by Katrina Kahl
Adding lapatinib (trade name Tykerb) to the chemotherapy drug capecitabine (Xeloda) delays disease progression in women with HER2-positive advanced or metastastic breast cancer, according to a study published in the December 2006 issue of the New England Journal of Medicine.1 The study did not show any difference in survival from the addition of Tykerb. The time to progression of disease increased from 4.4 months with Xeloda alone to 8.4 months with a combination of Tykerb and Xeloda. However, in both groups, 22 percent of the women had died by the end of the study.
The study enrolled 324 women with HER2-positive locally advanced or metastic breast cancer that had progressed after treatment with chemotherapy and trastuzumab (Herceptin). To be eligible for the study, women must have been previously treated with Herceptin (alone or in combination with chemotherapy), as well as an anthracycline and a taxane as adjuvant therapy or for metastatic disease. Additionally, only women with normal cardiac function were enrolled in the study. Eligible women were randomized to receive Xeloda alone (control group) or a combination of Xeloda and Tykerb (combination group). At the end of the study, the combination group had 49 women with disease progression and 36 deaths, compared to 72 women with disease progression and 35 deaths in the control group. Time to progression of disease is often used as a surrogate marker for survival but, as exemplified in this study, delaying progression does not always result in a survival benefit.
The trial was stopped early because of the delay in disease progression seen in the Tykerb group. Because the trial was stopped early, long-term side effect data is not available for Tykerb. Additionally, at the time the trial was stopped, women in the control group were offered Tykerb. The crossing over of women from the control group to the combination group means that long-term safety and survival data will be difficult, if not impossible, to measure.
The researchers also report that the addition of Tykerb did not result in an increase in serious toxic effects, including cardiac toxicity, which is associated with the use of Herceptin. However, the researchers noted a bias in the study design, because only women with normal cardiac function after treatment with chemotherapy and Herceptin were allowed to enroll in the study. Therefore, the study may have excluded women who would have been prone to cardiac problems as a result of treatment with Tykerb. Again, because the trial was ended early, the possibility of adverse cardiac events happening in the long term cannot be ruled out.
The initial results of this study were presented at the June 2006 American Society of Clinical Oncology (ASCO) conference. As compared to Herceptin, Tykerb was touted as having less cardiac toxicity, the potential to affect central nervous system metastases (which includes the brain), and an easier, once-a-day pill format. To read more about the results from ASCO, see “Lapatinib News From ASCO” in BCA Newsletter #91, June/July 2006.
The study was funded and conducted by the makers of Tykerb, GlaxoSmithKline. In the United States, the European Union, Switzerland, Australia, Canada, and New Zealand, Tykerb is currently awaiting approval for women with advanced or metastatic HER2-positive breast cancer that has progressed despite chemotherapy and Herceptin. Another study, the Tykerb Evaluation After Chemotherapy (TEACH), is underway, evaluating Tykerb in the treatment of earlier breast cancer. At present, Tykerb is not approved for use in the treatment of breast cancer and, therefore, is not available to the public.
1 Charles E. Geyer, et al., “Lapatinib Plus Capecitabine for HER2-positive Advanced Breast Cancer,” The New England Journal of Medicine 355(26), December 2006, pp. 2733-2743.