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Capecitabine Plus Bevacizumab Combination May Produce Clinical Benefit in Patients With Advanced Breast Cancer

Interim Phase 2 XCALIBr Study Results Shows Combination is Well Tolerated

SAN ANTONIO, TX -- December 20, 2006 -- An interim analysis of the XCALIBr (Xeloda in Combination with Avastin as First-Line Treatment for HER2-Negative Metastatic Breast Cancer) trial suggested that first-line therapy with oral Xeloda(R) (capecitabine) in combination with Avastin(R) (bevacizumab) may offer clinical benefit in metastatic breast cancer patients who have no prior history of treatment. These data were presented at the 29^th Annual San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas.
At the time of study analysis, 72% of enrolled patients experienced a clinical benefit (a measure of response rate and stable disease) with Xeloda plus Avastin. The combination regimen was well tolerated by patients, with the majority of adverse events being mild or moderate.

"We are very encouraged by these data which suggest that oral Xeloda in combination with Avastin may provide clinical benefit for women with advanced breast cancer," said clinical trial investigator William J. Gradishar, MD, Associate Professor of Medicine in the Division of Hematology and Medical Oncology at Northwestern University Medical School. "Although the medical community has made great strides in the treatment of early-stage breast cancer, there is still an urgent need for novel treatment strategies to improve outcomes in advanced disease, which currently has a five-year survival rate of only 20 percent."

Breast cancer is the most common cancer among women, other than skin cancer. It is the second leading cause of cancer death in women, after lung cancer. According to the American Cancer Society, about 212,920 women in the United States will be found to have invasive breast cancer in 2006 and about 40,970 women will die from the disease this year. Currently, there are an estimated 2 million women living in the United States who have been treated for breast cancer.

"These promising interim Phase II results in advanced breast cancer patients underscore the potential of combinations using cornerstone anti- cancer therapies such as Xeloda," said Lars Birgerson, MD, PhD, Vice President, Medical Affairs, Roche. "Roche is committed to supporting ongoing clinical trial programs that explore the potential of Xeloda in combination with targeted and anti-angiogenic therapies."

Mature data from the XCALIBr trial will be presented at a future major medical meeting.

About the Study
The primary objective of the multi-center, single arm, Phase II trial was to evaluate progression-free survival in chemotherapy-naive metastatic breast cancer patients receiving first-line Xeloda/Avastin combination therapy. The first phase of the study was designed to evaluate efficacy and tolerability. Study participants were limited to female outpatients diagnosed with HER2- negative metastatic breast cancer or locally recurrent breast cancer who are age 18 and older and are not pregnant.

In the study, patients received first-line therapy with Xeloda 1000 mg/m2 twice a day for 14 days with seven days off in combination with Avastin 15mg/kg IV in three-week cycles until first progression or intolerance to treatment. Once progression was documented, patients were treated with second-line therapy of Avastin 10mg/kg IV every two weeks in combination with either weekly paclitaxel 80 mg/m2 or vinorelbine 25 mg/m2 on four-week cycles. Clinical investigators chose whether the patient received paclitaxel or vinorelbine.

In an interim study analysis of 103 patients from a total of 109 patients enrolled, 44 patients (42.7%) remained progression free on first-line therapy with Xeloda plus Avastin and 21 patients (20%) had progressed to second-line therapy after a median duration of 4.2 months of treatment. Forty-three patients were off protocol for reasons not related to adverse reactions.

Treatment with Xeloda plus Avastin produced a 72% clinical benefit, a measure of response rate and stable disease. Specifically, the combination regimen resulted in a 5% complete response and a 29% partial response for an overall response rate of 34% (95% CI: 24.9-44); 38% of patients had stable (non-progressed) disease following combination treatment.

The analysis demonstrated that treatment with Xeloda plus Avastin was well tolerated in most patients. The most common grade 3 adverse events were hand- foot syndrome (13%), a skin condition that is commonly seen with fluoropyrimidine agents, and pain (10%). The only grade 4 toxicity reported was pulmonary embolism (2%). In those patients who have died (18%), the cause of death was breast cancer or other causes unrelated to study medication.

About Xeloda
Xeloda is the only FDA-approved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer. Inactive in pill form, Xeloda is enzymatically activated within the body; when it comes into contact with a naturally occurring protein called thymidine phosphorylase, or TP, Xeloda is transformed into 5-FU, a cytotoxic (cell-killing) drug. Because many cancers have higher levels of TP than does normal tissue, more 5-FU is delivered to the tumor than to other tissue.

A clinically important drug interaction between Xeloda and warfarin has been demonstrated; altered coagulation parameters and/or bleeding and death have been reported. Clinically significant increases in prothrombin time (PT) and INR have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda. For patients receiving both drugs concomitantly, frequent monitoring of INR or PT is recommended. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Xeloda is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil, and in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. Xeloda is contraindicated in patients with severe renal impairment. For patients with moderate renal impairment, dose reduction is required.

The most common adverse events (greater than or equal to 20%) of Xeloda monotherapy were diarrhea, nausea, stomatitis and hand-foot syndrome. As with any cancer therapy, there is a risk of side effects, and these are usually manageable and reversible with dose modification or interruption.


SOURCE: Roche

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