Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review.

Advanced and metastatic renal cell cancer (RCC) is resistant to conventional chemotherapy. Only a very small number of patients survive long term after immunotherapy. However, any effect of interleukin-2 (IL-2) and/or interferon on median overall survival is small, and treatment-associated toxicities may be severe. The disease is therefore an area of high unmet medical need. Activation of the VEGF and EGF/RAS/RAF/MAP kinase pathways is frequent in solid tumours such as RCC. Such activation is implicated in tumour angiogenesis and proliferation. VEGF and EGF receptors and molecules (such as RAF kinase) involved in downstream signalling are therefore potential appropriate targets for drug therapy. Several antibodies and low molecular weight tyrosine kinase inhibitors (TKIs) have completed phase II clinical trials. Phase II studies of multitargeted agents, which include inhibition of VEGFR tyrosine kinase in their repertoire (sorafenib, sunitinib and AG 013736), show clear second-line activity in metastatic RCC. The same is true of the anti-VEGF antibody, bevacizumab. In a randomised phase III comparison against placebo in pretreated patients, sorafenib doubled median progression free survival (24 versus 12 weeks). Studies now in progress will determine whether benefits seen second-line will also be evident first-line, and whether the activity of novel agents can be increased by combining them with each other, with cytokines, or with chemotherapy.