Pfizer, and Regeneron; institutional research funding from Bristol Myers Squibb, EMD Serono, and MedImmune/AstraZeneca; and travel, food and/or beverage expenses from AstraZeneca, Bristol Myers Squibb, Dava Oncology, Genentech, IDEOlogy Health, International Association for the Study of Lung Cancer, OncLive, Parker Institute for Cancer Immunotherapy, Physicians’ Education Resource, and Society for Immunotherapy of Cancer. DS reports research funding to the institution from Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Array; patient fees to the institution for clinical studies from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma; consulting fees/honoraria from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma, OncoSec, Replimune, NeraCare, Sandoz, Ultimovacs; reimbursement from the Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape Oncology and PeerView Institute for travel; nonfinancial support from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Pierre-Fabre, Pfizer, InFlaRX, NeraCare, Nektar, Sun Pharma, Sandoz; consulting/advisory role fees from MedImmune, AstraZeneca, Bristol Myers Squibb, Merck& Co., Genentech, Arrowhead Pharmaceuticals, and EMD Serono; institutional clinical research funding from Boehringer Ingelheim, MedImmune, AstraZeneca, EMD Serono, and Bristol Myers Squibb. DTL reports serving on advisory boards for Merck, Bristol Myers Squibb, Nouscom, G1 Therapeutics, and Janssen; receiving research funding from Merck, Bristol Myers Squibb, Curegenix, Nouscom, and AbbVie; speaking honoraria from Merck; being an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. MRS reports support for present manuscript from Bristol Myers Squibb; participation on a data safety monitoring or advisory board with Pilant Therapeutics; stock or stock options with Bristol Myers Squibb. FB reports financial interest with AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Takeda. WS reports grants and personal fees from Bristol Myers Squibb, Merck, and Novartis; personal fees from Regeneron; and grants from Genentech. JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, F-star, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MacroGenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; consulting fees from 7 Hills, Bright Peak, Exo, F-star, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, MacroGenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, Stingthera, Synlogic, Synthekine; provisional patents in cancer immunotherapy (serial no. 15/612,657) and microbiome biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic, and therapeutic uses thereof (PCT/US18/36052); participation on a data safety monitoring board or advisory board with AbbVie, Immutep, Evaxion; leadership or fiduciary role with Society for Immunotherapy of Cancer; stock or stock options with Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest. IM reports support for the current manuscript from Bristol Myers Squibb; grants or contracts from Bristol Myers Squibb, Roche, Genmab, Highlight Therapeutics, AstraZeneca; consulting fees from Bristol Myers Squibb, Roche, Genmab, Merus, Pieris, AstraZeneca, Numab, Highlight Therapeutics; payment or honoraria from Bristol Myers Squibb; support for attending meetings and/or travel from Bristol Myers Squibb and Roche. DL, JN and JH are employees and stock owners of Bristol Myers Squibb. AS is an employee of Boston Scientific. SS, AS, RS and SE report employment with Bristol Myers Squibb. NHS reports consulting fees from ABL Bio, Agenus, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Numab, Puretech, Regeneron, Revitope, and Roche/Genentech; and research funding from Agenus, AstraZeneca, Bristol Myers Squibb, Immunocore, Merck, Pfizer, Puretech, Regeneron, and Roche/Genentech.
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