Phase 1/2 dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab: Initial results from dose escalation.
Authors: Starodub Alexander , Powderly John D. , Kim Sung-Bae , Davar Diwakar , Hill Andrew Graham , Yeku Oladapo O. , Gabrail Nashat Y. , Krapp Christian , Pihl Susanne , Zhang Ying , Slavsky Sibel , Torrejon Castro Davis Y , Uyei Anne , Singel Stina Mui , Kwatra Vineet 
Published: June 2023

e14597

Background: TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 analog (IL-2 β/γ) designed to optimally address the drawbacks of interleukin-2 (IL-2) therapy. IL-2 β/γ was created by permanently attaching a 5 kDa mPEG in the IL-2Rα binding site. To improve the pharmacokinetic (PK) properties, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon linker creating a prodrug, TransCon IL-2 β/γ. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the carrier via autocleavage in a controlled manner. The associated long effective half-life and sustained IL-2 β/γ exposure results in robust activation of IL-Rβ/γ+ cytotoxic immune cells, at a lower Cmax compared to IL-2 therapy. The primary objectives of the IL-Believe trial are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: In dose escalation (3+3 design), patients aged ≥18 with advanced solid tumors receive TransCon IL-2 β/γ as monotherapy or in combination with pembrolizumab with IV dosing every 3 weeks. Disease is assessed every 9 weeks using RECIST 1.1. Safety, PK, and pharmacodynamics (PD) are evaluated. Results: As of 25 Jan 2023, 27 patients were treated in dose escalation: 18 in monotherapy (Dose Levels (DL) 1-4) and 9 in combination therapy (DL1, DL2). The most common tumor types in monotherapy and in combination therapy were head & neck (19%), colorectal (11%) and endometrial (11%). Patients received a median of 3 prior lines of therapy in monotherapy. The most common Treatment Related Adverse Events (TRAEs) in monotherapy and in combination therapy were pyrexia (30%), Cytokine Release Syndrome (CRS) (26%) and fatigue (22%). Grade 3 (G3) TRAEs in monotherapy were anemia (17%), CRS (6%), thrombocytopenia (6%), hypoxia (6%), all reported at DL4. 1 Dose Limiting Toxicity of G3 CRS was reported at DL4. Preliminary PK results showed systemic drug exposure of TransCon IL-2 β/γ with a half-life of ~ 35 hours and no PK interaction with pembrolizumab was observed. PD data were consistent with sustained activation and dose dependent expansion of cytotoxic effector cells, in comparison, Tregs were only expanded minimally. Absolute lymphocyte counts increased in a dose dependent manner while eosinophils remained low. Prolonged stable disease ( > 32 weeks) was observed in one pancreatic cancer patient on monotherapy. Conclusions: TransCon IL-2 β/γ is generally well-tolerated as monotherapy and in combination with pembrolizumab. The pharmacodynamics data confirm a durable activation and expansion of IL-2Rβ/γ+ cytotoxic immune cells over IL-2Rα+ eosinophils and Tregs. Clinical trial information: NCT05081609 .