Abstract CT080: Pharmacokinetic and pharmacodynamic analysis of M7824, a dual anti-PD-L1 and TGFβ TRAP molecule, in the first-in-human phase I dose escalation study

Abstract Introduction: M7824 is a bifunctional molecule that blocks both PD-L1 and TGFβ1-3. In this first-in-human phase I dose escalation study, in addition to monitoring the pharmacokinetics of M7824, we aimed to confirm its mechanism of action, particularly against the TGFβ cytokines. Methods: Patients were treated with M7824 intravenously at 5 dose levels of 0.3, 1, 3, 10, and 20 mg/kg every two weeks. PK analyses were performed from samples up to day 85 (7th dose). PD-L1 target occupancy was measured in CD3+ PBMCs by flow cytometry from patient blood collected at pre-dose, Day 2 (D2), D15, and D43. Further, the blood levels of TGFβ1-3 and pro-inflammatory cytokines were measured at these time points with an additional time point at D8 using analytically validated Luminex bead- and ECLIA-based multiplex immunoassays. Results: Results indicated a half-life of 4-8 days for M7824, which increased with dose up to 3 mg/kg, and was subsequently dose independent at dose levels of > 3 mg/kg. M7824 PK exposure during the first cycle increased in an approximately dose-proportional manner between 3 to 20 mg/kg, without significant accumulation within the first 85 days of treatment. There was PD-L1 target occupancy plateaued at about 80% for dose levels 3-20 mg/kg which was maintained throughout the dosing interval. Furthermore, there was a small (1.7 fold on D2) but significant induction of IFNγ at 0.3-20 mg/kg (p=0.001, n=19). TGFβ1-3 blood levels were reduced by a minimum of 99%, 92%, and 91%, respectively, at all time points for dose levels 1-20 mg/kg. At the dose of 0.3 mg/kg, TGFβ1-3 levels were depleted at D2 and D8, but not at D15 with an average reduction of 63%, 42% and 67%, respectively. Moreover, there was a correlation between the drug PK levels and the TGFβ trapping. Thus, TGFβ1-3 trapping was achieved in the circulation at drug dose level of 1 mg/kg and above. Conclusion: This study demonstrates in vivo evidence for highly significant trapping (>90%) of circulating TGFβ molecules (β1, β2, β3) by the bifunctional agent M7824 at dose levels of 1 mg/kg and higher, in addition to its high degree of peripheral PD-L1 target occupancy (80%). Further studies to evaluate the PK/PD, safety, and efficacy profile of M7824 are ongoing. Citation Format: Liang Cao, Zhigang Kang, Linghui Li, Julius Strauss, Isabelle Dussault, James Gulley. Pharmacokinetic and pharmacodynamic analysis of M7824, a dual anti-PD-L1 and TGFβ TRAP molecule, in the first-in-human phase I dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT080. doi:10.1158/1538-7445.AM2017-CT080