Abstract
Tuvusertib is an investigational, orally administered inhibitor of ATR protein kinase, currently in Phase II clinical development. Here, we present an integrated nonclinical and clinical assessment of the effect of tuvusertib on QTc interval. In vitro inhibition by tuvusertib of the hERG potassium channel was evaluated, and in vivo ECG assessments evaluated the effect on QTc in dogs. PK-matched triplicate ECGs in patients receiving tuvusertib in Part A1 of the Phase I DDRiver Solid Tumors 301 study (N = 55; dosing regimens: 5-270 mg QD, 180-220 mg QD 2 weeks on/1 week off, or 150 mg BID 4 days on/3 days off) contributed to concentration-QTc analyses via linear mixed-effects modeling. In vitro, tuvusertib inhibited hERG with an IC(50) of 2.83 μM, which is ~2.5 times its steady-state unbound C(max) at the clinical RDE (180 mg QD 2 weeks on/1 week off). In vivo, tuvusertib did not affect QTc up to 5 mg/kg/day in dogs (unbound C(max) comparable to that at clinical RDE). In patients with advanced solid tumors receiving tuvusertib at up to threefold higher plasma concentrations than at the RDE, the risk for clinically relevant QTc prolongation was assessed to be low (upper limit of 90% CI of model-predicted ΔQTcF < 20 ms). There was no relationship between tuvusertib plasma concentration and RR interval, suggesting no effect on HR. Early integrated concentration-QTc assessments of tuvusertib monotherapy in Phase I were crucial in informing the low risk for clinically relevant QTc prolongation, thereby facilitating efficient evaluation of investigational tuvusertib combination strategies in ongoing clinical development.