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Tykerb May Offer Benefit When Herceptin Fails

Experimental drug Tykerb (lapatinib) may help women with HER2-positive breast cancer in whom Herceptin (trastuzumab) has failed, according to a new study. Results from the study were presented at the 2006 meeting of the American Society of Clinical Oncology and summarized in an article in The New York Times on June 4.

Herceptin has been touted as a wonder drug for a certain type of breast cancer because it extends life and prevents tumor recurrence in some women. However, Herceptin has been found to be in fact is ineffective for some women, and it stops working entirely after a time in others.

In this study, Tykerb almost doubled the time that the cancer did not progress in women who no were longer taking Herceptin (because it was no longer effective).

Although initial reports said lapatinib (manufactured by GlaxoSmithKline) would be used only as a "backup" for Herceptin, doctors now say the drug may replace Herceptin for some patients.

Lapatinib offers a practical treatment advantage, as it is taken a once-daily pill, whereas Herceptin is administered by infusion.

Clinical Trial

Among the 160 women who received both Tykerb and capecitabine (an approved chemotherapy drug), the average time before tumors began to grow was about 8.5 months - compared with about 4.5 months for the 161 women who received only capecitabine.

Researchers stopped the trial early, when the therapeutic advantage of offering Tykerb made continuing the trial unethical. At this point, all women were offered both drugs.

"Those results are quite impressive and clearly more impressive than any of us would have expected," said Dr Eric Winer, a breast cancer specialist at the Dana-Farber Cancer Institute in Boston, who has been involved in testing Tykerb, according to The New York Times.

Dr Winer predicted at a symposium that death from HER2-positive breast cancer would no longer happen within 10 years. He conceded in an interview that the development of other drugs would be necessary, but he said he was confident this would happen. Dr Winer has consulted for GlaxoSmithKline (GSK), which manufactures Tykerb.

Despite these encouraging trial results and hope for improved future treatment of HER2-positive breast cancer, experts note that Tykerb does not work for all women, and the drug has not yet been demonstrated to prolong life.

Tykerb versus Herceptin

GlaxoSmithKline plans to apply by late 2006 for approval of Tykerb. If the US Food and Drug Administration (FDA) approves Tykerb, it could be on the market in 2007. However, GSK said it would make Tykerb available to appropriate patients before then, according to rules that permit compassionate use of unapproved drugs by patients in great need.

Both Herceptin (manufactured by Genentech; approved in 1998) and Tykerb target tumors that have an excessive amount of the protein HER2. They work by interfering with mechanisms that tumor cells use to grow or survive - in this case, HER2, whose activation ultimately causes cells to grow and proliferate.

HER2 tumors constitute about 20-25% of all breast cancer cases.

By binding to a specific area of HER2, herceptin prevents initial HER2-protein activation, and thus the cascade of events leading to cell growth and proliferation. In contrast, Tykerb exerts its effects inside tumor cells, preventing the chain-reaction from starting.

Because the two drugs exert their effects in different areas of the cell, Tykerb may work even if Herceptin does not, or if Herceptin has stopped working. Some doctors believe that using the drugs together may be beneficial.

"It shows we're in the next generation of targeted drugs," said Dr Roy S Herbst of the M D Anderson Cancer Center in Houston, according to The New York Times. "We're working in patients who have become resistant" to the first generation.

An FDA Advisory Committee recently recommended approval of dasatinib, a drug used for leukemia patients no longer helped by Gleevec, one of the earliest and most successful targeted leukemia drugs.

Dasatinib will be marketed under the brand-name Sprycel by Bristol-Myers Squibb.

Tykerb's Benefits and Adverse Effects

Tykerb may have an advantage over Herceptin, in that it may help prevent tumors from spreading from the breast to the brain - an event that occurs in 25-45% of women on Herceptin, Dr Winer reportedly said. Even if Herceptin keeps a breast tumor in check, brain tumors can lead to neurological problems such as blindness and paralysis - and can be fatal.

The Herceptin molecule is too large to cross the blood-brain barrier, which protects the brain from most things in the bloodstream. However, preliminary evidence suggests that Tykerb can cross the blood-brain barrier and enter the brain.

The clinical trial results showed that, among women with breast cancer receiving Tykerb, cancer was less likely to spread to the brain, compared with women receiving only capecitabine; however, these results did not reach statistically significance.

Results of another recent small study suggested that Tykerb could somewhat reduce the size of shrink brain tumors that had spread from breast tumors.

Tykerb also may have a better cardiac profile: The drug has not been associated with the heart failure found among a percentage of women who receive Herceptin in combination with chemotherapy, according to Dr Charles E Geyer Jr. of Allegheny General Hospital in Pittsburgh, the trials' lead investigator. However, he noted that our of the 160 women who received Tykerb experienced a small decrease in heart function that reversed itself when the drug was stopped.

Dr Winer commented that he thought Tykerb's cardiac safety had not been fully established.

Tykerb may have other applications, too: The drug blocks not only the HER2 protein, but also the epidermal growth factor (EGF) receptor, another protein that advances tumor growth. The EGF receptor is a protein targeted by drugs approved for lung cancer and colon cancer.

Until recently, Herceptin has mainly been used to treat women with advanced-stage breast cancer. However, now the drug is increasingly being given to women in the early stages of the disease, after surgical removal of tumors. Study results indicate that Herceptin may reduce breast cancer recurrence by half, and plans are underway to test Tykerb's ability to prevent recurrence of cancer after surgery.

Source: New Drug Holds Promise for Type of Breast Cancer, The New York Times, June 4, 2006.

Posted: June 2006