title: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.
  
  
  METHODS
  KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status.
  
  
  RESULTS
  KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population.
  
  
  CONCLUSIONS
  Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
authors.affiliation: Amgen, Inc, One Amgen Center Dr, MS 38-2-B, Thousand Oaks, CA 91320-1799, USA. ramado@amgen.com
authors.forename: Rafael G
authors.initials: RG
authors.lastname: Amado
authors.forename: Michael
authors.initials: M
authors.lastname: Wolf
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Freeman
authors.forename: Todd
authors.initials: T
authors.lastname: Juan
authors.forename: Robert
authors.initials: R
authors.lastname: Sikorski
authors.forename: Sid
authors.initials: S
authors.lastname: Suggs
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: Scott D
authors.initials: SD
authors.lastname: Patterson
authors.forename: David D
authors.initials: DD
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077544:Panitumumab; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins