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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, phar...

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Autores principales: Hamid, Omid, Chiappori, Alberto A, Thompson, John A, Doi, Toshihiko, Hu-Lieskovan, Siwen, Eskens, Ferry A L M, Ros, Willeke, Diab, Adi, Spano, Jean-Philippe, Rizvi, Naiyer A, Wasser, Jeffrey S, Angevin, Eric, Ott, Patrick A, Forgie, Alison, Yang, Wenjing, Guo, Cen, Chou, Jeffrey, El-Khoueiry, Anthony B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9621185/
https://www.ncbi.nlm.nih.gov/pubmed/36302562
http://dx.doi.org/10.1136/jitc-2022-005471
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author Hamid, Omid
Chiappori, Alberto A
Thompson, John A
Doi, Toshihiko
Hu-Lieskovan, Siwen
Eskens, Ferry A L M
Ros, Willeke
Diab, Adi
Spano, Jean-Philippe
Rizvi, Naiyer A
Wasser, Jeffrey S
Angevin, Eric
Ott, Patrick A
Forgie, Alison
Yang, Wenjing
Guo, Cen
Chou, Jeffrey
El-Khoueiry, Anthony B
author_facet Hamid, Omid
Chiappori, Alberto A
Thompson, John A
Doi, Toshihiko
Hu-Lieskovan, Siwen
Eskens, Ferry A L M
Ros, Willeke
Diab, Adi
Spano, Jean-Philippe
Rizvi, Naiyer A
Wasser, Jeffrey S
Angevin, Eric
Ott, Patrick A
Forgie, Alison
Yang, Wenjing
Guo, Cen
Chou, Jeffrey
El-Khoueiry, Anthony B
author_sort Hamid, Omid
collection PubMed
description 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.
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spelling pubmed-96211852022-11-01 First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors Hamid, Omid Chiappori, Alberto A Thompson, John A Doi, Toshihiko Hu-Lieskovan, Siwen Eskens, Ferry A L M Ros, Willeke Diab, Adi Spano, Jean-Philippe Rizvi, Naiyer A Wasser, Jeffrey S Angevin, Eric Ott, Patrick A Forgie, Alison Yang, Wenjing Guo, Cen Chou, Jeffrey El-Khoueiry, Anthony B J Immunother Cancer Clinical/Translational Cancer Immunotherapy 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. BMJ Publishing Group 2022-10-27 /pmc/articles/PMC9621185/ /pubmed/36302562 http://dx.doi.org/10.1136/jitc-2022-005471 Text en © 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. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Clinical/Translational Cancer Immunotherapy
Hamid, Omid
Chiappori, Alberto A
Thompson, John A
Doi, Toshihiko
Hu-Lieskovan, Siwen
Eskens, Ferry A L M
Ros, Willeke
Diab, Adi
Spano, Jean-Philippe
Rizvi, Naiyer A
Wasser, Jeffrey S
Angevin, Eric
Ott, Patrick A
Forgie, Alison
Yang, Wenjing
Guo, Cen
Chou, Jeffrey
El-Khoueiry, Anthony B
First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
title First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
title_full First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
title_fullStr First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
title_full_unstemmed First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
title_short First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
title_sort first-in-human study of an ox40 (ivuxolimab) and 4-1bb (utomilumab) agonistic antibody combination in patients with advanced solid tumors
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9621185/
https://www.ncbi.nlm.nih.gov/pubmed/36302562
http://dx.doi.org/10.1136/jitc-2022-005471
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