PI-012 - CONCENTRATION-QT ANALYSIS FOR BAY 2927088 INDICATES NO CLINICALLY RELEVANT QTC INTERVAL PROLONGATION

C. Chen¹, B. Ploeger², M. Damaske², S. Reif², S. Pu³, P. Grassi⁴, B. Brennan³; ¹Bayer, Whippany, USA, ²Bayer, Berlin, Germany, ³Bayer, Whippany, NJ, USA, ⁴Bayer, Milan, Italy.

Background: BAY 2927088 is an oral reversible tyrosine kinase inhibitor (TKI) being developed for treatment of adult patients with unresectable or metastatic non-small cell lung cancer harboring HER2 activating mutations. QT interval prolongation, a condition where the electrical cycle of the heart is delayed, potentially leading to serious arrhythmias like Torsades de Pointes, has been observed with many TKIs. The relationship between observed BAY 2927088 plasma concentration and QT interval (C-QTc) warrants investigation during drug development.

Methods: During the first in human (FiH) study, 12-lead ECG central readings were performed in triplicate at screening, pre-dose and time-matched to PK post-dose on Day 1 and at steady-state at various dose levels. Fridericia’s method (QTcF) was used to correct for heart rate. The C-QTc linear mixed effects approach to analysing any change in QTcF from baseline (QTcF) included fixed effects for the slope of the concentration-effect relationship, the difference of the individual baseline QTcF and the mean QTcF baseline of all patients and random effects for slope and intercept.

Results: Although a slight and statistically significant (p < 0.05) increase in QTcF with increasing BAY 2927088 plasma concentration was observed, the upper limit of the 90% confidence interval (CI) of QTcF did not exceed the threshold of regulatory concern (20 ms) at the highest observed concentration. The predicted Cmax after nominal dosing of the recommended dose of 20 mg twice daily for 21 days is considerably lower than the highest plasma concentration observed in the initial FiH study.

Conclusion: Based on the evaluation of high-quality ECG measurements, including a concentration-QTc analysis, there is no evidence of any clinically relevant QTc interval prolongation with BAY 2927088.