A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

Ann Oncol. 2015 May;26(5):943-949. doi: 10.1093/annonc/mdv035. Epub 2015 Jan 28.


Background: Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown.

Patients and methods: ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1 : 1 to receive GEMOX (800 mg/m(2) gemcitabine and 85 mg/m(2) oxaliplatin) or C-GEMOX (500 mg/m(2) cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR).

Results: The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P = 0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P = 0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS.

Conclusions: Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.

Clinical trials number: This study is registered at ClinicalTrials.gov (NCT01267344). All patients gave written informed consent.

Keywords: KRAS mutation; biliary tract cancer; cetuximab; chemotherapy.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biliary Tract Neoplasms / drug therapy*
  • Biliary Tract Neoplasms / genetics
  • Biliary Tract Neoplasms / mortality
  • Biliary Tract Neoplasms / pathology
  • Cetuximab / administration & dosage*
  • Cetuximab / adverse effects
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Disease Progression
  • Disease-Free Survival
  • Drug Administration Schedule
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation*
  • Organoplatinum Compounds / adverse effects
  • Organoplatinum Compounds / therapeutic use
  • Phenotype
  • Proportional Hazards Models
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Taiwan
  • Time Factors
  • Treatment Outcome


  • KRAS protein, human
  • Organoplatinum Compounds
  • Deoxycytidine
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab

Supplementary concepts

  • gemcitabine-oxaliplatin regimen

Associated data

  • ClinicalTrials.gov/NCT01267344