Dual targeting of vascular endothelial growth factor (VEGF) with sorafenib and bevacizumab: Clinical and translational results

Abstract

3542 Background: VEGF is a major mediator of angiogenesis in malignancy. We targeted the VEGF pathway in series by combining the VEGFR2/Raf kinase inhibitor sorafenib (S) with bevacizumab (B), a selective anti-VEGF antibody. We hypothesized that this combination would suppress angiogenesis and tumor growth, with corresponding changes in correlative dynamic imaging. Methods: Eligible pts had non-curable solid tumors, ECOG performance status 0–1, good end organ function, and no prior exposure to S or B. We enrolled pts at S 200 mg po BID and B 5 mg/kg IV q2weeks (dose level [DL] 1) and escalated each drug sequentially. The MTD was DL1; 24 additional pts were enrolled at this dose and randomized to single agent S (Arm 1) or B (Arm 2) for one month, then S+B thereafter. Serum samples for cytokine analysis, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18FDG- PET scans were performed at 0, 2, and 6 weeks. DCE-MRI and PET scans measured vascular permeability (Ktrans) and metabolic activity (standardized uptake values [SUV]), respectively. The Wilcoxon signed rank test was used to evaluate the differences between the paired imaging values at the test time points in an exploratory fashion. Results: 7/38 pts (6/14 ovarian ca pts and 1/3 renal cell ca pts) had partial responses (8+-20 mo; median 15). Grade 3–4 toxicities included hypertension (10), proteinuria (2, DLT), and thrombocytopenia (1, DLT). Common grade 2 toxicities were hand-foot syndrome (18), fatigue (13), infection (13), and hypertension (12). DCE-MRI Ktrans decreased with S+B compared to baseline (p<0.03, both arms); no significant change occurred with either S or B treatment alone or between arms. No significant changes in PET SUV measurements occurred with treatment. Correlation of dynamic imaging parameters with response was not possible due to the limited patient numbers. Serial cytokine analysis is presently being performed and will be included at the time of presentation. Conclusions: S+B is active in solid tumors with manageable toxicity. DCE-MRI shows a decrease in vascular permeability with S+B treatment. A larger trial is necessary to evaluate if DCE-MRI changes can be predictive of response and is ongoing now in ovarian cancer. No significant financial relationships to disclose.