Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti‐angiogenic treatment
Authors: Mancuso Andrea , Di Paola Eugenio Donato , Leone Alvaro , Catalano Alfonso , Calabrò Fabio , Cerbone Linda , Zivi Andrea , Messina Carlo , Alonso Silvia , Vigna Leonardo , Caristo Rita , Sternberg Cora N. 
Published: December 2011

Study Type – Therapy (individual cohort)Level of Evidence 2bWhat's known on the subject? and What does the study add?Sorafenib is an oral receptor tyrosine kinase inhibitor that inhibits RAF serine/threonine kinases and receptor tyrosine kinases (vascular endothelial growth factor receptors 1, 2, 3 and platelet‐derived growth factor‐beta, Flt‐3 and c‐kit) that are implicated in tumourigenesis and tumour progression. Sorafenib is approved for the treatment of advanced renal cell cancer.B‐RAF mutations (V600E and K601E) may be interesting negative predictive markers in metastatic kidney cancer patients treated with Sorafenib. Larger trials are needed to validate this hypothesis and should include B‐RAF molecular analysis for better patient selection.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.