Renewed hope in the treatment of renal cell carcinoma

Abstract

Metastatic renal cell carcinoma (RCC) is one of the most inherently resistant tumors, with only a small subset of patients gaining a clinically meaningful benefit from interferon-α and/or interleukin-2 therapy. It has thus been identified as a priority malignancy for the development and study of novel therapies [1]. Recent developments in the molecular biology of renal cell carcinoma have identified several pathways associated with the development of this cancer [2]. In particular, angiogenesis has been identified as playing a key role in the pathophysiology of clear cell RCC and vascular endothelial growth factor (VEGF) is an important mediator of this process [2]. A number of strategies have been developed to target angiogenesis in metastatic RCC. These include inhibition of VEGF receptor tyrosine kinases, binding of the VEGF protein, or blockade of the VEGF receptor (VEGFR). Such approaches have demonstrated significant activity in phase II and, more recently, phase III trials, placing VEGF antagonist approaches at the forefront of current treatment strategies for RCC. Sunitinib (SU11248) is an orally bioavailable small molecule that inhibits multiple split kinase domain receptor kinases, including VEGFR-1 and -2, platelet derived growth factor (PDGF)-α and -β, c-Kit, and fms-like tyrosine kinase 3 (Flt3) [3]. Motzer et al. recently reported the initial results of a phase III study comparing sunitinib with interferon-α as first-line therapy in 750 patients with metastatic renal cell carcinoma of clear cell histology [4]. The response rate to sunitinib was 31% (103 partial responses) and to interferon-α 6% (20 partial responses, p <0.000001), as assessed by an independent central review. The median progression-free survival (PFS) was 11 months for sunitinib and 5 months for interferon-α (hazard ratio 0.415, p<0.000001); the median overall survival had not been reached for either drug at the time of reporting. This is the first phase III trial demonstrating the benefit of a nonimmune therapeutic agent in first-line therapy in metastatic RCC, and the authors conclude that sunitinib is a new reference standard for the first-line treatment of metastatic RCC. Sunitinib is not the only tyrosine kinase inhibitor (TKI) to show activity in RCC. Sorafenib (BAY 43-9006) is an orally bioavailable small molecule that was initially found to inhibit Raf-1, but it has also subsequently been shown to inhibit several receptor tyrosine kinases, including VEGFR2 and -3, Flt3, PDGFR-α and -β, and c-Kit [3, 5]. The role, if any, that Raf kinase inhibition plays in its clinical activity remains unclear. A phase II randomized discontinuation trial of sorafenib in advanced RCC demonstrated that disease stabilization, observed in a large proportion of patients, was attributable to the study drug [6]. The cytostatic mode of action of many targeted therapies requires just such a novel approach to clinical trial design. The interim results of a multicenter phase III randomized placebo-controlled double-blind trial of sorafenib in RCC in patients who had progressed after one prior systemic therapy have been reported in abstract form [7]. This analysis reported that the median time to progression for patients receiving sorafenib (n=335) was 24 weeks versus 12 weeks for patients (n=337) in the placebo arm (p= <0.01×10). Only 2% of patients achieved partial responses to sorafenib, whereas 78% had stable disease. The relatively lower partial response rate seen with sorafenib compared to sunitinib may reflect their apparent Targ Oncol (2007) 2:1–2 DOI 10.1007/s11523-006-0036-z