Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial.
BACKGROUND
Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers.


METHODS
In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m(2)) and oxaliplatin (100 mg/m(2)) with or without cetuximab (500 mg/m(2)), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149.


RESULTS
Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52-74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43-65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1-7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7-6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1-13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6-16·0) in the chemotherapy alone group. The most common grade 3-4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group.


CONCLUSIONS
The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option.


BACKGROUND
Institut National du Cancer, Merck Serono.
Institut Gustave Roussy, Villejuif, Université Paris Sud, Paris, France. Electronic address: david.malka@gustaveroussy.fr.
David
D
Malka
Saint-Antoine University Hospital, Paris, France.
Pascale
P
Cervera
Institut Gustave Roussy, Villejuif, Université Paris Sud, Paris, France.
Stéphanie
S
Foulon
West German Cancer Center, University Hospital Essen, Essen, Germany.
Tanja
T
Trarbach
Centre Léon Bérard, Lyon, France.
Christelle
C
de la Fouchardière
Centre Eugène Marquis, Rennes, France.
Eveline
E
Boucher
Saint-Antoine University Hospital, Paris, France.
Laetitia
L
Fartoux
Beaujon University Hospital, Clichy, France.
Sandrine
S
Faivre
Saint-André University Hospital, Bordeaux, France.
Jean-Frédéric
JF
Blanc
Institut Paoli-Calmette, Marseille, France.
Frédéric
F
Viret
Centre Val d'Aurelle, Montpellier, France.
Eric
E
Assenat
Ulm University, Ulm, Germany.
Thomas
T
Seufferlein
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
Thomas
T
Herrmann
Henri-Mondor University Hospital, Créteil, France.
Julien
J
Grenier
Beaujon University Hospital, Clichy, France.
Pascal
P
Hammel
Halle University Hospital, Halle (Saale), Germany.
Matthias
M
Dollinger
Pitié-Salpêtrière University Hospital, Paris, France.
Thierry
T
André
Regensburg University Hospital, Regensburg, Germany.
Philipp
P
Hahn
University of Munich, Munich, Germany.
Volker
V
Heinemann
Institut Gustave Roussy, Villejuif, Université Paris Sud, Paris, France.
Vanessa
V
Rousseau
Institut Gustave Roussy, Villejuif, Université Paris Sud, Paris, France.
Michel
M
Ducreux
Institut Gustave Roussy, Villejuif, Université Paris Sud, Paris, France.
Jean-Pierre
JP
Pignon
Saint-Antoine University Hospital, Paris, France.
Dominique
D
Wendum
Saint-Antoine University Hospital, Paris, France.
Olivier
O
Rosmorduc
Hannover Medical School, Hannover, Germany.
Tim F
TF
Greten
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics; D001653:Bile Ducts, Intrahepatic; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D000068818:Cetuximab; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics; D003138:Common Bile Duct Neoplasms / Q000188:drug therapy / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics; D000093542:Gemcitabine
D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D003841:Deoxycytidine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D000093542:Gemcitabine