Lapatinib (Tyverb) is a biological agentwhich targets the Epidermal Growth Factor Receptor-2 called HER2 which is over expressed (HER2+ve) in about 20% of breast cancers. Blocking HER over expression has been shown to encourage cancer cells to be less aggressive and improved outcomes within their previous trials. Lapatinib is a small molecule called a tyrinase kinase inhibitor which is absorbed into the cell and binds to the segment of the HER receptor inside the cell as opposed to trastuzumab which is a monoclonal antibody which attaches to the segment of the HER2 receptor which lies on the outside of the cell.
The landmark study
A total of 392 patients with advanced, HER2-positive breast cancer were enrolled in this international phase III clinical trial. All of the patients had disease that had begun to progress after treatment with trastuzumab. Patients were randomly assigned to receive either the drug capecitabine alone or capecitabine in combination with lapatinib. Capecitabine is approved by the U.S. Food and Drug Administration to treat breast cancer that has continued to grow despite previous therapy.The study’s results were so compelling that in March 2006 an independent committee monitoring the trial decided to end the trial early and offer patients in the capecitabine-only group the choice of switching to the lapatinib regimen.
At the time the trial was stopped, data were available for 321 of the 392 patients. In patients treated with lapatinib plus capecitabine (161 patients), the median time to disease progression was 8.5 months, compared with 4.5 months for those treated with capecitabine alone (160 patients), a statistically significant finding. Fewer patients receiving lapatinib had disease recurrence in the brain. Women treated with lapatinib were somewhat more likely to experience mild to moderate diarrhea and hand-foot syndrome, a condition characterized by tenderness and sensitivity in the hands and feet. Other side effects were similar in the two groups.
All patients in the lapatinib study were closely monitored for the development of heart abnormalities. Four of the 161 patients in the lapatinib group developed minor heart problems that reversed when treatment was stopped. No patients withdrew from the study because of heart problems.
(Note: final results from the trial were subsequently published in 2006, New England Journal of Medicine; see the journal abstract.)
Advantages of lapatinib:
Possible side effects
More recently some trials have questioned whether Lapatinib is not as effective as Herceptin as first line therapy (see below) so the current recommendation in the UK is that it is given with capecitabine after Herceptin progression or relapse.
study called the NCIC CTG MA.31/ GSK EGF 108919RCT was a real battle of the pharmaceutical titans. It aimed to unearth which
of the blockbuster biological agents Herceptin (Trastuzumab) or Tyverb (lapatinib)
was better when combined with a taxane based chemotherapy agent in women
presenting with metastatic disease. Both these biological agents target the
Epidermal Growth Factor Receptor-2 called HER2 which is over expressed (HER2+ve)
in about 20% of breast cancers. Both agents block HER over expression and have
shown to encourage cancer cells to be less aggressive and improved outcomes
within their own previous trials. They exert their therapeutic effect in
different ways. Trastuzumab is a monoclonal antibody which attaches to the
segment of the HER2 receptor which lies on the outside of the cell whilst trade
name lapatinib is a smaller molecule called a tyrinase kinase inhibitor which is
absorbed into the cell and binds to the segment of the HER receptor inside the
cell. A head to head comparison of these agents had hitherto not been performed
in this group of women.
study involved 652 women presenting for the first time with metastatic breast
cancer whose cancers had over expressed HER 2. They all received taxane based
chemotherapy (either taxotere or paclitaxel at three weekly intervals for 24
weeks but were randomised to receive either lapatinib or trastuzumab until
disease progression. The result
showed that although there was no difference in overall survival there was a
significant difference in time to progression indicating a superiority for
trastuzumab. Rash and diarrhoea was worse for lapatinib and reduction in cardiac
function for trastuzumab.
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