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Lapatinib (Tyverb)

     Clinical development,  indications and side effects

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Lapatinib (Tyverb) is a biological agent which 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 trastuzumabwhich  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:

  • Oral administration
  • Less heart damage than herceptin
  • More likely to cross blood brain barrier and prevent or treat brain metastasies

Possible side effects

  • Skin rash
  • Hand Foot syndrome
  • small chance of cardiac damage so heart function monitoring is required

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.

Lapatinib versus transtuzumab?

A 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.

This 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.

 Conclusion and comments: This trial indicates that trastuzumab was better at delaying progression than lapatinib in this group of women. In this study, however, only 18% of women had received trastuzumab previously in the adjuvant setting,  as women first started recruiting 6 years ago when this practice was not established across the world. Nowadays the majority of HER+ve will have received trastuzumab. The trial did not published a subgroup analysis of the women who had received prior herceptin probably because the small numbers would not have been statistically valid. It is doubtful whether GlaxoSmithKline would fund another trial to prove better effectiveness in this group so it will remain unknown.  Lapatinib had a lower risk for left ventricular function so still remains the main choice if cardiac function is a concern. Likewise, it has already been established form previous studies that, as it is a smaller molecule it is better at crossing into the brain.

 

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