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
BackgroundTransforming 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. Livmonip...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-10-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2024.1376551/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832576102055280640 |
|---|---|
| author | Toshio Shimizu Toshio Shimizu John Powderly Albiruni Abdul Razak Patricia LoRusso Kathy D. Miller Steven Kao Sarah Kongpachith Catherine Tribouley Michelle Graham Brian Stoll Maulik Patel Mohammad Sahtout Martha Blaney Rachel Leibman Talia Golan Talia Golan Anthony Tolcher |
| author_facet | Toshio Shimizu Toshio Shimizu John Powderly Albiruni Abdul Razak Patricia LoRusso Kathy D. Miller Steven Kao Sarah Kongpachith Catherine Tribouley Michelle Graham Brian Stoll Maulik Patel Mohammad Sahtout Martha Blaney Rachel Leibman Talia Golan Talia Golan Anthony Tolcher |
| author_sort | Toshio Shimizu |
| collection | DOAJ |
| description | BackgroundTransforming 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).MethodsThe 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.ResultsFifty-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.ConclusionLivmoniplimab 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. |
| format | Article |
| id | doaj-art-ecaf119bc00648e1807c616981421d5c |
| institution | Kabale University |
| issn | 2234-943X |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-ecaf119bc00648e1807c616981421d5c2025-01-31T11:15:21ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-10-011410.3389/fonc.2024.13765511376551First-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 tumorsToshio Shimizu0Toshio Shimizu1John Powderly2Albiruni Abdul Razak3Patricia LoRusso4Kathy D. Miller5Steven Kao6Sarah Kongpachith7Catherine Tribouley8Michelle Graham9Brian Stoll10Maulik Patel11Mohammad Sahtout12Martha Blaney13Rachel Leibman14Talia Golan15Talia Golan16Anthony Tolcher17Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, JapanDepartment of New Experimental Therapeutics and International Cancer New Drug Development Center, Kansai Medical University Hospital, Osaka, JapanCarolina BioOncology Institute, Huntersville, NC, United StatesCancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, ON, CanadaYale Cancer Center, Yale University, New Haven, CT, United StatesDepartment of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United StatesDepartment of Medical Oncology, Chris O’Brien Lifehouse, Sydney, NSW, AustraliaAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesAbbVie Bay Area, South San Francisco, CA, United StatesInstitute of Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel0Oncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University, Tel Aviv, Israel1New Experimental Therapeutics (NEXT) Oncology, San Antonio, TX, United StatesBackgroundTransforming 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).MethodsThe 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.ResultsFifty-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.ConclusionLivmoniplimab 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.https://www.frontiersin.org/articles/10.3389/fonc.2024.1376551/fulladvanced solid tumorsTGF-ß1GARPimmunotherapyanti-PD-1 antibodycombination drug therapy |
| spellingShingle | Toshio Shimizu Toshio Shimizu John Powderly Albiruni Abdul Razak Patricia LoRusso Kathy D. Miller Steven Kao Sarah Kongpachith Catherine Tribouley Michelle Graham Brian Stoll Maulik Patel Mohammad Sahtout Martha Blaney Rachel Leibman Talia Golan Talia Golan Anthony Tolcher 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 Frontiers in Oncology advanced solid tumors TGF-ß1 GARP immunotherapy anti-PD-1 antibody combination drug therapy |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | advanced solid tumors TGF-ß1 GARP immunotherapy anti-PD-1 antibody combination drug therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2024.1376551/full |
| work_keys_str_mv | AT toshioshimizu firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT toshioshimizu firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT johnpowderly firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT albiruniabdulrazak firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT patricialorusso firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT kathydmiller firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT stevenkao firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT sarahkongpachith firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT catherinetribouley firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT michellegraham firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT brianstoll firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT maulikpatel firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT mohammadsahtout firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT marthablaney firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT rachelleibman firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT taliagolan firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT taliagolan firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors AT anthonytolcher firstinhumanphase1doseescalationresultswithlivmoniplimabanantibodytargetingthegarptgfß1complexasmonotherapyandincombinationwiththeantipd1antibodybudigalimabinpatientswithadvancedsolidtumors |