A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma
Background Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). Patients and Methods A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC. Results We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients. Conclusion Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC. © 2014 Elsevier Inc. All rights reserved.
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
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