Lapatinib: A Novel Dual Tyrosine Kinase Inhibitor with Activity in Solid Tumors

@article{Nelson2006LapatinibAN,
  title={Lapatinib: A Novel Dual Tyrosine Kinase Inhibitor with Activity in Solid Tumors},
  author={Michael H Nelson and Christian R. Dolder},
  journal={Annals of Pharmacotherapy},
  year={2006},
  volume={40},
  pages={261 - 269}
}
Objective: To review the pharmacology, pharmacokinetics, clinical trials, adverse effects, and drug interactions of lapatinib. Data Sources: A PubMed search was conducted (1966–August 2005) using the following terms: lapatinib, GW572016, and dual tyrosine kinase inhibitor. Additional information sources included meeting abstracts, clinical trial data, and bibliographies from articles identified through PubMed. Study Selection and Data Extraction: Preclinical and clinical trials that evaluated… 

Tables from this paper

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer

While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated.

Lapatinib in breast cancer.

Improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.

Pharmacology of epidermal growth factor inhibitors.

New combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.

Lapatinib: current status and future directions in breast cancer.

Results of phase II and III clinical trials of lapatinib in metastatic breast cancer, evidence for its potential in patients with brain metastases, and current clinical trials as adjuvant treatment in early-stage disease are reviewed.

Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants

This non‐clinical study shows that lapatinib and capecitabine modulate each other’s molecular determinants of response and that concomitant dosing seems to be the optimal way to combine these drugs.

Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments

The tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development are given, and the future role of TKIs in the treatment of solid tumors is discussed.

Lapatinib

Ongoing and future studies will explore lapatinib's role in the (neo)adjuvant therapy setting, in further drug combinations as well as in the treatment of HER2-positive tumors other than breast cancer.

Lapatinib for the treatment of breast cancer in the People’s Republic of China

Lapatinib warrants further evaluation in HER2-positive metastatic and early-stage breast cancer patients, as it can cross the blood–brain barrier and may have a role in preventing cancer progression in the central nervous system.

Clinical Experience with Lapatinib in Patients with ErbB2-Overexpressing Metastatic Breast Cancer

Lapatinib may overcome trastuzumab resistance linked to the overexpression of a truncated form of ErbB2 (p95) which can be detected in an estimated 9% of breast cancer cells.
...

References

SHOWING 1-10 OF 110 REFERENCES

Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies.

  • N. SpectorW. Xia S. Bacus
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2005
Preliminary evidence of biologic and clinical activity in ErbB1 and/or Erb B2-overexpressing tumors is exhibited, however, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.

Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib.

Assessment of biologic correlates in patients with metastatic breast cancer indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response; lapatinib currently is being evaluated in phase II and phase III trials.

A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)

The slow off-rate ofGW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells and the differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.

A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen

Patients with metastatic breast cancer that overexpress the ErbB2 protein 2+ or 3+ were enrolled at escalating dose levels of lapatinib in combination with weekly, standard dosing of trastuzumab, and diarrhea, anorexia, fatigue and rash were the common toxicities.

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.

  • H. BurrisH. Hurwitz N. Spector
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2005
Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily and clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

Small molecule tyrosine kinase inhibitors in pancreatic cancer

This review summarizes the present clinical development of tyrosine kinase inhibitors in pancreatic cancer and strategies for future drug development.

Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics.

The current state-of-the-art using agents that target as prototypes Bcr-Abl, platelet-derived growth factor receptor (PDGFR), KIT, KIT (stem cell factor receptor), and epidermal growth factor receptors (EGFR) are reviewed.

Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer

Results of two Phase II trials in metastatic breast cancer (MBC) suggest activity of lapatinib in trastuzumab (T) pretreated patients, and a combined biomarker analysis from these two large studies was evaluated to evaluate correlations between clinical parameters, tissue/serum biomarker expression and response to Lapatinib.

The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.

Data indicate that quinazoline and pyrido-[3,4-d]-pyrimidine small molecules have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.

Clinical activity of GW572016 in EGF10003 in patients with solid tumors.

  • M. VersolaH. Burris N. Spector
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2004
QD administration of GW572016 is well tolerated with evidence of clinical activity in this heavily pre-treated population and serum VEGF levels represent an easily accessible pharmacodynamic endpoint forGW572016 therapy since VEGf is regulated in part by ErbB receptor signaling.
...