alexa Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment.
Medicine

Medicine

Translational Medicine

Author(s): Mancuso A, Di Paola ED, Leone A, Catalano A, Calabr F,

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Abstract OBJECTIVE: To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. METHODS: Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. Drug-focused translational research on tissues (i.e. B-RAF) and plasma (VEGFR-α, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics. Patients with mRCC pretreated with an anti-angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 and adequate organ function were eligible. Patients received sorafenib 400 mg twice a day continuously in 4-week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0-1 94.8\%; median (range) age 62 (41-81) years; nephrectomy 100\%; surgery for metastatic disease 26.4\%; clear cell 79.1\%; papillary cell 15.7\%; sarcomatoid/high grade 5.2\%; two or more metastatic sites 84\%. Overall, 11 patients (58\%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression-free survival (PFS) of 8.3 months was observed. Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7\%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild-type B-RAF (2.5 vs 9.1 month, P < 0.05). The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade ≥1 diarrhoea and grade 2-3 hand-foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient. CONCLUSIONS: Sorafenib at doses of 400-600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure. In progressive patients, treatment with a higher dose could be a valid option and B-RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial. © 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL. This article was published in BJU Int and referenced in Translational Medicine

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