Abstract C162: Assessment of the potential for QTc prolongation by the investigational ATR inhibitor tuvusertib in patients with advanced solid tumors using integrated nonclinical and clinical assessments

Abstract

Abstract Background: Tuvusertib (M1774) is a potent, selective, orally administered inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR) with demonstrated antitumor activity in preclinical models. Tuvusertib is currently being evaluated in phase I and II trials as monotherapy and in combination with other DNA damage response inhibitors and immune checkpoint inhibitors. Assessment of an investigational agent’s potential to cause delayed ventricular repolarization (QTc prolongation) is essential in drug development. QTc prolongation is assessed using nonclinical studies and concentration-QTc (c-QTC) analysis of phase I clinical data across a wide dose range and/or a thorough QT/QTc (TQT) clinical study. Here, we assess tuvusertib’s potential to cause QTc prolongation by integrating nonclinical evaluations and clinical c-QTc analyses. Methods: Nonclinical evaluations included in vitro binding of tuvusertib to the ether-a-go-go-related gene (hERG) channel and telemetry of tuvusertib in male beagle dogs and minipigs. Pharmacokinetics-time-matched triplicate electrocardiograms were collected in patients with advanced solid tumors from the first-in-human (FIH) trial (NCT04170153) for tuvusertib 5−270 mg QD along with intermittent dosing regimens. Based on exploratory analyses, a linear mixed-effect model (Garnett C, et al. J Pharmacokinet Pharmacodyn 2018;45:383–97) was chosen to describe the relationship between tuvusertib plasma concentrations and selected heart rate (HR)-corrected QT using the Fridericia correction (QTcF). Results: In vitro hERG channel binding potency for tuvusertib 0.3–10.0 µM was calculated with a half-maximal inhibitory concentration (IC50) of 2.8 µM. Nonclinical telemetry studies showed no treatment effect on QT/QTc prolongation at doses of up to 3 mg/kg in male beagle dogs and minipigs. c-QTc analyses in 55 patients from the FIH trial revealed a small positive slope of drug effect (slope estimate [95% CI] = 0.00244 [0.000708, 0.00417] ms/(ng/mL)). This increase in model-predicted QTcF from baseline was not considered to be clinically meaningful (<20 ms threshold) at steady-state maximum concentration (Cmax) achieved with the recommended dose for expansion (RDE) of 180 mg QD 2w on/1w off (mean [upper bound of 95% CI] = 3.4 [5.5] ms) and up to 3 times the RDE (10.3 [16.5] ms). Concentration-HR modeling found no relationship between tuvusertib concentration and HR, suggesting the absence of an effect. Conclusions: Integrating nonclinical and clinical assessments revealed no clinically meaningful effect of tuvusertib on QTc at concentrations achieved with the RDE and up to 3-times higher concentrations. Citation Format: Jatinder Kaur Mukker, Timothy A. Yap, Anthony W. Tolcher, Johann S. de Bono, Ruth Plummer, Rohan Kulkarni, Han Witjes, Paul Matthias Diderichsen, Axel Krebs-Brown, Rainer Strotmann, Zoltan Szucs, Ioannis Gounaris, Karthik Venkatakrishnan. Assessment of the potential for QTc prolongation by the investigational ATR inhibitor tuvusertib in patients with advanced solid tumors using integrated nonclinical and clinical assessments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C162.