Dataset Information

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

ABSTRACT:

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 (?QTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (??QTcF). Linear mixed-effects modeling evaluated potential exposure-response relationships between ?QTcF 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 ??QTcF (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 ??QTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration-QTc modeling showed no apparent relationship between ?QTcF 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.

SUBMITTER: Garg A

PROVIDER: S-EPMC3825499 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Garg Amit A Li Jing J Clark Emma E Knott Adam A Carrothers Timothy J TJ Marier Jean-François JF Cortés Javier J Brewster Michael M Visich Jennifer J Lum Bert B

Cancer chemotherapy and pharmacology 20130903 5

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 23999693

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Project description:BackgroundIn patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.MethodsWe randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.ResultsThe median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.ConclusionsIn patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Project description:IntroductionMyocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer.Patients and methodsPatients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points.ResultsSixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline.ConclusionThe absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer.Implications for practiceDual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.

Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

Similar Datasets

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