Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06)

Background Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC). Methods Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m(2) (days 1 and 8), oral capecitabine 500 mg/m(2) twice a day (final dose after adjustment, days 1-14), and oral sorafenib 400 mg twice a day (days 1-21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov, number NCT00496301. Findings 44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11.1 months (95% CI 7.9-17.1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug. Interpretation PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration.