title: Sorafenib for the treatment of advanced renal cell carcinoma.
abstract: OBJECTIVE
  This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC).
  
  
  METHODS
  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 hand-foot 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.
authors.affiliation: Division of Drug Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993-0004, USA. robert.kane@fda.hhs.gov
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kane
authors.forename: Ann T
authors.initials: AT
authors.lastname: Farrell
authors.forename: Haleh
authors.initials: H
authors.lastname: Saber
authors.forename: Shenghui
authors.initials: S
authors.lastname: Tang
authors.forename: Gene
authors.initials: G
authors.lastname: Williams
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Jee
authors.forename: Chengyi
authors.initials: C
authors.lastname: Liang
authors.forename: Brian
authors.initials: B
authors.lastname: Booth
authors.forename: Nallaperumal
authors.initials: N
authors.lastname: Chidambaram
authors.forename: David
authors.initials: D
authors.lastname: Morse
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sridhara
authors.forename: Patricia
authors.initials: P
authors.lastname: Garvey
authors.forename: Robert
authors.initials: R
authors.lastname: Justice
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004341:Drug Evaluation; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008954:Models, Biological; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010919:Placebos; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010919:Placebos; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib