Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas

Abstract

Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression

“…We then studied the effect of another ErbB2-targeting agent, GW583340, which has similar composition as the clinical compound lapatinib/Tykerb and has been shown to be more effective compared with trastuzumab in inhibiting ErbB2 signaling and inducing tumor apoptosis in ErbB2-overexpressing advanced metastatic breast cancer patients (17) and breast tumor lines (18,29,35,36). Immunoblot analysis of the cell lysates at 48 h post-GW583340 treatment revealed a significant inhibition of p-AKT expression at the lowest concentration of 1 Amol/L with complete inhibition at higher concentrations (Fig.…”

“…However, subsets of women with ErbB2-overexpressing tumors do not respond and resistance is common (15,16). Lapatinib (GW583340/ GW572016/Tykerb), a dual inhibitor of the oncogenic ErbB2 and ErbB1 receptor tyrosine kinases, blocks ErbB2 tyrosine autophosphorylation with consequential downstream inhibitory effects on MAPK-Erk1/2 and PI3K-Akt growth/survival signaling in tumor cell lines, tumor xenografts, and in patients, notably those with ErbB2-overexpressing breast cancers where lapatinib induces tumor cell apoptosis (17)(18)(19). In a recent clinical trial, lapatinib showed a 50% clinical response rate in ErbB2-overexpressing IBC patients compared with ErbB2 overexpressing non-IBC patients (20); however, acquired resistance is a common outcome even in those patients who show an initial clinical response.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…www.nature.com/reviews/cancer in LVEF were observed 32 , despite pharmacodynamic evidence of inhibition of ERBB2 signalling in breast cancer cell lines and patient tumour samples. Although a definitive safety profile for lapatinib must await the completion of several randomized phase III trials in breast cancer, it seems likely that the frequency of cardiac dysfunction will be low.…”

“…If inhibition of ERBB2 signalling induces cardiomyocyte dysfunction, then cardiotoxicity would also be expected with small-molecule inhibitors of ERBB2 kinase activity. However, early clinical results with lapatinib (GW572016), a quinazoline compound that is an orally available dual kinase inhibitor of EGFR and ERBB2, suggest that it has minimal cardiotoxicity 32 . Because of the trastuzumab experience, prospective monitoring of cardiac function is an integral part of phase I-III trials of lapatinib.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…No thorough exposure–response or exposure–toxicity studies have been reported for lapatinib, although one trial found that the majority of responders had a C min in the 300–600 ng/ml range 37. Future studies should focus on establishing exposure–response and exposure–toxicity relationships.…”