Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers

Abstract

5035 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity. This study evaluated the safety and activity of sunitinib in mRCC patients (pts) previously treated with the VEGF-neutralizing antibody, bevacizumab. Levels of angiogenic biomarkers, including plasma VEGF and soluble VEGFR-3 (sVEGFR-3), were assessed for predictive significance with clinical response. Methods: Pts were required to have mRCC with disease progression following bevacizumab- based therapy, measurable disease, ECOG performance status 0 or 1, and adequate organ function. Pts were treated with sunitinib 50 mg daily in 6-week cycles (4 weeks on, followed by 2 weeks off). The primary endpoint was objective response according to RECIST. Plasma VEGF and sVEGFR-3 levels were measured in pre-treatment samples and at multiple timepoints on study. Results: A total of 61 pts were enrolled. The objective partial response rate was 23% (95% CI: 13%, 36%); 35 pts (57%) demonstrated stable disease. The median duration of response was 36 weeks (95% CI: 26, NA) and progression-free survival was 30 weeks (95% CI: 18, 34). Plasma VEGF levels increased from baseline (3-fold mean elevation), while plasma sVEGFR-3 levels decreased from baseline (40% mean reduction). Pre-treatment VEGF levels were significantly higher in pts (n=34) with <10 weeks between cessation of bevacizumab and start of sunitinib (p<0.001); ELISA specificity suggests that detected VEGF is not bevacizumab-bound. Pre-treatment sVEGFR-3 levels were significantly lower at baseline in responding pts vs. non-responding pts (p<0.0318). A greater reduction in sVEGFR-3 levels was seen in responding pts vs. non-responding pts (p<0.10). Pretreatment VEGF and VEGF fold-changes did not differ according to clinical response. Conclusions: Sunitinib has significant antitumor activity in bevacizumab-refractory mRCC pts, suggesting absence of cross-resistance between bevacizumab and sunitinib. Biomarkers including plasma VEGF and sVEGFR-3 may have predictive potential in sunitinib-treated patients. No significant financial relationships to disclose.