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

Abstract

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 immune signatures could be observed when comparing BSL vs OT biopsies in S1. CONCLUSION: RG6292, consistent with its proposed mechanism of action, induces profound and preferential depletion of Treg cells over CD8+CD25+ in the periphery and in the TME at clinically safe doses between 35-70mg. Further development of RG6292 is currently being explored. Citation Format: Tamara Tanos, Kevin Smart, Valentina Gambardella, Kristoffer Rohrberg, Michael Ong, Maria Esperanza Rodriguez Ruiz, Jean-Pascal Machiels, Miguel Fernández Sanmamed, Josep Tabernero, Anna Spreafico, Daniel Renouf, Stephen Luen, Rachel Galot, Bernard Doger, Emiliano Calvo, Aung Naing, Samira Curdt, Nicolas Staedler, Mike Flores, Enrique Gómez Alcaide, Chiahuey Ooi, Michael Hettich, Sebastian Dziadek, Yuying Xie, Gabriel Schnetzler, Theresa Kolben, Linxinyu Xu, Vaios Karanikas, Christophe Boetsch. Pharmacokinetic/pharmacodynamic (PK/PD) relationships of the novel Treg depleter RG6292 in Phase Ia and Ib studies in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT176.

Deciphering Regulatory T-Cell Dynamics in Cancer Immunotherapy: Mechanisms, Implications, and Therapeutic Innovations

“…This breakthrough supports the clinical development of RG6292, suggesting a novel approach to cancer immunotherapy by combining Treg depletion with immune checkpoint blockade to potentiate antitumor responses. The drug exhibited a linear and time-independent pharmacokinetic profile without any observable antidrug antibodies, indicating favorable characteristics for RG6292’s advancement as a promising therapeutic candidate for solid tumors . Characterized by the FOXP3 marker, Tregs serve as critical immunoregulators within this scenario, potentially protecting cancer cells within the TME.…”

“…The drug exhibited a linear and time-independent pharmacokinetic profile without any observable antidrug antibodies, indicating favorable characteristics for RG6292's advancement as a promising therapeutic candidate for solid tumors. 47 Characterized by the FOXP3 marker, Tregs serve as critical immunoregulators within this scenario, potentially protecting cancer cells within the TME. However, strategically targeting these cells presents a challenging endeavor due to the risk of provoking unwanted immune responses, rendering success contingent upon tumor type.…”