First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors.

BACKGROUND

Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

METHODS

Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every 4 weeks (Q4W)) intravenously. Dose-expansion: patients with melanoma (n=10) and NSCLC (n=20) who progressed on prior anti-programmed death receptor 1/programmed death ligand-1 and/or anti-cytotoxic T-lymphocyte-associated antigen 4 (melanoma) received ivuxolimab 30 mg Q2W intravenously plus utomilumab 20 mg Q4W intravenously. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and immune-related RECIST (irRECIST). Paired tumor biopsies and whole blood were collected to assess pharmacodynamic effects and immunophenotyping. Whole blood samples were collected longitudinally for immunophenotyping.

RESULTS

Dose-escalation: 57 patients were enrolled; 2 (3.5%) patients with melanoma (0.3 mg/kg+20 mg and 0.3 mg/kg+100 mg) achieved partial response (PR), 18 (31.6%) patients achieved stable disease (SD); the disease control rate (DCR) was 35.1% across all dose levels. Dose-expansion: 30 patients were enrolled; 1 patient with NSCLC achieved PR lasting >77 weeks. Seven of 10 patients with melanoma (70%) and 7 of 20 patients with NSCLC (35%) achieved SD: median (range) duration of SD was 18.9 (13.9-49.0) weeks for the melanoma cohort versus 24.1 (14.3-77.9+) weeks for the NSCLC cohort; DCR (NSCLC) was 40%. Grade 3-4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively. There were no grade 5 AEs deemed attributable to treatment. Ivuxolimab area under the concentration-time curve increased in a dose-dependent manner at 0.3-3 mg/kg doses.

CONCLUSIONS

Ivuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients.

TRIAL REGISTRATION NUMBER

NCT02315066.

Informations de copyright

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: OH reports consulting fees from Aduro, Akeso, Amgen, Beigene, Bioatia, Bristol Myers Squibb, Roche Genentech, GlaxoSmithKline, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, SeaGen, Tempus, and Zelluna; honoraria for speaker bureaus from Bristol Myers Squibb, Novartis, Pfizer, and Sanofi Regeneron; and participation on a data safety monitoring board or advisory board for Aduro, Akeso, Amgen, Beigene, Bioatia, Bristol Myers Squibb, Roche Genentech, GlaxoSmithKline, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, SeaGen, Tempus, and Zelluna. AAC reports grants or contracts from AstraZeneca and Bristol Myers Squibb; consulting fees from Jazz, Janssen, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Blueprint, Genentech, Merck, Novartis, and Takeda; and participation on a data safety monitoring board or advisory board for AstraZeneca, Bristol Myers Squibb, Ipsen, and Novartis. JAT reports grants or contracts from Pfizer. TD reports grants or contracts to his institution from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, IQVIA, Janssen Pharma, Merck Serono, MSD, Novartis, Pfizer, Sumitomo Dainippon, and Taiho; consulting fees from AbbVie, Bayer, Chugai Pharma, Otuska Pharma, Rakuten Medical, Sumitomo Dainippon, Taiho, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Oncolys Bio Pharma, Ono Pharma, Rakuten Medical, and Taiho; and participation on a data safety monitoring board or advisory board for AbbVie, Amgen, Astellas Pharma, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Janssen Pharma, MSD, and Novartis. SH-L reports consulting fees from Amgen, Astellas, Bristol Myers Squibb, Genmab, Merck, Regeneron, and Xencor; and research grants from Astellas, Boehringer Ingelheim, Checkmate, Dragonfly, F Star, Kite Pharma, Merck, OncoC4, Vedanta, and Xencor. AD reports grants or contracts from Apexigen, Idera, and Nektar; and consulting fees from Idera and Nektar. J-PS reports consulting fees from AstraZeneca, Bristol Myers Squibb, Daiichi-Sakyo, Gilead, GlaxoSmithKline, LeoPharma, Eli Lilly, MSD, Mylan, Novartis, Pierre Fabre Oncology, Pfizer, Roche Genentech; and support for attending meetings and/or travel from Amgen, AstraZeneca, and Pfizer. NR reports research grants from Pfizer; personal fees from AbbVie, Apricity Therapeutics, AstraZeneca, Bellicum Pharmaceuticals, Boehringer Ingelheim, Brooklyn ImmunoTherapeutics, Calithera Biosciences, Dracen Pharmaceuticals, Editas Medicine, Eli Lilly and Company, EMD Serono Inc, G1 Therapeutics, Genentech, Gilead Sciences, GlaxoSmithKline, Gritstone Bio, Illumina, Merck, Neogenomics Laboratories, Novartis, Takeda Pharmaceutical Company, and Synthekine; and royalties related to a patent filed by Memorial Sloan Kettering Cancer Center: determinants of cancer response to immunotherapy, (PCT/US2015/062208) licensed to Personal Genome Diagnostics. EA reports consulting fees from Celgene Research, GlaxoSmithKline, MedImmune, and Merck Sharp & Dohme; and support for attending meetings and/or travel from AbbVie, MedImmune, Pfizer, Roche, and Sanofi. ABE-K reports personal fees from Agenus, ABL Bio, Bayer, BMS, Exelixis, Eisai, and AstraZeneca; grants and personal fees from Astex, Pieris, Cytomx, Gilead, EMD Serono, Roche/Genentech, and Merck; and grants from Fulgent outside the submitted work. PAO reports grants or contracts from Amgen, Armo BioSciences, Array, AstraZeneca/MedImmune, Bristol Myers Squibb, Celldex, CytomX, Merck, Neon Therapeutics, Novartis, Oncorus, Pfizer, Roche Genentech, and Xencor; consulting fees from Array, Merck, Bristol Myers Squibb, Evaxion, and Novartis; and participation on a data safety monitoring board or advisory board for Array, Merck, Bristol Myers Squibb and Novartis. FALME, WR, and JSW have nothing to disclose. JC and AF were employees of Pfizer at the time of the study and hold stock or stock options in Pfizer. CG and WY are employees of Pfizer and hold stock or stock options in Pfizer.