Summary
Abstract
Lapatinib (Tyverb®, Tykerb®) is an orally active, small molecule, reversible, dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 1 (HER1) and type 2 (HER2). In the EU, lapatinib in combination with capecitabine is indicated for the treatment of women with HER2-overexpressing, advanced or metastatic breast cancer that has progressed after treatment with regimens that include anthracyclines, taxanes and, in the metastatic setting, trastuzumab.
The orally administered combination of lapatinib and capecitabine was a more effective treatment than capecitabine alone, and was a generally well tolerated, conveniently administered combination for women with trastuzumab-refractory, HER2-positive advanced or metastatic breast cancer in a clinical trial. Lapatinib combined with capecitabine provides an effective therapeutic option for a group of patients who currently have few treatment choices.
Pharmacological Properties
Lapatinib is an orally active, low molecular weight, reversible inhibitor of the tyrosine kinase activity of both HER1 (also termed epidermal growth factor receptor) and HER2.
In vitro, lapatinib exhibited additive effects in combination with fluorouracil (the active metabolite of capecitabine) and enhanced or synergistic effects in combination with trastuzumab. Lapatinib also showed activity against HER2-positive, trastuzumab-resistant, breast cancer cell lines, suggesting a lack of cross-resistance between these two HER2-directed agents.
Lapatinib demonstrated modest single-agent CNS antitumour activity in phase II studies in women with progressive brain metastases from HER2-positive breast cancer who had previously received trastuzumab; additional activity was seen when capecitabine was added to lapatinib.
The absorption of lapatinib is incomplete and variable after oral administration. Peak serum concentrations of lapatinib are achieved 4 hours after administration. Steady-state serum concentrations of the drug are reached within 6–7 days during repeated dosing. Coadministration of lapatinib with food results in increased systemic exposure to the drug; the timing of dosing in relation to food intake (at least 1 hour before or after) should be standardized to minimize variability in systemic exposure. Lapatinib is extensively (>99%) bound to plasma proteins.
Lapatinib undergoes extensive metabolism (largely by cytochrome P450 isoenzymes 3A4 and 3A5); several oxidated metabolites plus unchanged drug are primarily excreted in the faeces. Accumulation of lapatinib during repeated dosing results in an effective half-life of 24 hours. No clinically meaningful pharmacokinetic drug-drug interactions were observed during coadministration of lapatinib with capecitabine or trastuzumab.
Therapeutic Efficacy
An orally administered combination of lapatinib and capecitabine, as compared with capecitabine alone, significantly delayed disease progression in a randomized, open-label, multicentre, phase III trial in women with HER2-positive, advanced or metastatic breast cancer who had progressed despite treatment with anthracycline-, taxane- and trastuzumab-containing regimens (EGF100151 study). In the end-of-enrolment (intent-to-treat) analysis of 399 patients, the primary endpoint of the time to progression (as determined by a blinded, independent review panel), was significantly longer in the combination therapy group than in the capecitabine monotherapy group (by a median 8.5 weeks).
In addition, progression-free survival, overall response rate and clinical benefit rate were significantly improved in lapatinib plus capecitabine recipients compared with capecitabine monotherapy recipients. Overall survival was not significantly improved in the combination therapy group compared with the capecitabine monotherapy group in analyses conducted after approximately one-third and three-quarters of trial participants had died.
In exploratory analyses, lapatinib plus capecitabine combination therapy slowed disease progression and improved overall survival compared with capecitabine monotherapy in patients treated with less than three prior chemotherapy regimens and second-line patients treated with one prior trastuzumab regimen in the metastatic setting. Combination therapy also slowed disease progression in patients treated with three or more prior chemotherapy regimens, regardless of setting (neoadjuvant, adjuvant or metastatic).
Lapatinib plus capecitabine combination therapy did not have a deleterious effect on patient health-related quality of life, and increased quality-adjusted time without symptoms of disease or toxicity of treatment, compared with capecitabine monotherapy.
Tolerability
Oral lapatinib was generally well tolerated when administered alone, or in combination with other anticancer agents, to women with HER2-positive, trastuzumab-refractory, advanced or metastatic breast cancer in clinical trials.
The most frequent adverse events occurring in more patients treated with lapatinib plus capecitabine than with capecitabine alone in the EGF100151 study included (but were not limited to) diarrhoea, palmar-plantar erythrodysaesthesia (PPE), nausea, rash and vomiting. The majority of adverse events in both treatment groups were mild to moderate (grade 1–2) in severity. The most common severe (grade 3–4) adverse events in either treatment group were diarrhoea and PPE, and the incidence of these adverse events did not differ between treatment groups. Adverse events resulted in study drug discontinuation in 14% of patients in both treatment groups; diarrhoea was the most common adverse event leading to cessation of therapy.
Lapatinib (as monotherapy or in combination with other anticancer agents) appears to be associated with a low rate of cardiotoxicity.
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Various sections of the manuscript reviewed by: Q.S. Chu, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA; D.L. Nielsen, Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; O. Obajimi, Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, New Jersey, USA; F. Petrelli, Division of Medical Oncology, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, Italy; G.G. Steger, First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.
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Sources: Medical literature published in any language since 1980 on ‘lapatinib’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘lapatinib’ and (‘advanced breast cancer’ or ‘breast neoplasms’) or (‘lapatinib’ and [‘advanced’ or ‘metastatic’] and ‘second-line’). Searches were last updated 27 August 2009.
Selection: Studies of lapatinib in combination with capecitabine in women with human epidermal growth factor receptor type 2 (HER2)- overexpressing, advanced or metastatic breast cancer that was refractory to trastuzumab therapy. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Breast cancer, HER2-targetted therapies, trastuzumab, lapatinib, capecitabine, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
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Frampton, J.E. Lapatinib. Drugs 69, 2125–2148 (2009). https://doi.org/10.2165/11203240-000000000-00000
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DOI: https://doi.org/10.2165/11203240-000000000-00000