To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: FDA Approves Xeloda (Capecitabine)/Taxotere (Docetaxel) Combination For Metastatic Breast Cancer URL: http://www.pslgroup.com/dg/205DD6.htm Doctor's Guide September 10, 2001
NUTLEY, NJ -- September 10, 2001 -- Roche announced today that the U.S. Food and Drug Administration (FDA) has approved its oral cancer drug, Xeloda® (capecitabine), in combination with Taxotere® (docetaxel), given by infusion, for the treatment of metastatic breast cancer. The approval pertains to patients whose anthracycline treatment has failed. The combination of Xeloda and Taxotere is the first and only chemotherapy combination to significantly extend survival in these patients compared to Taxotere alone. The median survival was extended by three months over Taxotere alone (median survival 14.5 months versus 11.5 months).
Previous to this combination, Taxotere monotherapy (100 mg/m2 dose on Day One of each 21 day cycle) has been the only regimen to show improved survival over a standard regimen of mitomycin and vinblastine combination. The recent findings indicate that patients treated with the combination Xeloda and Taxotere had a superior survival with a 22.5 percent reduced risk of death (hazard ratio=0.775, p=0.013) compared to those treated with Taxotere alone.
In addition to demonstrating a significant survival advantage, the combination of Xeloda and Taxotere also demonstrated a statistically significant superior tumor response of 32 percent compared to Taxotere monotherapy of 22 percent (p=0.009) in this large Phase III study of 511 patients.Furthermore, time to disease progression is significantly longer for patients treated with Xeloda+Taxotere: median 6.1 months versus 4.2 months with Taxotere alone (p=0.001, Hazard Ratio=0.643).
"Xeloda combined with Taxotere is an important treatment improvement for women with metastatic breast cancer," said Joyce O'Shaughnessy, MD, Co-Director of breast cancer research at Baylor-Sammons Cancer Center and U.S. Oncology. "The clinical data showed significant improvements in survival, tumor response and time-to-disease-progression for the combination compared to Taxotere alone in patients after failure of anthracycline treatment. This represents a major advance in the management of women with metastatic breast cancer as improvements in survival are the bottom line."
"Physicians use a combination of anti-cancer drugs, radiation and surgery to fight breast cancer and extend life," said Carolyn Aldige, President of the Cancer Research Foundation of America. "Xeloda+Taxotere is a critical addition to the arsenal of cancer treatments a physician now has to treat metastatic breast cancer."
The FDA decision was based on the results of a large Phase III study comparing Xeloda in combination with Taxotere to women treated with Taxotere alone. The study looked at survival, time to disease progression and tumor response rate. Women with metastatic breast cancer whose anthracycline treatment has failed were randomized into either combination (oral Xeloda - 1250mg/m2, twice daily, Days One-14 with one week of rest, plus intravenous Taxotere - 75mg/m2, Day One of each 21 day treatment cycle) or monotherapy (intravenous Taxotere 100mg/m2, Day One of each 21-day treatment cycle) groups.
Xeloda+Taxotere combination was significantly better than Taxotere alone in all major outcome measures. Median survival among women treated with Xeloda+Taxotere compared to Taxotere alone was 14.5 months versus 11.5 months, (p=0.013). Median time to disease progression was 6.1 months versus 4.2 months (p=0.001). Tumor response rate was 32 percent versus 22 percent (p=0.009). The Xeloda+Taxotere study was conducted in the United States, Canada, Australia and countries in Europe, Asia and Latin America.
The combination of Xeloda and Taxotere caused more adverse events than Taxotere alone including more diarrhea, stomatitis, hand-foot syndrome and nausea and vomiting. These were manageable with appropriate medical intervention and by dose interruptions.
Dose reductions decreased the overall incidence of adverse events in subsequent cycles. Patients receiving Taxotere alone experienced a higher incidence of neutropenic fever, myalgia and arthralgia.
Xeloda is the first oral drug that is enzymatically converted into the cancer-fighting substance 5-fluorouracil (5-FU). The enzyme thymidine phosphorylase (TP), is higher at the site of the tumor than surrounding normal tissue. This finding has not been adequately studied in the clinical setting. Taxotere, marketed in the U.S. by Aventis Pharmaceuticals, works independently to interrupt tumor cell division (mitosis).
In its decision today, the FDA has also granted full approval for Xeloda NDA. In April 1998, Xeloda received accelerated approval from the FDA for the treatment of patients with metastatic breast cancer resistant to both paclitaxel- and an anthracycline- containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated.
In May 2001, the FDA also approved Xeloda for the treatment of patients with metastatic colorectal cancer, the second leading cause of cancer mortality among Americans. Xeloda is indicated as first-line treatment of patients with metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit has not been demonstrated with Xeloda monotherapy as with the combination chemotherapy. Use of Xeloda instead of 5-FU/LV combination has not been adequately studied to assure safety or preservation of the survival advantage.
Xeloda is contraindicated in patients with severe renal impairment and those with hypersensitivity to 5-fluorouracil. For patients with moderate renal impairment dose reduction is recommended. Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.
A clinically important Xeloda-warfarin drug interaction was demonstrated in a clinical pharmacology trial. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking Xeloda concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Post-marketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time Xeloda was introduced. These events occurred within several days and up to several months after initiating Xeloda therapy and, in a few cases, within one month after stopping Xeloda. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
Xeloda can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Incidence of grade 3 or 4 treatment-related adverse events and serious adverse events are greater in patients greater than or equal to 60 years of age receiving Xeloda in combination with docetaxel.
Xeloda may cause fetal harm if given during pregnancy. Patients taking phenytoin concomitantly with Xeloda should be carefully monitored for plasma phenytoin levels; phenytoin dose may need to be reduced. Grade 3 and Grade 4 adverse events (greater than or equal to 5 percent of patients) are hand-foot syndrome, diarrhea, nausea, vomiting, stomatitis, abdominal pain, fatigue, decreased appetite, dehydration, venous thrombosis and dermatitis.
Taxotere is currently approved in the United States to treat patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy, and patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy.
The most common severe side effects associated with Taxotere include low blood cell count, fluid retention, hypersensitivity, nausea and diarrhea. These side effects are generally reversible and manageable. A pre-medication regimen with corticosteroids is recommended in order to prevent or reduce hypersensitivity and fluid retention. Taxotere is not appropriate therapy for patients with significant liver impairment.
SOURCE: Hoffmann-La Roche Inc.
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