Lapatinib

Structural formula
General
Non-proprietary name	Lapatinib
other names	N - [3-chloro-4- (3-fluorobenzyloxy) phenyl] -6- {5- [4- (methylsulfonyl) -2-azabutyl] -2-furyl} quinazolin-4-amine ( IUPAC ) ; Lapatinibum ( Latin );
Molecular formula	C 29 H 26 ClFN 4 O 4 S
External identifiers / databases
PubChem	208908
ChemSpider	181006
DrugBank	DB01259
Wikidata	Q420323
Drug information
ATC code	L01 XE07
Drug class	Cytostatic
Mechanism of action	Tyrosine kinase - inhibitor
properties
Molar mass	581.06 g · mol -1
Melting point	144-146 ° C
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 319-362-413
	P: 201-260-263-264-270-273-280-305 + 351 + 338-308 + 313
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Lapatinib is a dual tyrosine kinase - inhibitor , which as a drug for the treatment of malignant tumors is used.

Lapatinib was developed by GlaxoSmithKline and is marketed under the trade name Tykerb ^® (USA) and Tyverb ^® (Europe). It is suitable for the treatment of patients with HER2 / neu positive breast cancer ( breast cancer ) if the cancer cells increasingly develop (express) the receptors Erb1 ( EGFR ) and Erb2 (HER2 / neu) on their surface, which is about 25% of breast cancer patients Case is.

Mechanism of action

The small molecule penetrates the cancer cell and blocks the tyrosine kinase domain of the EGFR and HER2 receptors. Growth factors can then still attach to the binding sites of the receptors on the surface of the cell, but the signals that trigger the cell division process are no longer transmitted.

Because of its small molecule size , unlike other breast cancer drugs, lapatinib can cross the blood-brain barrier and could therefore also be effective in patients with brain metastases - so far, however, its effectiveness has not been proven beyond doubt.

Current study situation

Initial clinical studies have shown efficacy on tumors, especially in advanced and metastatic breast cancer. The response rate was 35%. In the study on which the approval is based, therapy with lapatinib significantly increased the time it took for the disease to progress. Lapatinib is currently being further investigated in several clinical studies, for example for neoadjuvant and adjuvant therapy and for use in inflammatory breast cancer .

Comparative data from clinical trials have shown that combination therapies containing lapatinib are less effective than those containing trastuzumab (Herceptin ^® ) in certain treatment situations .

application

In Switzerland, lapatinib has been approved since May 2007 for the combination treatment with capecitabine in patients with advanced or metastatic breast cancer with overexpression of HER2 with relapse after or non-response to trastuzumab . Since 2008, lapatinib has been approved in the EU for the combination treatment with capecitabine in patients with advanced or metastatic HER2-positive breast cancer who have already been pretreated with anthracyclines , taxanes and, in the metastatic situation, with trastuzumab. The approval was expanded in 2010: since then, lapatinib has also been approved in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor-positive and HER2-positive metastatic breast cancer (see current studies).

One advantage is that the drug can be taken in tablet form. One infusion therapy like trastuzumab is not required.

Unwanted side effects

So far, side effects have been skin rash, nausea and diarrhea; serious side effects have not been observed. The cardiac tolerance was good. However, the safety data verified by the manufacturer showed that hepatotoxic reactions can occur during therapy with lapatinib . Primarily there were increased levels of transaminases , rarely the hepatotoxicity was severe or even lethal . GlaxoSmithKline informed doctors about the side effect by red hand letter dated March 27, 2008, and the specialist information was adapted accordingly. Particular attention is drawn to regular liver function tests ( bilirubin , transaminases, alkaline phosphatase ).

Web links

Studies on lapatinib
Public Assessment Report (EPAR) of the European Medicines Agency (EMA) on: Tyverb

Individual evidence

↑ ^a ^b ^c Entry on lapatinib at Toronto Research Chemicals , accessed December 1, 2018 ( PDF ).
↑ HER2-positive breast cancer: "small molecule" lapatinib also helps with brain metastases. Dtsch Arztebl 2007; 104 (30): A-2146 / B-1900 / C-1836.
↑ Burris, HA (2004): Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR / ErbB-2 inhibitor lapatinib. In: Oncologist . Vol. 9, pp. 10-15, PMID 15163842 .
↑ Nelson, MH & Dolder, CR (2006): Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. In: Ann Pharmacother . Vol. 40, pp. 261-269, PMID 16418322 .
↑ Cameron D et al .: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyzes . In: Breast Cancer Res Treat . 2008 Dec; 112 (3): 533-543, PMID 18188694 .
↑ Important information for specialists on Tyverb ^® (Lapatinib) (PDF; 803 kB), notification from GSK dated December 10, 2012.
↑ Tyverb Lapatinib and hepatotoxic reactions (primarily an increase in transaminases) ( Memento from April 7, 2013 in the web archive archive.today ), Rote-Hand-Brief from GlaxoSmithKline from March 27, 2008.

[TRC-1] Entry on lapatinib at Toronto Research Chemicals , accessed December 1, 2018 ( PDF ).

[2] HER2-positive breast cancer: "small molecule" lapatinib also helps with brain metastases. Dtsch Arztebl 2007; 104 (30): A-2146 / B-1900 / C-1836.

[3] Burris, HA (2004): Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR / ErbB-2 inhibitor lapatinib. In: Oncologist . Vol. 9, pp. 10-15, PMID 15163842 .

[4] Nelson, MH & Dolder, CR (2006): Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. In: Ann Pharmacother . Vol. 40, pp. 261-269, PMID 16418322 .

[5] Cameron D et al .: A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyzes . In: Breast Cancer Res Treat . 2008 Dec; 112 (3): 533-543, PMID 18188694 .

[6] Important information for specialists on Tyverb ^® (Lapatinib) (PDF; 803 kB), notification from GSK dated December 10, 2012.

[7] Tyverb Lapatinib and hepatotoxic reactions (primarily an increase in transaminases) ( Memento from April 7, 2013 in the web archive archive.today ), Rote-Hand-Brief from GlaxoSmithKline from March 27, 2008.