Dual VEGF/VEGFR inhibition in advanced solid malignancies

Abstract

Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients.

Patients with metastatic solid tumors received sunitinib (37.5 mg/d, 4 wk on/2 wk off) and bevacizumab (5 mg/kg intravenously every 2 wk). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays.

Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 wk of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold.

Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development.

Keywords: :

• angiogenesis
• VEGF
• VEGFR
• sunitinib
• bevacizumab

Disclosure of Potential Conflicts of Interest

Dr Rini has consulting and research funding from Pfizer.

Acknowledgments

We are appreciative to Ronald Grane and Barbara Jacobs for the careful and dedicated conduct of the pharmacodynamic assays.

Financial Support

CTEP Grant U01-CA062502 and a philanthropic gift to Taussig Cancer Institute from Maria and Carlos Tejada.