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SU11248 (sunitinib malate), a novel multitargeted tyrosine kinase inhibitor, showed activity as a single agent in patients with refractory metastatic breast cancer, Kathy Miller, MD, Indiana University Cancer Center, Indianapolis, IN, reported at the 41st Annual Meeting of the American Society of Clinical Oncology.
SU11248 has improved survival in gastrointestinal stromal tumors and has also demonstrated activity in metastatic renal cell carcinoma, Dr. Miller said. In her presentation, she described its benefits in 64 metastatic breast cancer patients refractory to treatment with taxanes and an anthracycline. In 51 patients who received SU11248 50 mg/d for 28 days followed by a 2-week rest period, for 6 cycles, partial responses were seen in 7 (14%) and stable disease was noted for at least 6 months in 1 patient (2%) resulting in an overall clinical benefit rate of 16%.
“Reponses were observed in patients who had fairly extensive pretreatment with chemotherapy and in patients with visceral disease at the time of enrollment,” Dr. Miller noted.
Toxicities were manageable, although about half the patients needed dose reductions. Common nonhematologic toxicities included grade 1–2 diarrhea (56%), mouth pain distinct from mucositis (49%), fatigue (47%), nausea (44%), skin discoloration (27%), headache (26%), and hypertension (17%). Grade 3 hematologic toxicity included neutropenia (39%), anemia (2%), and thrombocytopenia (15%).
“SU11248 has significant single-agent activity in highly refractory patients,” Dr. Miller concluded. “We look forward to moving this agent for use earlier in the course of the disease, with future studies to focus on less heavily pretreated patients. We are also interested in exploring alternative dosing schedules and combination regimens with other agents known to be effective in breast cancer and we will continue to develop methods to identify patients most likely to benefit.”
Study discussant, Andrew Seidman, MD, Memorial Sloan-Kettering Cancer Center, New York, NY, called the results “very encouraging,” especially in light of the level of pretreatment. “Durable responses in excess of 6 months were observed in visceral disease sites and among some patients with disease additionally resistant to capecitabine (Xeloda), vinorelbine, and gemcitabine (Gemzar), making this observation even more remarkable,” he noted.
“The efficacy of this agent, considered together with the ECOG 2100 data [showing survival benefits for bevacizumab (Avastin) added to paclitaxel], offers new possibilities for the strategic management of metastatic breast cancer. Clearly metastatic breast cancer is a book with many chapters—one that is being rewritten at this very ASCO meeting,” Dr. Seidman said.
Miller KD, Burstein HJ, Elias AD, et al. Phase II study of SU11248, a multitargeted receptor tyrosine kinase inhibitor (TKI), in patients (pts) with previously treated metastatic breast cancer (MBC). Paper presented at the 41st Annual Meeting of the American Society of Clinical Oncology; May 13–17, 2005; Orlando, Fla. Abstract 563.
Commentary |
SU11248 (sunitinib malate) is a multi-targeted oral tyrosine kinase inhibitor with broad-based activity against a number of receptors including PDGF, kit, and flt-3, as well as VEGFR. Clear single-agent activity was seen in this study, which included patients with extensive pre-exposure to chemotherapy. The primary toxicity of this agent is hematologic, with both neutropenia and thrombocytopenia complicating possible future combinations with chemotherapy. In addition, side effects include asthenia and temporary skin discoloration. Future studies are investigating lower dosing as well as combinations with chemotherapy, as it is likely that these agents will have their greatest effectiveness in combination. Along with the results of E2100, this study establishes the role of antiangiogenic therapy in the treatment of breast cancer. A number of multitargeted oral tyrosine kinase inhibitors are either in development or in clinical trials, including agents with effects on both the ErbB pathway as well as the VEGF receptors. In the future, we may be able to use a single agent to target multiple pathways. — Hope S. Rugo, MD SU11248 is an oral, multi-targeted, tyrosine kinase inhibitor. It has antitumor and antiangiogenic activities that target receptors are known to play important roles in the growth and survival of breast cancer. Although the data presented by Dr. Miller are promising, they represent only preliminary findings. Studies with larger cohorts are necessary to provide more information on the use of this drug. Bevacizumab (Avastin), a humanized anti-VEGF monocloncal antibody, has shown efficacy in colon cancer and thus may serve the same role in treating breast cancer. A large phase III clinical trial published earlier this year by Dr. Miller compared the efficacy and safety of capecitabine (Xeloda) with or without bevacizumab in women with metastatic breast cancer who had previously undergone chemotherapy. Dr. Miller found no differences in the toxicity profiles, with the exception of significantly greater hypertension occurring in those who received bevacizumab. Although significantly increased response rates were found with the use of bevacizumab, no differences were found in progression-free or overall survival. In contrast, the E2100 trial evaluated paclitaxel with or without bevacizumab as first-line therapy for previously untreated metastatic breast cancer. That study found significantly prolonged progression-free survival and increased objective response rates in patients who received bevacizumab. Further studies will be needed to define the appropriate dosages, combinations, and sequence of drugs to attain the best possible responses. — Catherine Jansen, RN, MS, OCN
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