A phase II study of bevacizumab and everolimus as treatment for refractory metastatic renal cell carcinoma.

BACKGROUND: Agents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade.
METHODS: In this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS.
RESULTS: The median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity.
CONCLUSIONS: In our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.