Figure S2. Population PK/PD modeling approach: The PK/PD model was used to simulate both RG6292 and FOXP3+ Treg levels, following a range of doses. The model which best describes the data is a model where previously defined drug levels (from the PK model) stimulate the loss of CD25+ cells from the plasma, in a Michaelis-Menten manner. The concentrations of RG6282 and the cell count of the respective T cells were modeled in a simultaneous manner. Proportional error was used for both PK and PD. PK/PD modeling utilized the measured plasma concentrations of different CD25+ cell types, like Treg cells or CD4+CD25+ following IV infusion administration of RG6292.
ARTICLE ABSTRACT
Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.
Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). Both studies included dose escalation and expansion parts to determine the maximum tolerated dose and recommended phase II dose.
RG6292 was well tolerated. Pruritus and rash were the most frequent adverse events and were manageable with supportive treatment. Serum RG6292 levels increased dose proportionally, independent of the atezolizumab combination. RG6292 induced a sustained dose-dependent depletion of peripheral Tregs with no apparent effect on other immune cells. Evidence of intratumoral Treg reduction (≥50% vs. baseline) was observed at RG6292 doses of 35 to 100 mg. The maximum tolerated dose was 165 mg every 3 weeks, and the recommended phase II dose was proposed as 70 mg every 3 weeks. Objective responses were limited to three partial responses in patients receiving RG6292 combined with atezolizumab.
RG6292 induced a dose-dependent peripheral blood and measurable intratumoral Treg depletion in concordance with the proposed mode of action; however, clinical efficacy as a single agent or combined with atezolizumab was insufficient to warrant further exploration in this population.
RG6292 (vopikitug) targets CD25 (IL-2Rα) and mediates regulatory T-cell depletion while not interfering with IL-2 signaling. Peripheral and intratumoral Treg depletion was shown in two phase I studies. However, RG6292 alone or in combination with atezolizumab was insufficient to reverse and rescue from established resistance mechanisms in solid tumors.
