Elsevier

The Lancet Oncology

Volume 15, Issue 8, July 2014, Pages 819-828
The Lancet Oncology

Articles
Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial

https://doi.org/10.1016/S1470-2045(14)70212-8Get rights and content

Summary

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/m2) and oxaliplatin (100 mg/m2) with or without cetuximab (500 mg/m2), 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.

Findings

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.

Interpretation

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.

Funding

Institut National du Cancer, Merck Serono.

Introduction

Cancers of the biliary tract are a heterogeneous group of rare tumours that include intrahepatic and extrahepatic cholangiocarcinomas, gallbladder carcinomas, and ampullary carcinomas.1 Most patients are diagnosed with advanced-stage disease, making them ineligible for complete surgical resection, which is the only potentially curative modality available. Furthermore, recurrence is common even after complete resection, and is usually only amenable to palliative chemotherapy.

Very few randomised trials of chemotherapy have been done in patients with advanced biliary-tract cancer.2 In a pooled analysis of 104 trials (including only two randomised phase 2 trials and one phase 3 trial) in 2810 patients with advanced biliary-tract cancer, the combination of gemcitabine and platinum compounds was more effective than gemcitabine alone.2 The UK ABC-02 phase 3 trial3 confirmed the superiority of gemcitabine plus cisplatin over gemcitabine alone. Several single-group studies4, 5, 6 and one randomised trial7 showed that the combination of gemcitabine and oxaliplatin has antitumour activity with a favourable toxic-effect profile in advanced biliary-tract cancer, and is more efficacious than best supportive care and fluorouracil plus folinic acid.7 However, patients with advanced biliary-tract cancer still have a poor outlook, with median overall survival of less than 1 year.2, 3, 7

The EGFR signalling pathway regulates biliary epithelial cell growth and proliferation, and EGFR is overexpressed in 67–100% of biliary cancers, making it a rational target for treatment.8, 9, 10, 11, 12 One phase 2 trial in 30 patients with advanced biliary-tract cancer showed encouraging results when cetuximab, a chimeric monoclonal antibody directed against EGFR, was added to gemcitabine and oxaliplatin.13

We designed the BINGO trial to assess the efficacy and tolerability of gemcitabine and oxaliplatin plus cetuximab or gemcitabine and oxaliplatin alone as first-line treatment for patients with advanced biliary-tract cancer.

Section snippets

Study design and participants

In this open-label, non-comparative, randomised phase 2 study, we recruited patients with biliary-tract cancer from university hospitals and cancer centres across France and Germany. Trial inclusion criteria were: age 18–75 years; histologically or cytologically confirmed adenocarcinoma of the biliary tract, including intrahepatic and extrahepatic bile ducts, gallbladder, and ampulla of Vater; and locally advanced (non-resectable) or metastatic disease. Because proper tumour staging (ie,

Results

From Oct 10, 2007, to Dec 18, 2009, 150 patients with advanced biliary-tract cancer were enrolled in the study across 11 centres in France and seven centres in Germany, with 76 patients randomly assigned to receive gemcitabine and oxaliplatin plus cetuximab and 74 assigned to gemcitabine and oxaliplatin alone (figure 1). Six (8%) patients in the chemotherapy plus cetuximab group and 11 (15%) patients in the chemotherapy alone group were not assessable for disease response for the whole duration

Discussion

Our data suggest that any potential antitumour activity of cetuximab does not translate into a survival advantage when combined with gemcitabine and oxaliplatin in patients with advanced biliary-tract cancer compared with chemotherapy alone. Neither tumour KRAS or BRAF mutations, nor EGFR overexpression (identified in nearly a quarter of patients), seemed to help to select patients able to respond to therapy.

Although gemcitabine and platinum-based chemotherapy has been established as the

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