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Sunitinib has substantial antitumor activity in metastatic renal cell carcinoma patients who failed bevacizumab therapy, according to results of a phase II trial.
"We tested the idea of using this multi-tyrosine kinase inhibitor in the setting of patients that had already been exposed to the VEGF-neutralizing antibody bevacizumab [Avastin]," said the lead author, Dr. Daniel J. George. "The results that we see clinically suggest that about one-fourth of patients are getting significant tumor reduction, and data suggest there's also a delay in disease progression, so we think there's a rationale for using these agents in sequence."
Sunitinib (Sutent) is approved for use in patients with advanced kidney cancer and with gastrointestinal stromal tumors that have stopped responding to imatinib (Gleevec).
The single-arm multicenter trial enrolled 61 people with bevacizumab-refractory metastatic renal cell carcinoma. The members of the cohort, with a median age of 59, were treated with daily oral sunitinib 50 mg in 6-week cycles (4 weeks on and 2 weeks off).
One-fourth of the patients had had radiation therapy, one-third had prior bevacizumab monotherapy, and half had prior cytokine-based therapy. Only seven patients had achieved partial responses with bevacizumab-based therapy, said Dr. George, director of genitourinary medical oncology at Duke University, Durham, N.C.
After 12 weeks on sunitinib, 14 patients had partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The median duration of response was 36 weeks. Also, 36 patients had stable disease and tumors got smaller in 32. Five patients had continued disease progression and another six were indeterminate or missing.
The mean plasma levels of vascular endothelial growth factor (VEGF) declined in the first cycle. Relative to baseline, plasma levels of sVEGF-3 and VEGF-C decreased by 38% and 23%, respectively, Dr. George said, suggesting that these two biomarkers might predict response to sunitinib.
"Our biomarker data are more hypothesis generating as to who is really benefiting and who is progressing, and whether there are any insights into the biology," Dr. George said. "However, it's entirely possible that differences in biomarker levels, such as VEGF-C, will help to identify a subset of patients with a higher likelihood of responding or of progressing during therapy."
If a patient has a low VEGF-C level, using a monotherapy such as sunitinib makes sense, whereas a high level might indicate the need for a drug-combination approach or continuous dosing with sunitinib, he said, emphasizing the hypothetical nature of his comments. "There are a lot of ways tyrosine kinase inhibitors can be given, and with this ... patient population perhaps we ought to be thinking differently in terms of treatment when VEGF levels are high."
George D.J. et al. Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers. Abstract 5035.
Commentary |
Kidney cancers are highly vascular tumors and work done predominantly at the National Cancer Institute has identified overexpression of vascular endothelial growth factor (VEGF) as a key molecular step in the development of kidney cancer. Accordingly, most new treatments have focused on blocking VEGF activity. One of the most promising agents is the tyrosine kinase inhibitor sunitinib, recently approved for patients with advanced kidney cancer. Bevacizumab, the VEGF-neutralizing antibody, is another promising agent. Since sunitinib's approval, however, questions have arisen regarding timing of these agents and whether one will work after others fail. This recent study from George et al. at Duke University and the Duke Prostate Center suggests that sunitinib has activity even in patients who failed bevacizumab. The authors enrolled 61 people with bevacizumab-refractory metastatic renal cell carcinoma in a single-arm multicenter phase II study. After 12 weeks on sunitinib, 14 patients (23%) had a partial response with a median duration of response of 9 months. These responses, in patients with bevacizumab-recurrent tumors, were only slightly inferior to the 31% objective response rate and median duration of response of 11 months reported for sunitinib as primary therapy (N. Engl. J. Med. 2007;356:115-24). These exciting results will continue to solidify the role of sunitinib, not only in first-line therapy, but also in salvage therapy for advanced kidney cancer. Future studies need to address best treatments for those failing sunitinib and whether combination treatments improve outcomes relative to sunitinib alone. — Stephen J. Freedland, M.D., and Judd W. Moul, M.D.
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