Abstract CT176: Pharmacokinetic/pharmacodynamic (PK/PD) relationships of the novel Treg depleter RG6292 in Phase Ia and Ib studies in patients with solid tumors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (8_Supplement), p.CT176-CT176
• Main Authors: Tanos, Tamara, Smart, Kevin, Gambardella, Valentina, Rohrberg, Kristoffer, Ong, Michael, Rodriguez Ruiz, Maria Esperanza, Machiels, Jean-Pascal, Sanmamed, Miguel Fernández, Tabernero, Josep, Spreafico, Anna, Renouf, Daniel, Luen, Stephen, Galot, Rachel, Doger, Bernard, Calvo, Emiliano, Naing, Aung, Curdt, Samira, Staedler, Nicolas, Flores, Mike, Alcaide, Enrique Gómez, Ooi, Chiahuey, Hettich, Michael, Dziadek, Sebastian, Xie, Yuying, Schnetzler, Gabriel, Kolben, Theresa, Xu, Linxinyu, Karanikas, Vaios, Boetsch, Christophe
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-CT176

INTRODUCTION: Activated Tregs in the tumor micro-environment are correlated with poor outcomes, and are considered as key players in tumor immune-escape. So far, Treg depletion has not been successful in patients, either because adequate Treg depletion was not achieved or because Teff cells have either been impacted or depleted as well. RG6292 is the first anti-human CD25 antibody developed to specifically deplete human Tregs while preserving IL-2R STAT5 signaling and Teff activity. It has been optimized for ADCC and selective depletion of cells with high CD25 density (Treg). MATERIALS and METHODS: Adult patients with advanced solid tumors were given RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) in a Ph1 dose escalation study. 76 pts have been treated at dose levels ranging from 0.3 mg to 165 mg in S1 and 48 pts at dose levels ranging from 0.3 mg to 160 mg in S2. In both studies a Bayesian logistic regression model with overdose control guided dose escalation was utilized. Data cutoff was May 27, 2022. Pharmacokinetic and pharmacodynamic analyses were undertaken in peripheral blood and tumor tissue. PK/PD modeling applied to Treg and Teff cells helped characterize and identify the optimal therapeutic window to ensure (1) relevant Treg depletion and (2) limited impact on T effector. RESULTS: RG6292 has a linear and time independent PK with no ADA detected. A Population PK-PD modeling approach was applied to Treg and Teff cells in the periphery. To predict the RG6292 effects in the tumor microenvironment (TME), the PK/PD relationships observed and characterized in the periphery for all cell subpopulations were considered the same, a tumor uptake factor of 15% was considered. At steady-state trough, a 70 mg Q3W dose was predicted to lead to 72% of patients with concentration above the Treg (%CD4) EC50 in tumor and 40% of patients with concentration above the Non-Treg (%CD4) EC50 in plasma. RG6292 induced a dose-dependent peripheral and intratumoral Treg depletion in on-treatment biopsies taken 28 days after initiation of treatment. Treatment did not appear to impact the number nor the functionality of intratumoral CD8 T cells nor any evident effect observed on PDL1 expression. In blood, stable levels of all other immune cells were observed after treatment. Moreover, in both studies a marginal increase of IFNg, CXCL10, IL-10, TNF was observed. No consistent gene expression alterations nor imm