Toshio Shimizu ^1,2* John Powderly ³ Albiruni Ryan Abdul Razak ⁴ Patricia Lorusso ⁵ Kathy D. Miller ⁶ Steven Kao ⁷ Sarah Kongpachith ⁸ Michelle Graham ⁸ Brian Stoll ⁸ Maulik Patel ⁸ Mohammad Sahtout ⁸ Martha Blaney ⁸ Rachel Leibman ⁸ Talia Golan ^10,9 Anthony Tolcher ¹¹

• ¹ Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Tokyo, Japan
• ² Department of Pulmonary Medicine and Medical Oncology, Wakayama Medical University, Wakayama, Wakayama, Japan
• ³ Carolina BioOncology Institute (CBI), Huntersville, North Carolina, United States
• ⁴ Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
• ⁵ Cancer Center, School of Medicine, Yale University, New Haven, Connecticut, United States
• ⁶ Melvin and Bren Simon Comprehensive Cancer Center, Department of Medicine, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
• ⁷ Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, New South Wales, Australia
• ⁸ AbbVie (United States), North Chicago, Illinois, United States
• ⁹ Institute of Oncology, Sheba Medical Center, Ramat Gan, Tel Aviv District, Israel
• ¹⁰ Tel Aviv University, Tel Aviv, Tel Aviv, Israel
• ¹¹ NEXT Oncology, San Antonio, Texas, United States

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. Conclusions: 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.