First-in-human phase 1 dose-escalation results with livmoniplimab, an antibody targeting the GARP:TGF-ß1 complex, as monotherapy and in combination with the anti-PD-1 antibody budigalimab in patients with advanced solid tumors.

Autor:	Shimizu T; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.; Department of New Experimental Therapeutics and International Cancer New Drug Development Center, Kansai Medical University Hospital, Osaka, Japan., Powderly J; Carolina BioOncology Institute, Huntersville, NC, United States., Abdul Razak A; Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, ON, Canada., LoRusso P; Yale Cancer Center, Yale University, New Haven, CT, United States., Miller KD; Department of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States., Kao S; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia., Kongpachith S; AbbVie Bay Area, South San Francisco, CA, United States., Tribouley C; AbbVie Bay Area, South San Francisco, CA, United States., Graham M; AbbVie Bay Area, South San Francisco, CA, United States., Stoll B; AbbVie Bay Area, South San Francisco, CA, United States., Patel M; AbbVie Bay Area, South San Francisco, CA, United States., Sahtout M; AbbVie Bay Area, South San Francisco, CA, United States., Blaney M; AbbVie Bay Area, South San Francisco, CA, United States., Leibman R; AbbVie Bay Area, South San Francisco, CA, United States., Golan T; Institute of Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.; Oncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University, Tel Aviv, Israel., Tolcher A; New Experimental Therapeutics (NEXT) Oncology, San Antonio, TX, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2024 Oct 29; Vol. 14, pp. 1376551. Date of Electronic Publication: 2024 Oct 29 (Print Publication: 2024).
DOI:	10.3389/fonc.2024.1376551
Abstrakt:	Background: Transforming growth factor (TGF)-ß1 is a pleiotropic cytokine that can promote tumor growth and suppress antitumor immune responses. Latent TGF-ß1 associates with glycoprotein-A repetition predominant (GARP) on the surface of regulatory T cells prior to its activation and release. Livmoniplimab is a monoclonal antibody (mAb) that binds the GARP:TGF-ß1 complex to inhibit activation and release of TGF-ß1. It is in clinical development in combination with budigalimab, an anti-programmed cell death protein 1 Fc-modified mAb. The first-in-human, phase 1, dose-escalation results are presented herein (ClinicalTrials.gov: NCT03821935). Methods: The dose-escalation phase enrolled adult patients with advanced solid tumors. Patients received escalating doses of livmoniplimab ranging from 3mg to 1500mg, once every 2 weeks (Q2W), as monotherapy or in combination with a 500mg fixed dose of budigalimab Q4W. The primary objective of the dose escalation was to determine the recommended phase 2 dose. Secondary objectives were to assess safety and pharmacokinetics (PK), and exploratory objectives included evaluating preliminary efficacy. Results: Fifty-seven patients enrolled in the dose escalation: 23 in monotherapy cohorts and 34 in combination therapy cohorts. Dose-limiting toxicities were limited, no maximum tolerated dose was reached, and the maximum administered dose of 1500mg was selected for dose expansion. The most common adverse events reported in monotherapy-treated patients were fatigue, anemia, and nausea, and those in combination therapy-treated patients were pruritus, fatigue, nausea, and anemia. Livmoniplimab exhibited dose-proportional PK, and peripheral blood biomarker data demonstrated saturation of the GARP:TGF-ß1 complex on platelets at livmoniplimab doses within the linear PK range. No objective tumor responses were observed in the monotherapy dose escalation. However, the objective response rate was 15% in the combination dose escalation, with a median response duration of 8.4 months. Conclusion: Livmoniplimab was well-tolerated as monotherapy and in combination with budigalimab in the dose-escalation phase. Encouraging preliminary efficacy was demonstrated in the combination dose escalation in heavily pretreated patients, supporting further development of this novel drug combination in patients with advanced solid tumors. Competing Interests: AT: Advisory/Consultancy: AbbVie, Aclaris Therapeutics, Adagene, Agenus, Aro Biotherapeutics, Asana BioSciences, Ascentage, AxImmune, Bayer, BioInvent, BluPrint Oncology, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Deka Biosciences, Eleven Bio, Elucida, EMD Serono/Merck KGaA, Gilde Healthcare Partners, HBM Partners, HiberCell Inc, IDEA Pharma, Ikena Oncology, Immuneering, Immunome, ImmunoMet Therapeutics, IMPACT Therapeutics US, Janssen, Jazz, Karma Oncology B.V., Lengo Therapeutics, Mekanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, NBE Therapeutics, Ocellaris Pharma/Eli Lilly, Partner Therapeutics, Pelican, Pfizer, Pieris Pharma, Pierre Fabre, Pyxis Oncology, Ryvu Therapeutics, Seattle Genetics, SK Life Science, SOTIO Biotechnology Company, Spirea Limited, Sunshine Guojian Pharma Shangai, Transcenta Therapeutics, Trillium Therapeutics, Vincerx, Zentails, ZielBio, Zymeworks Biopharma. RL, MB, BS, MG, MP, SaK, CT: AbbVie Inc. employees and may own stock. MS: Former employee of AbbVie Inc., currently employed by Scholar Rock, and may own AbbVie stock. JP: Aavocyte, Writing Engagement, Personal, Consulting; Boxer Capital, Other, Personal, Consulting; BioCytics Inc., Member of Board of Directors, Personal, Founder and Owner; Carolina BioOncology Institute, PLLC, Member of Board of Directors, Personal, Founder and Owner; BioCytics Inc., Ownership Interest, Personal, Founder and Owner; Carolina BioOncology Institute, PLLC, Ownership Interest, Personal, Founder and Owner of phase 1 cancer research clinic; BioCytics Inc, Other, Personal, Founder and Owner, developing intellectual property for cellular therapies; Aavocyte, Other, Personal and Institutional, Financial interest, Aavocyte and AavoBioCytics are jointly developing cellular therapies with BioCytics Human Applications Lab for point-of-care manufacturing; AbbVie, Local PI, Personal and Institutional, No financial interest; Adagene, Local PI, Personal and Institutional, No financial interest; Alkermes, Local PI, Personal and Institutional, No financial interest; Allarity, Local PI, Personal and Institutional, Financial interest; Apros, Local PI, Personal and Institutional, No financial interest; Aptevo, Local PI, Personal and Institutional, Financial interest; Arcus BioSciences, Local PI, Personal and Institutional, No financial interest; AstraZeneca/MedImmune, Local PI, Personal and Institutional, No financial interest; Atreca, Local PI, Personal and Institutional, No financial interest; Aulos, Local PI, Personal and Institutional, Financial interest; BJ Bioscience, Local PI, Personal and Institutional, No financial interest; Bristol Myers Squibb, Local PI, Personal and Institutional, No financial interest; Calico Life Sciences, Local PI, Personal and Institutional, No financial interest; Conjupro Biotherapeutics, Local PI, Personal and Institutional, No financial interest; CUE Biopharma, Local PI, Personal and Institutional, Financial interest; Cullinan, Local PI, Personal and Institutional, No financial interest; EMD Serono, Local PI, Personal and Institutional, No financial interest; Fate Therapeutics, Local PI, Personal and Institutional, No financial interest; FLX Bio, Local PI, Personal and Institutional, No financial interest; Genentech/Roche, Local PI, Personal and Institutional, No financial interest; GI Innovation, Local PI, Personal and Institutional, Financial interest; Harbour BioMed, Local PI, Personal and Institutional, Financial interest; I-Mab Pharma, Local PI, Personal and Institutional, No financial interest; IconOVir Bio, Local PI, Personal and Institutional, Financial interest; IGM Biosciences, Local PI, Personal and Institutional, Financial interest; Immune-Onc, Local PI, Personal and Institutional, No financial interest; Incyte, Local PI, Personal and Institutional, No financial interest; Jounce Therapeutics, Local PI, Personal and Institutional, No financial interest; MacroGenics, Local PI, Personal and Institutional, No financial interest; Medikine, Local PI, Personal and Institutional, Financial interest; Merck, Funding, Institutional, No financial interest; ModernaTX, Local PI, Personal and Institutional, Financial interest; Molecular Templates, Local PI, Personal and Institutional, No financial interest; MT Group, Funding, Institutional, No financial interest; NextCure, Local PI, Personal and Institutional, No financial interest; Nuvation, Local PI, Personal and Institutional, No financial interest, Also funding for contract laboratory services; PEEL Therapeutics, Local PI, Personal and Institutional, Financial interest; Phanes Therapeutics, Local PI, Personal and Institutional, Financial interest; Pieris Pharmaceuticals, Local PI, Personal and Institutional, Financial interest; PIOMA, Funding, Personal and Institutional, Financial interest; Precision for Medicine, Funding, Institutional, No financial interest; Qurgen, Local PI, Personal and Institutional, Financial interest; Repertoire Immune Medicines, Local PI, Personal and Institutional, No financial interest; Replimmune, Funding, Institutional, No financial interest; Riboscience, Local PI, Personal and Institutional, Financial interest; Seattle Genetics, Local PI, Personal and Institutional, No financial interest; Sequenom, Local PI, Personal and Institutional, No financial interest; Simcere, Local PI, Personal and Institutional, Financial interest; SK Life Science, Local PI, Personal and Institutional, Financial interest; STEMCELL Technologies, Funding, Institutional, No financial interest; Tempest Therapeutics, Local PI, Personal and Institutional, No financial interest; Top Alliance Biosciences, Local PI, Personal and Institutional, No financial interest; Trethera, Local PI, Personal and Institutional, No financial interest; Wugen, Funding, Personal and Institutional, Financial interest, Wugen is sponsor of contract laboratory translational research; Xilio Therapeutics, Local PI, Personal and Institutional, No financial interest; Xilis, Funding, Institutional, No financial interest; Zenshine Pharma, Local PI, Personal and Institutional, No financial interest; BioCytics Inc., Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy. TS: Advisory Role: AbbVie, Daiichi Sankyo, Chordia Therapeutics, Chugai, Kyowa Kirin; Research expenses: AbbVie, Eli Lilly, LOXO Oncology, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Eisai, Takeda Oncology, AstraZeneca, Incyte, Chordia Therapeutics, 3D Medicines, SymBio Pharmaceuticals, PharmaMar, Astellas Pharma, Pfizer. PL: Advisory Board: AbbVie 2018-2019, Genmab 2016-2019, Genentech 2016-2019, CytomX 2016-2019, Takeda 2017-2020, Cybrexa 2018-2019, Agenus 2018-2021, IQVIA 2019-2021, TRIGR 2019-2020, Pfizer 2019-2020, ImmunoMet 2018-2020, Black Diamond 2019-2020, GlaxoSmithKline 2019-2020, QED Therapeutics 2019-2021, AstraZeneca 2019-2020, EMD Serono 2019-2020, Shattuck 2019-2020, Astellas 2019-2020, Salarius 2019-2020, Silverback 2019-2020, MacroGenics 2019-2020, Kyowa Kirin Pharmaceutical Development 2020-2021, Kineta, Inc. 2020-2021, Zentalis Pharmaceuticals 2020-2021, Molecular Templates 2020-2022, ABL Bio 2020-2021, STCube Pharmaceuticals 2020-2021, Bayer 2020, I-Mab 2020-2022, Seagen 2021, ImCheck 2021, Relay Therapeutics 2021, Stemline 2021, Compass BADX 2021, Mekanist 2021, Mersana Therapeutics 2022, BAKX Therapeutics 2022, Scenic Biotech 2022, Qualigen 2022, NeuroTrials 2022; Data Safety Monitoring Board: Agios 2016-2019, Five Prime 2017-2020, Halozyme 2016-2019, Tyme 2018-2019; imCORE Alliance: Roche-Genentech 2016-2019; Consultant: SOTIO 2018-2019, SK Life Science 2020, I-Mab 2020-2022, Roivant Sciences 2022. TG: Research funding—AstraZeneca, MSD Merck, and consulting/advisory role—AbbVie, AstraZeneca, Bayer, BioLine, MSD Merck, Roche, Teva, and travel expenses—AstraZeneca, MSD Merck. E.M.O.: research funding—Genentech/Roche, Celgene/BMS, BioNTech, BioAtla, AstraZeneca, Arcus, Elicio, Parker Institute, AstraZeneca, Chiesi Faramaceutici S.p.A., and consulting role—CytomX Therapeutics DSMB, Rafael Therapeutics DSMB, Sobi, Silenseed, Tyme, Seagen, Molecular Templates, Boehringer Ingelheim, BioNTech, Ipsen, Polaris, Merck, AstraZeneca, NOXXON, BioSapien, Bayer spouse, Genentech-Roche spouse, Celgene-BMS spouse, and Eisai spouse. AAR: Honoraria self: Boehringer Ingelheim; Advisory/Consultancy: Boehringer Ingelheim, Lilly, Merck; Medison; Research grant/Funding institution: CASI Pharmaceuticals, Lilly, Boehringer Ingelheim, Novartis, Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Boston Biomedical, BMS, MedImmune, Amgen, GSK, Blueprint Medicines, Merck, AbbVie, Adaptimmune. StK: Served on advisory boards: AstraZeneca, Pfizer, MSD, BMS, Roche, Amgen, BeiGene; honorarium partly to my institution: MSD, BMS, Roche, AstraZeneca, Pfizer, Takeda, BeiGene; Research grant to my institution: AstraZeneca. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Shimizu, Powderly, Abdul Razak, LoRusso, Miller, Kao, Kongpachith, Tribouley, Graham, Stoll, Patel, Sahtout, Blaney, Leibman, Golan and Tolcher.)
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