SPECIAL REPORT: New Drug Breakthrough for Advanced Breast Cancer
By Mary Batten
Lapatinib, an experimental drug with the brand name Tykerb, promises to become a major treatment option and perhaps a new standard of care for women with HER2/neu-positive breast cancer that becomes resistant to trastuzumab (Herceptin). Results from a phase III international multicenter trial, reported June 3, 2006, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Atlanta, Georgia, showed that women with metastatic breast cancer who were given a combination of lapatinib and capecitabine (brand name Xeloda) went almost twice as long before their cancer progressed as women who took capecitabine only. These results were so impressive that in March 2006, an independent committee monitoring the study unanimously recommended stopping the trial early and offering women in the capecitabine-only group the choice of switching to lapatinib.
"This is one of the most striking differences seen to date in breast cancer oncology. It's a major breakthrough," says oncologist John Link, MD, director of Breastlink Medical Group in Manhattan Beach, California, and founder of the Breastlink.org website.
Dr. Link points out that over time, many women with HER2/neu-positive breast cancer will become resistant to trastuzumab. Until the results of the lapatinib trial were announced, the only other treatment option for these patients was to combine trastuzumab with a taxane, such as paclitaxel. Recent studies showed that trastuzumab could enhance the effectiveness of certain chemotherapy agents.
About 20 percent of breast cancers overexpress, or make too many copies of, the HER2 gene, an abnormal protein. In the late 1980s, Dr. Dennis Slamon, an oncologist and researcher at UCLA, discovered that the abnormal protein located on the cancer cells' surface was a growth factor receptor. (HER stands for human epidermal growth factor receptor.) Cancer cells that make too much HER2 are faster growing and more difficult to treat. The development of the molecular targeted drug trastuzumab in the late 1990s by Dr. Slamon and the genetics research company Genentech revolutionized the treatment of HER2-positive breast cancer. Lapatinib is the most significant development since trastuzumab for this type of cancer. Like trastuzumab, lapatinib targets the HER2/neu protein but it works differently. Trastuzumab blocks the protein on the cell's surface; lapatinib blocks it inside the cell and it also blocks a second abnormal protein known as HER1.
"One of the mechanisms proposed for the resistance to Herceptin is that there's a HER1 receptor and somehow the signal can bypass HER2 and go through the HER1 system to the cell nucleus. Lapatinib blocks both the HER2 and the HER1 message," Dr. Link says.
In the clinical trial reported at ASCO, lapatinib also showed signs of being able to prevent cancer from metastasizing to the brain. Four of the 161 women given lapatinib and capecitabine developed brain metastasis compared to 16 of the 160 women who received capecitabine alone.
"This is an effective treatment that should be considered the new standard of care," said Charles E. Geyer, Jr., MD, Director of Breast Medical Oncology at Allegheny General Hospital in Pittsburgh and the principal investigator of the phase III study. But before it can become the standard of care, it must be approved for use in clinical practice.
Lapatinib is currently an investigational drug that is approved only for use in clinical trials, but the U.S. Food and Drug Administration (FDA) has granted fast track status for commercial production to GlaxoSmithKline, the pharmaceutical company that manufacturers the drug. "Things are going to happen very quickly now," says Dr. Link. He points out that GlaxoSmithKline is initiating a number of protocols to investigate several questions: "One is whether lapatinib in combination with Herceptin is better than Herceptin alone in advanced breast cancer. There's a protocol in place recruiting women with relapse in the central nervous system.
In the not-too-distant future, it might even be possible to talk in terms of curing HER2-positive breast cancer, says Dr. Link. "That may be hyperbole but the result of this trial is so sensational with such advanced disease that we now have two extremely powerful tools to treat women with this kind of disease. Lapatinib in combination with Herceptin may prove to be basically curative. Now that's speculation and it's very optimistic but I don't think it's unrealistic. This is a huge breakthrough."
GlaxoSmithKline has opened an Expanded Access Program (EAP) that allows women all over the world to have access to lapatinib if they qualify. In order to qualify, a woman must have metastatic breast cancer that has progressed on Herceptin after treatment with Adriamycin and taxanes. For more information about this program, call 1-888-4TYKERB (489-5372). Physicians outside the United States should e-mail: breastcancereap@gks.com
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