News Reports from the 2007 Breast Cancer Symposium

By John Zoidis, MD
Published: Wednesday, Jun 30, 2010

The Combination of Sunitinib Plus Paclitaxel Demonstrates Promising Activity in the First-Line Treatment of Advanced Breast Cancer

Preliminary Results from a Phase I Trial

During a poster session, Mark Kozloff, MD, University of Chicago Medical Center, Chicago, IL and Ingalis Hospital, Harvey, IL, presented the results of a Phase I study evaluating the safety and pharmacokinetics of sunitinib (Sutent) combined with paclitaxel (Taxol) for the first-line treatment of advanced breast cancer. Dr. Kozloff was lead investigator of the study.

Sunitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor. It inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs), including plateletderived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs), which play a role in both tumor angiogenesis and tumor-cell proliferation. The simultaneous inhibition of these targets leads to reduced tumor vascularization and cancer cell death. Sunitinib also inhibits KIT—the RTK that drives the majority of gastrointestinal stromal tumors—as well as other RTKs including RET and FLT3. Sunitinib has demonstrated single-agent activity in patients with previously-treated metastatic breast cancer.

Enrollees in the Phase I trial were patients with metastatic or locally recurrent breast cancer. Exclusion criteria included previous cytotoxic therapy for advanced disease and failure of taxane-based adjuvant therapy within 12 months prior to enrollment. Patients received a starting dose of sunitinib of 25 mg/day (continuous dosing schedule; escalation to 37.5 mg/day or reduction to 12.5 mg/day depending on tolerability) plus paclitaxel (1-hour infusion) 90 mg/m2 per week in 4-week cycles (3 weeks on treatment, followed by 1 week off; with reduction to 65 mg/m2 per week as needed).

A total of 20 patients were treated. Median age was 57 years (range, 37 to 74 years). Of these, 17 patients had measurable disease and 7 were chemotherapy-naive. Disease sites included bone (55%), liver (40%), lung (30%), lymph node (55%), and local (40%). A median of 6 cycles were delivered; 9 patients continue on treatment. Eight patients discontinued due to disease progression, 2 due to non–treatment related illness, and 1 due to resection of remaining lesion.

Grade 3 adverse events included fatigue (29%), diarrhea (14%), hand–foot syndrome (10%), and neuropathy (10%). Neutropenia was the primary hematologic toxicity. Granulocyte colony-stimulating factor was given if the neutrophil count fell below 1500/μL, to support delivery of full-dose paclitaxel. Neutrophil nadirs were sharp, with rapid rebound despite continuous sunitinib dosing. Preliminary results indicated no pharmacokinetic interaction between paclitaxel and sunitinib. As of this analysis, there were 5 confirmed objective responses (3 partial and 2 complete) according to Response Evaluation Criteria in Solid Tumors, and 3 patients had stable disease for 6 months or more.

Dr. Kozloff concluded that sunitinib plus paclitaxel was generally well tolerated and showed promising activity in the first-line treatment of advanced breast cancer. He said that a Phase III trial comparing this combination with paclitaxel plus bevacizumab is underway.

The Combination of Capecitabine and Trastuzumab Appears to Be Effective and Safein Heavily Pre-Treated Patients With Metastatic Breast Cancer

Further Study Is Warranted

Dr. Rupert Bartsch, First Department of Medicine and Cancer Centre, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria, presented the results of a preliminary trial that evaluated the efficacy and tolerability of capecitabine (Xeloda) plus trastuzumab (Herceptin) after anthracycline and docetaxel or vinorelbine failure and prior trastuzumab exposure.

In HER2-positive metastatic breast cancer, taxanes or vinorelbine plus trastuzumab are among the most widely applied options in the first-line setting. Capecitabine, a nucleoside analog, is the only FDAapproved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer. Although inactive in pill form, capecitabine is enzymatically activated within the body. When it comes into contact with thymidine phosphorylase, a naturally occurring protein, capecitabine is transformed into 5-fluorouracil, a cytotoxic drug.

Forty patients were enrolled in the trial. All had prior exposure to an anthracycline, at least one antimicrotuble agent (ie, a taxane or vinorelbine), and one earlier trastuzumabcontaining treatment regimen for metastatic disease. Capecitabine was administered at a daily dose of 2500 mg for 2 consecutive weeks every 3 weeks, with dose modifications if necessary. Trastuzumab was administered in 3 weekly cycles. The primary endpoint was time to progression (TTP). Response was evaluated every three months using Union International Contre Cancer (UICC) criteria. Overall survival (OS) was assessed secondarily.

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