TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial
Background M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant...
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BMJ Publishing Group
2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/2/e010584.full |
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| author | Wei Gao Ping Hu Aung Naing Meredith McKean Anthony Tolcher Lillian L Siu Keyvan Tadjalli-Mehr Anja Victor Emilia Richter Marco A F Nogueira Filho Thomas Kitzing Stephan Gleicher Daniel Holland |
| author_facet | Wei Gao Ping Hu Aung Naing Meredith McKean Anthony Tolcher Lillian L Siu Keyvan Tadjalli-Mehr Anja Victor Emilia Richter Marco A F Nogueira Filho Thomas Kitzing Stephan Gleicher Daniel Holland |
| author_sort | Wei Gao |
| collection | DOAJ |
| description | Background M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.Methods This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10–2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300–1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, maximum tolerated dose (MTD) and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics, pharmacodynamics and clinical activity (NCT04457778).Results Two dose-limiting toxicities were observed: grade 3 adrenal insufficiency (Part 1A: M6223 900 mg every 2 weeks) and grade 3 anemia (Part 1B: M6223 300 mg, only BA related). MTD was not reached. Overall, median overall survival and progression-free survival were 7.6 (95% CI 4.9, 12.0) and 1.4 (95% CI 1.3, 1.8) months, respectively. Stable disease as best response was observed in 13 (32.5%) and 5 (27.8%) patients in parts 1A and 1B, respectively. M6223±BA displayed a linear pharmacokinetic profile. Anti-TIGIT mode-of-action-related pharmacodynamic effects were observed in peripheral blood and in tumor tissue. RDEs were 1600 mg every 2 weeks or 2400 mg every 3 weeks for M6223 monotherapy and 1600+1200 mg every 2 weeks for M6223+BA.Conclusions M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530).Trial registration number NCT04457778. |
| format | Article |
| id | doaj-art-2bc752abb112475586885707089bcbde |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-2bc752abb112475586885707089bcbde2025-02-11T10:30:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-010584TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trialWei Gao0Ping Hu1Aung Naing2Meredith McKean3Anthony Tolcher4Lillian L Siu5Keyvan Tadjalli-Mehr6Anja Victor7Emilia Richter8Marco A F Nogueira Filho9Thomas Kitzing10Stephan Gleicher11Daniel Holland12EMD Serono, Billerica, Massachusetts, USAEMD Serono, Billerica, Massachusetts, USAThe University of Texas MD Anderson Cancer Centre, Houston, Texas, USASarah Cannon Research Institute, Nashville, Tennessee, USANEXT Oncology and Texas Oncology, San Antonio, Texas, USAPrincess Margaret Hospital Cancer Centre, Toronto, Ontario, CanadaMerck Healthcare KGaA, Darmstadt, GermanyMerck Healthcare KGaA, Darmstadt, GermanyMerck Healthcare KGaA, Darmstadt, GermanyMerck Healthcare KGaA, Darmstadt, GermanyMerck Healthcare KGaA, Darmstadt, GermanyMerck Healthcare KGaA, Darmstadt, GermanyMerck Healthcare KGaA, Darmstadt, GermanyBackground M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.Methods This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10–2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300–1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, maximum tolerated dose (MTD) and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics, pharmacodynamics and clinical activity (NCT04457778).Results Two dose-limiting toxicities were observed: grade 3 adrenal insufficiency (Part 1A: M6223 900 mg every 2 weeks) and grade 3 anemia (Part 1B: M6223 300 mg, only BA related). MTD was not reached. Overall, median overall survival and progression-free survival were 7.6 (95% CI 4.9, 12.0) and 1.4 (95% CI 1.3, 1.8) months, respectively. Stable disease as best response was observed in 13 (32.5%) and 5 (27.8%) patients in parts 1A and 1B, respectively. M6223±BA displayed a linear pharmacokinetic profile. Anti-TIGIT mode-of-action-related pharmacodynamic effects were observed in peripheral blood and in tumor tissue. RDEs were 1600 mg every 2 weeks or 2400 mg every 3 weeks for M6223 monotherapy and 1600+1200 mg every 2 weeks for M6223+BA.Conclusions M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530).Trial registration number NCT04457778.https://jitc.bmj.com/content/13/2/e010584.full |
| spellingShingle | Wei Gao Ping Hu Aung Naing Meredith McKean Anthony Tolcher Lillian L Siu Keyvan Tadjalli-Mehr Anja Victor Emilia Richter Marco A F Nogueira Filho Thomas Kitzing Stephan Gleicher Daniel Holland TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial Journal for ImmunoTherapy of Cancer |
| title | TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial |
| title_full | TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial |
| title_fullStr | TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial |
| title_full_unstemmed | TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial |
| title_short | TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial |
| title_sort | tigit inhibitor m6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors a first in human phase 1 dose escalation trial |
| url | https://jitc.bmj.com/content/13/2/e010584.full |
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