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Study Shows 14-Month Survival, Some Heart AEs for Breast Cancer Patients on Tykerb/Herceptin Combo

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By Turna Ray

GlaxoSmithKline announced results
from a study last week showing that breast cancer patients on a combination regimen containing Tykerb and Herceptin experienced 14 months median survival. However, a few patients on the investigational combination treatment experienced serious cardiac events and one died as a result of pulmonary thromboembolism.

The Phase III study, presented last week at the San Antonio Breast Cancer Symposium, involved 296 women with HER2-positive breast cancer whose cancer had recurred despite receiving a median of three previous Herceptin-based treatments. "The data presented at the San Antonio congress showed that patients overcame resistance to [Herceptin] with the introduction of the [Tykerb/Herceptin] combination," GSK said in a statement.

Researchers from GSK and other research institutions randomized the 296 women to receive either Tykerb or Tykerb in combination with Herceptin. If patients' disease progressed after four weeks, they were crossed over to the combination arm.

This study represents updated analysis of study EGF104900, which suggested that progression-free survival in patients treated with the Tykerb/Herceptin combination treatment was longer than those treated with Tykerb alone.

Of the women randomized to receive just Tykerb, 52 percent crossed over to the combination arm. "At data cut-off for updated overall survival, 218 deaths had occurred," the researchers reported. "Median overall survival following treatment with [Tykerb] plus [Herceptin] was 60.7 weeks compared with 41.4 weeks for [Tykerb] alone." Researchers also noted a trend toward a clinically relevant 25 percent reduction in the risk of death after adjusting for patients who crossed over.

"A statistically significant overall survival benefit was observed in women with heavily pretreated, HER2-positive metastatic breast cancer treated with [Tykerb] in combination with [Herceptin] compared with those treated with [Tykerb] alone," the researchers concluding, adding that the high frequency of crossover in the study may underestimate the survival benefit of the combination treatment.

"It's possible that, by [Tykerb] working inside the cell and [Herceptin] working outside the cell, the combination of agents is able to provide a more complete anti-tumor attack," said primary study investigator Kimberly Blackwell of Duke University Medical Center, in a statement announcing the study results. "To achieve a survival advantage of greater than one year for this aggressive form of breast cancer is very encouraging."

In explaining the survival advantage seen in the combination arm, Blackwell theorized that "the agents [Tykerb and Herceptin] may be acting together to form a sort of 'dual blockade' to obstruct the HER2 pathway necessary for the tumor to thrive."

When the US Food and Drug Administration initially approved Tykerb in 2007, the agency explained the different mechanisms of action for Tykerb and Herceptin. "Unlike, for example, [Herceptin] — a monoclonal antibody, which is a large protein molecule that targets the part of the HER2 protein on the outside of the cell — Tykerb is a small molecule that enters the cell and blocks the function of this and other proteins. Because of this difference in mechanism of action, Tykerb works in some HER2-positive breast cancers that have been treated with [Herceptin] and are no longer benefiting," the agency explained at the time.

Currently, Tykerb is approved in combination with Xeloda for the treatment of advanced or metastatic HER2-positive breast cancer patients who have received prior therapy including an anthracycline, a taxane, and Herceptin. Genentech markets Herceptin, which is administered to breast cancer patients after it is confirmed by immunohistochemistry or fluorescent in situ hybridization tests that they overexpress the HER2 gene.

GSK did not respond to questions about whether the company plans to pursue a new indication for Tykerb in combination with Herceptin.

Despite the promising efficacy of the Tykerb/Herceptin combination, there was also an increased risk of cardiac events seen in some patients receiving the dual HER2 inhibitor.

Among the Grade 3/4 adverse events observed in the trial, cardiac events were reported in three patients on the combination arm and in one patient on the monotherapy arm. One patient in the combination arm "experienced cardiac failure and later died due to pulmonary thromboembolism that was caused by disease progression and/or study medication," GSK said in a statement.

In studies, Herceptin alone or in combination with chemotherapy has been shown to cause serious heart problems, such as ventricular dysfunction and congestive heart failure, in a small number of women.

Tykerb has been reported to decrease left ventricular ejection fraction, and the drug's label cautions patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure, to not take the drug. "Confirm normal LVEF before starting Tykerb, and continue evaluations during treatment," the label advises.

Overall, the incidence of adverse events were similar among both treatment groups with the exception of the incidence of grade 1 and 2 diarrhea, which was "significantly higher" in the combination arm. The incidence of grade 3 or higher adverse events was similar among treatment groups. The most common adverse events observed in the study were diarrhea, nausea, rash, fatigue, and vomiting.

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