title: A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation.
abstract: OBJECTIVE
  Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib.
  
  
  METHODS
  In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks.
  
  
  RESULTS
  Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%).
  
  
  CONCLUSIONS
  Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.
authors.affiliation: Department of Pulmonary Diseases and GROW- School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Anne-Marie C
authors.initials: AM
authors.lastname: Dingemans
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Mellema
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Atie
authors.initials: A
authors.lastname: van Wijk
authors.forename: Sjaak A
authors.initials: SA
authors.lastname: Burgers
authors.forename: Peter W A
authors.initials: PW
authors.lastname: Kunst
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.forename: Danielle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010984:Platinum / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D000077157:Sorafenib; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D009536:Niacinamide; D010984:Platinum; D000077157:Sorafenib; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins