The Food and Drug Administration (FDA) has approved Tykerb (lapatinib), a new targeted anti-cancer treatment, to be used in combination with capectabine (Xeloda), another cancer drug, for patients with advanced, metastatic breast cancer that is HER2 positive (tumors that exhibit HER2 protein).
The combination treatment is indicated for women who have received prior therapy with other cancer drugs, including an anthracycline, a taxane, and trastuzumab (Herceptin). According to the American Cancer Society, about 180,000 new cases of breast cancer are diagnosed each year. Approximately 8,000 to 10,000 women die from metastatic HER2 positive breast cancer each year.
Tykerb, a new molecular entity (NME), is a kinase inhibitor working through multiple pathways (targets) to deprive tumor cells of signals needed to grow. Unlike, for example, trastuzumab - 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 trastuzumab and are no longer benefiting.
"This approval is a step forward in making new treatments available for patients who have progression of their breast cancer after treatment with some of the most effective breast cancer therapies available," said Steven Galson, MD, M.P.H., Director of FDA's Center for Drug Evaluation and Research. "New targeted therapies such as Tykerb are helping expand options for patients."
The approval of Tykerb was based on a randomized clinical trial in about 400 women with advanced or metastatic breast cancer that was also HER2 positive. In the trial, half the patients received Tykerb with capecitabine and half received capecitabine alone. Compared to patients receiving capecitabine alone, the group of patients receiving Tykerb with capecitabine had a statistically significant improvement in the time to tumor progression. In addition, the tumor response rate was higher in the group of patients receiving Tykerb with capecitabine (24 percent vs. 14 percent). The survival data are not yet mature.
The most commonly reported Tykerb-related side effects included diarrhea, nausea, vomiting, rash and hand-foot syndrome which may include numbness, tingling, redness, swelling and discomfort of hands and feet. Generally reversible decreases in heart function (that can lead to shortness of breath) have also been reported in a small percentage of patients. Patients should talk to their doctor about potential side effects, potential drug interactions, and other medical conditions including heart and liver problems. Tykerb is available in tablets of 250 mg. An undivided dose of 1,250 mg should be taken orally once daily for 21 days and in combination with capecitabine on days 1-14 of a 21 day cycle.
Tykerb will be distributed by GlaxoSmithKline, of Research Triangle Park, North Carolina.
The efficacy and safety of lapatinib ditosylate in combination with capecitabine in breast cancer were evaluated in a randomized trial
Patients eligible for enrollment had HER2 (ErbB2) over-expressing tumors (95 percent were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation), had locally advanced or metastatic breast cancer, and had disease progression after treatment that included taxanes, anthracyclines, and trastuzumab.
Patients were randomized to receive either lapatinib ditosylate 1,250 mg once daily on days 1-21 plus capecitabine 2,000 mg/m2/day on days 1-14 every 21 days, or to receive capecitabine alone at 2,500 mg/m2/day on days 1-14 every 21 days.
The primary endpoint of time-to-progression (TTP) was defined as time from randomization to tumor progression or death related to breast cancer. After the results of a pre-specified interim analysis of 324 patients were made available, further enrollment was discontinued after enrolling 399 patients of a planned 528 patients.
An updated efficacy analysis (399 patients) occurring four months after the interim analysis includes both independent and investigator assessments. The median TTP based on the independent review assessment was 27.1 vs. 18.6 weeks (HR 0.57, p=0.00013) for the lapatinib ditosylate combination and capecitabine-alone arms, respectively. The median TTP based on the investigator assessment was 23.9 vs. 18.3 weeks (HR 0.72, p=0.00762) for the lapatinib ditosylate combination and capecitabine alone arms, respectively. The response rates were 23.7 percent vs. 13.9 percent (independent assessment) and 31.8 percent vs. 17.4 percent (investigator assessment) for the lapatinib ditosylate combination and the capecitabine-alone arms, respectively. At the time of this update, survival data was not mature.
Although the toxicities observed in the lapatinib ditosylate combination arm were similar to those in the capecitabine-alone arm, an increased incidence of diarrhea and rash was noted with the combination. The most frequent adverse reactions during treatment with combination were diarrhea (65 percent), palmar-plantar erythrodysesthesia (PPE, 53 percent), nausea (44 percent), rash (28 percent), vomiting (26 percent), and fatigue (23 percent).
Grade 3 or 4 adverse events that occurred with a frequency greater than 5 percent in patients on the combination arm were diarrhea (13 percent) and PPE (12 percent). A 2 percent incidence of generally reversible decreased left ventricular function in the combination arm was noted. QT prolongation has been observed with lapatinib ditosylate use. Torsade de Pointes has not been reported.
The recommended dose of lapatinib ditosylate is 1,250 mg (five tablets) administered orally once daily for 21 days in combination with capecitabine 2,000 mg/m2/day (administered orally in two doses approximately 12 hours apart) on days 1-14 in a 21-day cycle. Lapatinib ditosylate should be taken at least one hour before or one hour after meals. Capecitabine should be taken with food or within 30 minutes after food. Lapatinib ditosylate should be taken once daily; dividing the daily dose is not recommended. Treatment should be continued until disease progression or unacceptable toxicity occurs.