title: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines.
abstract: OBJECTIVE
  This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.
  
  
  METHODS
  Patients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed.
  
  
  RESULTS
  The response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03).
  
  
  CONCLUSIONS
  Cetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Shirin
authors.initials: S
authors.lastname: Khambata-Ford
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Philip
authors.initials: P
authors.lastname: Gold
authors.forename: Philip
authors.initials: P
authors.lastname: Stella
authors.forename: Barry
authors.initials: B
authors.lastname: Mirtsching
authors.forename: Allen L
authors.initials: AL
authors.lastname: Cohn
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Pippas
authors.forename: Nozar
authors.initials: N
authors.lastname: Azarnia
authors.forename: Zenta
authors.initials: Z
authors.lastname: Tsuchihashi
authors.forename: David J
authors.initials: DJ
authors.lastname: Mauro
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011743:Pyrimidines / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011743:Pyrimidines; D000077150:Oxaliplatin; D000077146:Irinotecan; D000068818:Cetuximab; D002166:Camptothecin