The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors
To evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors.
This was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered two doses of matching placebo on day 1, 12 h apart and one dose in the morning on day 2. Two doses of lapatinib 2000 mg were administered orally on day 3, 12 h apart and one dose in the morning on day 4. Twelve-lead digital ECGs were extracted from continuous Holter recordings at pre-specified time points over the 24-h period on days 2 and 4. Venous blood samples for lapatinib concentrations were obtained immediately following the ECGs.
A maximum mean baseline-adjusted, placebo time-matched increase in QTcF, (ddQTcF) in the evaluable, (EV) population (n = 37) of 8.8 ms (90% CI 4.1, 13.4) occurred approximately 10 h after the third lapatinib dose. These results were consistent with those in the pharmacodynamic, PD population, (n = 52) (ddQTcF = 7.9 ms; 90% CI 4.1, 11.7). No subject experienced QTcF increases from baseline of > 60 ms on lapatinib or placebo. The geometric mean lapatinib Cmax of 3902 ng/mL was observed at 3.6 h post-dose.
These data show a relevant, treatment-related increase in QTcF after treatment with three doses of lapatinib 2000 mg. This study confirms the need for caution in patients with solid tumors treated with lapatinib, and who are concomitantly receiving drugs that are strong CYP3A inhibitors and/or prolong the QTc.
KeywordsLapatinib QTc effects Advanced cancer patients
We thank our patients and their families without whom this study would not have been possible. We also wish to thank our colleague oncologists, research nurses and study coordinators at each study site.
Original funding for this study (NCT01328054) was provided by GlaxoSmithKline. As of March 2015 lapatinib is an asset of Novartis Pharmaceutical Corporation, the current sponsor of this study.
Compliance with ethical standards
Conflict of interest
SAC: Has declared no conflicts of interest regarding the conduct of this clinical trial or drafting the manuscript. HIH: Received research funding from GlaxoSmithKline, paid through Duke University Medical Center at the time of this work and drafting the manuscript. He is currently employed by Genentech/Roche and owns Roche stock. SS: Received research funding from GlaxoSmithKline/Novartis at the time of this work and has served on GlaxoSmithKline and Novartis Advisory Boards. DW: Has declared no conflicts of interest regarding the conduct of this clinical trial or drafting the manuscript. JPZ: Is employed by Novartis. LDL: Received research funding from GlaxoSmithKline/Novartis, paid through Dartmouth College to support the costs of this study.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the participating institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255–6263. https://doi.org/10.1038/sj.onc.1205794 CrossRefGoogle Scholar
- 3.Tykerb(R) [package insert]. Novartis Pharmaceutical Corporation (2017). https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tykerb.pdf. Accessed Mar 2018
- 4.Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743. https://doi.org/10.1056/NEJMoa064320 CrossRefGoogle Scholar
- 5.Kloth JS, Pagani A, Verboom MC, Malovini A, Napolitano C, Kruit WH, Sleijfer S, Steeghs N, Zambelli A, Mathijssen RH (2015) Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors. Br J Cancer 112:1011–1016. https://doi.org/10.1038/bjc.2015.82 CrossRefGoogle Scholar
- 6.Miles DR, Lacy SA, Wada DR, Milwee S, Yaron Y, Nguyen LT (2017) Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes. Cancer Chemother Pharmacol 80:295–306. https://doi.org/10.1007/s00280-017-3349-y CrossRefGoogle Scholar
- 12.Agency EM (2008) Assessment report for Tyverb. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000795/WC500044960.pdf. Accessed 19 Jan 2019
- 15.Dogan E, Yorgun H, Petekkaya I, Ozer N, Altundag K, Ozisik Y (2012) Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: a single center experience. Med Oncol (Northwood, London, England) 29:3232–3239. https://doi.org/10.1007/s12032-012-0253-5 CrossRefGoogle Scholar
- 16.Chien AJ, Illi JA, Ko AH, Korn WM, Fong L, Chen LM, Kashani-Sabet M, Ryan CJ, Rosenberg JE, Dubey S, Small EJ, Jahan TM, Hylton NM, Yeh BM, Huang Y, Koch KM, Moasser MM (2009) A phase I study of a 2-day lapatinib chemosensitization pulse preceding nanoparticle albumin-bound paclitaxel for advanced solid malignancies. Clin Cancer Res 15:5569–5575. https://doi.org/10.1158/1078-0432.ccr-09-0522 CrossRefGoogle Scholar
- 19.Hsieh S, Tobien T, Koch K, Dunn J (2004) Increasing throughput of parallel on-line extraction liquid chromatography/electrospray ionization tandem mass spectrometry system for GLP quantitative bioanalysis in drug development. Rapid Commun Mass Spectrom 18:285–292. https://doi.org/10.1002/rcm.1327 CrossRefGoogle Scholar
- 20.GlaxoSmithKline (2007) A phase I, open-label, multiple dose, dose-escalation study of GW572016 in patients with solid tumors. https://www.gsk-studyregister.com/study/7491. Accessed 19 Jan 2019
- 21.Administration UFaD (2005) E14 Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073153.pdf. Accessed 21 Aug 2017
- 22.Harmonisation ICf (2016) ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs questions & answers (R3). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf. Accessed 3 Mar 2018
- 26.Therapeutics ACfE, Research o (2018) CredibleMeds :: QTDrugs lists (registration required). https://crediblemeds.org/new-drug-list. Accessed 25 Mar 2018
- 29.Abbas R, Hug BA, Leister C, Sonnichsen D (2012) A randomized, crossover, placebo- and moxifloxacin-controlled study to evaluate the effects of bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects. Int J Cancer 131:E304–E311. https://doi.org/10.1002/ijc.27348 CrossRefGoogle Scholar
- 30.Heath EI, Infante J, Lewis LD, Luu T, Stephenson J, Tan AR, Kasubhai S, LoRusso P, Ma B, Suttle AB, Kleha JF, Ball HA, Dar MM (2013) A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors. Cancer Chemother Pharmacol 71:565–573. https://doi.org/10.1007/s00280-012-2030-8 CrossRefGoogle Scholar