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Combined data from four clinical trials, three of which are still ongoing, show no increased cardiac risk in women with metastatic breast cancer being treated with lapatinib plus trastuzumab-containing regimens.
Two of the 393 women with HER2-positive metastatic breast cancer in the trials had symptomatic decreases in left ventricular ejection fraction (LVEF), and one died with heart failure. An additional 10 women had asymptomatic decreases in LVEF, 7 of whom recovered.
"This relatively limited experience would suggest that combined HER2 inhibition with lapatinib and trastuzumab does not increase the risk of cardiac events to any great extent beyond what is expected with trastuzumab alone," said Dr. Anna M. Storniolo, professor of clinical medicine at Indiana University, Indianapolis.
Lapatinib (Tykerb), an oral, small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and HER2/neu, was approved in March for the treatment of HER2-positive metastatic breast cancer in patients whose prior therapy included an anthracycline, a taxane, and trastuzumab (Herceptin). Lapatinib has a synergistic effect with trastuzumab, which may translate into improved anticancer activity.
The analysis, sponsored by lapatinib's manufacturer, GlaxoSmithKline, evaluated whether adding lapatinib to trastuzumab would be cardiotoxic. All women were required to have a normal LVEF at study entry, and the mean LVEF at baseline was 61% (range 47%-88%). Their median age was 51 years (range 22-81 years). They were monitored by multiple gated acquisition scan or echocardiogram at baseline, every 8 weeks while on treatment, and at study conclusion.
The two patients with symptomatic falls in LVEF had received prior anthracycline and trastuzumab. In the first, a 65-year-old woman with no prior cardiac risk factors, ejection fraction dropped from 58% to 25% after 52 weeks with lapatinib alone. Treatment was withheld, and she recovered in 2 weeks.
In the second patient, who received both trastuzumab and lapatinib, the ejection fraction dropped from 69% to 23% at 6 weeks. Treatment was withheld, but she died with symptomatic heart failure at age 60 years.
Asymptomatic drops in LVEF occurred a median of 55 days after beginning lapatinib or lapatinib plus trastuzumab therapy and lasted a median of 9 days. Three women continue to have abnormal ejection fractions.
"The numbers are too small to allow any conclusions about whether or not it is safe to continue treatment despite these drops," she commented.
Dr. Storniolo added that the cardiac monitoring recommended for single-agent HER2 inhibitors appears to be sufficient for lapatinib and trastuzumab administered in combination.
Storniolo A.M. et al. Cardiac safety in patients (pts) with metastatic breast cancer (MBC) treated with lapatinib (L) and trastuzumab (TRA). Abstract 514.
Commentary |
Lapatinib in combination with capecitabine is now approved for advanced HER2-positive breast cancer pretreated with trastuzumab, anthracycline, and paclitaxel. The indication is based on data showing improved progression-free survival, compared with capecitabine alone. Further, treating trastuzumab-naive advanced HER2-positive breast cancer with lapatinib results in single-agent response rates similar to those with trastuzumab. Based on these encouraging results, the recently opened ALTO trial will evaluate the role of lapatinib as adjuvant therapy for women with early-stage, HER2-overexpressing breast cancer. Some 8,000 women will be randomized in this four-armed trial to chemotherapy with 1 year of either trastuzumab, lapatinib, the combination, or the sequence. Similar trials are evaluating lapatinib in the neoadjuvant setting. The lack of cardiotoxicity from treatment with lapatinib alone or in combination with trastuzumab suggests the mechanism of cardiotoxicity may require interaction with the extracellular portion of the HER2 receptor. It will be interesting to see if lapatinib can be a safe alternative to therapy with trastuzumab in advanced disease and perhaps in the adjuvant setting for women with reduced ejection fractions or those at particularly high risk for trastuzumab-induced cardiotoxicity. — Hope S. Rugo, M.D.
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