UroToday - Standard front-line cisplatin-based combination chemotherapy for metastatic transitional cell carcinoma (TCC) with either MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) or GC (gemcitabine, cisplatin) yields a median survival of approximately 15 months. The response rate with these regimens is 40-60% and subsequent progression is almost universal, with salvage chemotherapy being relatively ineffective. Angiogenesis and VEGF (vascular endothelial growth factor) appear to have key roles in TCC progression and invasion, making this an attractive target for therapeutic manipulation. Sunitinib malate is an orally administered small molecule, multitargeted receptor tyrosine kinase inhibitor selective for VEGF receptor (R)-1,2 and 3, platelet-derived growth factor receptor (PDGFR)- α and β, Flt3, RET and Kit. It is approved multinationally for the treatment of advanced renal cell carcinoma and imatinib-resistant or intolerant gastrointestinal stromal tumors.

We pre-clinically evaluated the combination of sunitinib and cisplatin in TCC. Concentrations of free and active sunitinib achieved in vivo and in human subjects are in the low nanomolar range, and low nanomolar concentrations exhibited no direct anti-proliferative or pro-apoptotic cytotoxicity and did not enhance the activity of cisplatin in vitro. However, a one-log higher sunitinib concentration of 100nM exhibited modest direct in vitro pro-apoptotic activity, and at 1µM induced significant apoptosis. Modest anti-proliferative activity was observed at 1µM. This suggests that sunitinib may induce apoptosis independent of an impact on proliferation and angiogenesis by an uncertain mechanism and at lower concentrations. Sunitinib alone at 20 mg/kg/day or 40 mg/kg/day (which is known to attain active nanomolar plasma concentrations toxic to endothelial cells) were significantly active against murine xenografts of human TCC. In addition, the combination of sunitinib 20 mg/kg/day and cisplatin 4 mg/kg/week was significantly more active than untreated controls and cisplatin alone. Cisplatin displayed anti-proliferative and anti-angiogenic activity, while sunitinib induced significant tumor apoptosis in conjunction with more modest anti-proliferative activity and stromal anti-angiogenic activity.

Thus, these data support the evaluation of sunitinib alone and in combination with cisplatin for human patients with TCC. Recent preliminary data do demonstrate activity for sunitinib against human patients with advanced TCC in the frontline setting (Spanish trial) as well as when progressing after prior chemotherapy (Memorial Sloan Kettering Cancer Center trial).

An ongoing randomized trial led by the University of Michigan is comparing maintenance placebo with sunitinib in patients with stable or responding disease following frontline chemotherapy. Another ongoing trial is evaluating neoadjuvant sunitinib alone before cystectomy for muscle-invasive bladder cancer. Separate clinical trials are also in late stages of planning to evaluate the combination of GC and sunitinib in the neoadjuvant setting (by the Hoosier Oncology Group) before cystectomy for muscle-invasive TCC of the bladder and in the frontline setting for metastatic TCC (by US Oncology Research).

Guru Sonpavde, MD, as part of Beyond the Abstract on UroToday.

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