A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC)

Abstract

e16056 Background: Everolimus, a mTOR inhibitor and Sorafenib, a Raf kinase inhibitor had shown their efficacy in RCC, as single agents. Combining these two active agents could have potential additive or synergistic effects. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of this combination in patients with progressive mRCC. Methods: Patients predominantly had clear cell RCC, and progressive measurable diseases on prior treatments including immunotherapy, TKI and/or Everolimus. Patients were evaluated weekly for toxicities and every 8 weeks for radiological response, including at least both PET/CT and CT scans at baseline and 1st staging. Patients received daily Everolimus and twice daily sorafenib both orally at escalating dose levels of 2.5mg/400mg (dose level 0), 5mg/400mg (+1), and 10mg/400mg (+2). Results: 18 patients with mRCC were enrolled and 15 patients were evaluable. 6 patients were treated on dose level 0, dose- limited toxicity (DLT) was found in 2/6 patients, one with thrombocytopenia/leukopenia, the other with pneumonitis; 6 patients were treated on dose level +1, DLT of pulmonary embolism was found in 1/6 patient; and 3 patients were treated on dose level +2, without DLT. The most common side effect was grade 1/2 hand-foot syndrome (4/15, 27%). The MTD was dose level +2. Overall response by RECIST was 27% (4/15 patients): pathological complete response (CR) was 6% (1/15); radiographic CR was 6% (1/5); surgical CR after resection was 6% (1/15). 47% (7/15) of the patients had stable disease. Decreased FDG uptake was found in 67% (10/15) of the patients. The median PFS was 5.53 months (range, 1.4–14.7), and OS was 7.9 months (range, 2.3–23). Conclusions: The MTD of combining daily Everolimus 10mg and twice daily sorafenib 400mg are safe and effective for progressive metastatic RCC. The phase II trial is planned to start in early 2009. [Table: see text]