Objectives: PF-07220060 is a next-generation highly selective CDK4 inhibitor with significant sparing of CDK6 currently being investigated in participants with metastatic or advanced solid tumors with focus on HR+/HER2- metastatic breast cancer. The purpose of this work was to assess the impact of PF-07220060 plasma level on cardiovascular parameters, including RR-interval and heart rate-corrected QT interval (QTc), in patients from the ongoing first-in-human Phase 1/2a study (NCT04557449).
Methods: A preliminary PK/PD analysis (data-cut date: November 1, 2023) was conducted to explore the relationship between electrocardiogram (ECG) endpoints and plasma PF-07220060 concentration based on time-matched PK and triplicate mean ECG data. A graphical summary and linear mixed-effects modeling approach was applied. The ECG endpoints were RR interval and the change-from-baseline QTc corrected for heart rate. To obtain QTc values that are independent of the heart rate, three correction methods were evaluated: Fredericia’s formula (site reported QTcF), Bazett’s formula (QTcB), and study-specific estimated correction (QTcS). A 90% confidence interval (CI) of the slope which includes “zero” was interpreted as PF-07220060 having no statistically significant concentration-dependent effect on the ECG parameter.
Results: The dataset consisted of 3848 paired PK-ECG measurements collected from 164 patients in the dose escalation and dose expansion cohorts. The upper bound of 90% CI for the concentration-RR slopes was below 0, indicating that RR-intervals decrease with increasing drug concentrations. The predicted heart rate change at the observed steady state geometric mean Cmax at 300 mg BID was 0.97 bpm (90% CI: 0.01, 1.95) and the drug effect on heart rate is considered minimal. Using only baseline data, the confounding relationship between QT and RR was adequately eliminated by the Fridericia correction or study-specific correction. By visual inspection, QTcF was as effective as QTcS in correcting the effect of heart rate on the QT interval, therefore QTcF was chosen for the concentration-ΔQTc analysis. The 90% CI for the concentration-ΔQTcF slope included 0, indicating PF-07220060 did not have a statistically significant concentration-dependent effect on QTcF. The predicted ΔQTcF at the observed steady state geometric mean Cmax at 300 mg BID was 3.9 msec (90% CI: 1.9, 5.9). Even at a 2-fold greater concentration, the predicted ΔQTcF is 5.5 msec (90% CI: 1.9, 9.1), and the upper bound of the 90% CI of the predicted QTcF increase is beneath the ICH E14 threshold for regulatory concern (10 msec).
Conclusions: Initial concentration-QT analysis indicates that the effect of PF-07220060 on heart rate is minimal and PF-07220060 does not exhibit a concentration-dependent impact on QTcF, suggesting a low potential for QT prolongation at clinical doses to be evaluated in the future studies.
