Toxicity of sunitinib plus bevacizumab in renal cell carcinoma.

TO THE EDITOR: Inhibition of vascular endothelial growth factor (VEGF), either via antibody-mediated binding of the ligand or small molecule inhibition of the VEGF receptor, has demonstrated clinically relevant benefits in metastatic renal cell carcinoma (RCC) and other solid tumors. Recently, combinations of VEGFinhibiting approaches have been studied in an attempt to maximize VEGF blockade and extend the clinical benefit of these approaches. Sunitinib (Sutent; Pfizer Inc, New York, NY), a small-molecule tyrosine kinase inhibitor of a family of receptors including VEGF receptor and bevacizumab (Avastin; Genentech, South San Francisco, CA), a recombinant humanized monoclonal antibody that binds and neutralizes circulating VEGF, have been previously combined in two separate phase I trials. A phase I trial conducted exclusively in metastatic renal cell carcinoma (RCC) and with fixed bevacizumab dosing at 10 mg/kg intravenously every 2 weeks reported unacceptable toxicity, including thrombotic microangiopathy (TMA). We previously reported a similar phase I trial of this combination in 38 patients with advanced solid tumors, notable for the diverse tumor type as well as lower initial doses of bevacizumab. This trial failed to demonstrate laboratory or clinical evidence of TMA in any patent, including the six RCC patients (median, 8 cycles of therapy; range, 2 to 13), all of whom had undergone nephrectomy, and including all patients treated at the highest dose levels up to 20 months of treatment. Due to increased toxicity seen with chronic dosing at higher dose levels in our study and the TMA seen in the other trial, an expanded cohort of patients with RCC was planned to collect more safety experience at dosing of 37.5 mg sunitinib 4 weeks on followed by 2 weeks off and bevacizumab 5 mg/kg intravenously on days 1, 15, and 29 of a 42-day cycle. Five patients were enrolled in this expanded cohort. Three of five patients demonstrated laboratory evidence of TMA. This included low haptoglobin, thrombocytopenia, and schistocytes on peripheral blood smear at the end of cycles 2 and 4 for two patients, and an isolated single low haptoglobin value for the third patient. None of the patients had any clinical signs or symptoms associated with the laboratory abnormalities. Table 1 depicts the patient characteristics and relevant data for the three cases of TMA and the remainder of the patients with RCC enrolled on the initial study and expanded cohort. The first two TMA patients continued to have haptoglobin levels lower than 20 mg/dL for 2 and 20 weeks after discontinuation of bevacizumab (both patients continued on sunitinib monotherapy). The third patient developed the isolated low haptoglobin while receiving sunitinib monotherapy after bevacizumab had been discontinued 8 weeks prior. The haptoglobin normalized 2 weeks later and remained in normal range with continued sunitinib monotherapy for this patient. All five patients on the expanded cohort discontinued bevacizumab when TMA was observed in the initial two patients. Further accrual of patients with RCC was suspended due to this safety signal.