Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment.
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.
Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy. mancusoan@gmail.com
Andrea
A
Mancuso
Eugenio Donato
ED
Di Paola
Alvaro
A
Leone
Alfonso
A
Catalano
Fabio
F
Calabrò
Linda
L
Cerbone
Andrea
A
Zivi
Carlo
C
Messina
Silvia
S
Alonso
Leonardo
L
Vigna
Rita
R
Caristo
Cora N
CN
Sternberg
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001557:Benzenesulfonates / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D016879:Salvage Therapy / Q000379:methods; D000077157:Sorafenib; D016896:Treatment Outcome
D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor