Background: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and sorafenib, a RAF kinase inhibitor, has shown efficacy in renal cell cancer (RCC) as single agents. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of combining these agents for potential additive or synergistic effects when treating progressive metastatic RCC (mRCC).
Patients and methods: The 15 patients enrolled in the study had predominantly clear cell RCC (cRCC) and progressive measurable disease with previous treatment that included immunotherapy, tyrosine kinase inhibitors, and/or everolimus. Patients received daily everolimus and twice-daily sorafenib at escalating dose levels of 2.5 mg/400 mg (cohort 1), 5 mg/400 mg (cohort 2), and 10 mg/400 mg (cohort 3), and they were evaluated weekly for toxicity and every 8 weeks for response, using computed tomography/positron emission tomography (CT/PET) and CT at baseline and at first staging.
Results: In cohort 1, 2 of 6 patients experienced dose-limited toxicity (DLT) of thrombocytopenia/leukopenia and pneumonitis. In cohort 2, 1 of 6 patients experienced a DLT of pulmonary embolism, and the 3 patients in cohort 3 experienced no DLTs. The MTD was 10 mg/400 mg. Common adverse events included grade 1/2 hand-foot syndrome. Using Response Evaluation Criteria in Solid Tumors (RECIST), 1 patient achieved a pathologic complete response (CR), 1 patient achieved a radiographic CR, and 1 patient achieved a surgical CR. Seven patients achieved stable disease; 10 patients had decreased fluorine-18 fluorodeoxyglucose uptake. Median progressive-free survival was 5.6 months; overall survival was 7.9 months.
Conclusion: The MTD of daily everolimus 10 mg and twice-daily sorafenib 400 mg is safe and effective for progressive mRCC.
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