title: Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy.
abstract: BACKGROUND
  The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data.
  
  
  METHODS
  Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively.
  
  
  RESULTS
  Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome.
  
  
  CONCLUSIONS
  Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.
authors.affiliation: Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Papa
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.forename: Riyaz
authors.initials: R
authors.lastname: Shah
authors.forename: A Toby
authors.initials: AT
authors.lastname: Prevost
authors.forename: Rohit
authors.initials: R
authors.lastname: Lal
authors.forename: Blair
authors.initials: B
authors.lastname: McLennan
authors.forename: Paul
authors.initials: P
authors.lastname: Cane
authors.forename: Loic
authors.initials: L
authors.lastname: Lang-Lazdunski
authors.forename: Zaid
authors.initials: Z
authors.lastname: Viney
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dunn
authors.forename: Sally
authors.initials: S
authors.lastname: Barrington
authors.forename: David
authors.initials: D
authors.lastname: Landau
authors.forename: James
authors.initials: J
authors.lastname: Spicer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068437:Pemetrexed; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D010984:Platinum / Q000008:administration & dosage; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016879:Salvage Therapy; D000077157:Sorafenib; D015996:Survival Rate
chemical_list: D005971:Glutamates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000068437:Pemetrexed; D009536:Niacinamide; D010984:Platinum; D006147:Guanine; D000077157:Sorafenib