Sorafenib for the Treatment of Advanced Renal Cell Carcinoma

Abstract

Purpose: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar,, a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC). Experimental Design: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study. Results: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P < 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95 % confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and handfoot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose. Conclusions: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

“…Recently, two novel kinase inhibitors have been introduced that lead to a detectable clinical response in RCC patients (Kane et al, 2006;Motzer et al, 2007). However, only a subset of patients did show this response.…”

Mechanisms of adverse effects of anti-VEGF therapy for cancer

“…In patients on sorafenib, hypertension had an overall incidence of 17% (3% had Grade 3 or 4) (Kane et al, 2006). An important part of the mechanism of hypertension associated with VEGF inhibition is thought to involve decreased production of nitric oxide (NO) in the wall of arterioles and other resistance vessels.…”

“…Left ventricular ejection fraction was below the lower limit of normal in 15% of patients receiving sunitinib for renal cell carcinoma, and 11% of patients on sunitinib required treatment for low ventricular ejection fraction in a study of GIST. Cardiac ischaemia or infarction was reported in 2.9% of patients on sorafenib in a randomised phase III trial in advanced renal cell carcinoma (Kane et al, 2006;Escudier et al, 2007). VEGF inhibition by systemic administration of soluble ectodomain of VEGFR-1 for 2 weeks resulted in a 32% reduction in cardiac output, but no change in myocardial vascularity, heart rate, left ventricular ejection fraction, or left ventricular fractional shortening in unanaesthetised adult mice (Kamba et al, 2006).…”

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

“…Sorafenib is a multikinase inhibitor that showed efficacy against a wide variety of tumours in pre‐clinical models13; it inhibits cell proliferation by targeting the Raf/MEK/ERK signalling pathways and exerts an anti‐angiogenic effect by inhibition of tumour angiogenesis through vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR) 14, 15. It is already approved in humans for the treatment of advanced hepatocellular carcinoma16 and advanced renal cell carcinoma 17. Common side effects of Sor are cutaneous like hand–foot syndrome or rash and gastrointestinal like diarrhoea or nausea, as well as alopecia and fatigue.…”