Exposure–response analysis of pertuzumab in HER2-positive metastatic breast cancer: absence of effect on QTc prolongation and other ECG parameters

PURPOSE: The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. METHODS: Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (–30 and –15 min) and after (0–15 and 60–75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia’s correction was applied to QT measurements (QTcF) and change from baseline (ΔQTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure–response relationships between ΔQTcF and observed pertuzumab concentrations. RESULTS: Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔQTcF (90 % CI) values at 0–15 min, 60–75 min, and 72 h post-infusion were −6.96 (−13.69, −0.23), −6.35 (−13.57, 0.88), and −4.08 (−12.64, 4.48), all of which were <5 ms, with upper CI limits <10 ms. One Cycle 3 post-infusion mean ΔΔQTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration–QTc modeling showed no apparent relationship between ΔQTcF and pertuzumab concentrations. CONCLUSIONS: Cardiac monitoring and concentration–QTc modeling demonstrated that pertuzumab, combined with trastuzumab and docetaxel, had no clinically relevant effects on QTcF and other electrocardiogram parameters. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-013-2279-6) contains supplementary material, which is available to authorized users.