Trastuzumab, in combination with carboplatin and docetaxel, does not prolong the QT interval of patients with HER2-positive metastatic or locally advanced inoperable solid tumors: results from a phase Ib study

Abstract

PurposeThis study evaluated the potential effect of trastuzumab on the electrocardiogram (ECG) QT interval and assessed the potential pharmacokinetic interaction between trastuzumab and carboplatin. Here, we report the QT and safety results.MethodsPatients with metastatic or inoperable HER2-positive solid tumors received docetaxel and carboplatin on Day 1 of each 3-week (q3w) cycle. Trastuzumab was administered intravenously, as an accelerated loading dose regimen, on Cycle 1, Day 2 and Cycle 1, Day 8, and then on Day 1 of each subsequent q3w cycle. ECG assessments were performed pre- and posttrastuzumab infusion in the first two cycles. Fridericia’s correction was applied to QT intervals (QTcF). Baseline-adjusted QTcF intervals (the change from baseline) and their 90 % confidence intervals (CIs) were calculated.ResultsThe study enrolled 59 patients. At all time points, the 90 % CI upper bound for the mean baseline-adjusted QTcF was <10 ms. At steady-state serum trastuzumab concentrations, the mean baseline-adjusted QTcF interval was −8.4 ms (90 % CI −11.1, −5.7). No patient exhibited an absolute QTcF interval of >480 ms. No relationship was observed between trastuzumab concentration and baseline-adjusted QTcF interval. At data cutoff, 84.5 % of patients had experienced grade ≥3 adverse events, the most common of which were hematologic and as expected. Left ventricular ejection fraction remained ≥45 % in all patients during the study.ConclusionsThe results suggest that trastuzumab had no clinically relevant effect on QTcF interval. The safety profile of trastuzumab in combination with carboplatin and docetaxel was consistent with the known safety profile of this combination.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2603-9) contains supplementary material, which is available to authorized users.

Effect of Trastuzumab Deruxtecan on QT/QTc Interval and Pharmacokinetics in HER2‐Positive or HER2‐Low Metastatic/Unresectable Breast Cancer

“…These results are consistent with those of studies of trastuzumab, 21 pertuzumab, 22 and T‐DM1, 15 in which QT prolongation in patients with HER2‐positive metastatic breast cancer was not significantly affected. In contrast with HER2‐targeted small molecules, such as the tyrosine kinase inhibitor lapatinib, antibody‐based therapies are not expected to affect ion channels in the heart because of their high specificity and large size 21,22 . Although an increased risk of LVEF decline and congestive heart failure has been observed with trastuzumab in patients with HER2‐positive breast cancer with or after anthracycline treatment, 20 there was no clear evidence of heart failure or LVEF decline in the current study, in which all patients had previously received anthracyclines.…”

Evaluation of QTc Interval Prolongation in Breast Cancer Patients after Treatment with Epirubicin, Cyclophosphamide, and Docetaxel and the Influence of Interobserver Variation

“…Cardiac toxicity could be more serious when HER2/neu-targeting agents are combined with anthracyclines [28][29][30]. Our findings, however, are in line with a novel study showing that a combination of docetaxel with trastuzumab has no additional effect on the QT interval [31].…”

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…For trastuzumab, despite its known effects on left ventricular ejection fraction, no relevant changes to QTc have been documented 117, 118, 165. Similarly, pertuzumab has not shown QTc effects 115, 116.…”

“…9, 14, 16, 17, 19, 24, 26, 27, 29-33, 35, 36, 38, 39, 72, 78, 81, 161-164 Monoclonal antibody-based TKIs For trastuzumab, despite its known effects on left ventricular ejection fraction, no relevant changes to QTc have been documented. 117,118,165 Similarly, pertuzumab has not shown QTc effects. 115,116 Bevacizumab has been used alone or in combination with other TKI and other chemotherapeutic agents without causing QTc prolongation, despite its cardiotoxicity potential.…”