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

Abstract

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.

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.

Conflict of interest statement

Declaration of interests

DM has consulted or advised for Roche, Amgen, Imclone, Bayer, Teva, Keocyt, Sanofi-Aventis, and Boehringer Ingelheim; has received honoraria from Merck Serono, Ipsen, Celgene, and Novartis; has received travel grants from Roche and Bayer; and has received research funding from Institut National du Cancer (INCa), Merck Serono, Amgen, Sanofi-Aventis, and Roche. TT has consulted or advised for Merck Serono, Lilly, Sanofi-Aventis, Amgen, Roche, AstraZeneca, and Ganymed; has received honoraria from Merck Serono, Lilly, Sanofi-Aventis, Amgen, Roche, AstraZeneca, and Ganymed; has received travel grants from Merck Serono, Lilly, Sanofi-Aventis, Amgen, Roche, AstraZeneca, and Ganymed; and has received research funding from Merck Serono, Amgen, Lilly, and Sanofi-Aventis. LF has received honoraria from Bayer, Bristol-Myers Squibb, Gilead, Boehringer Ingelheim, and Roche, and has received research funding from Ipsen. SFa has received honoraria from Merck Serono. TS has consulted or advised for Merck Serono, and has received travel grants from Merck Serono. TH has received honoraria from Amgen and Pfizer, and has received travel grants from Lilly, Merck Serono, Pfizer, Roche, and Sanofi-Aventis. PHam has consulted or advised for Merck Serono, and has received honoraria and research funding from Merck Serono. MDo has received research funding from Bayer. TA has received honoraria from Merck Serono. VH has consulted or advised for Merck Serono, and has received honoraria from, travel grants, and research funding from Merck Serono. MDu has consulted or advised for Roche, Merck Serono, Amgen, Lilly, Keocyt, Sanofi-Aventis, Ipsen, Celgene, Boehringer Ingelheim, and Novartis; has received honoraria from Roche, Amgen, Merck Serono, Lilly, and Novartis; has received travel grants from Roche, Amgen, Merck Serono, and Novartis; and has received research funding from Roche. J-PP has received research funding (unrestricted grant) from Roche, and has received honoraria from Merck Serono. OR has received honoraria from Bayer and Sirtex. TFG has consulted or advised for Merck Serono, and has received honoraria and research funding from Merck Serono. All other authors declare no competing interests.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1:

Trial profile

Figure 2:. Progression-free survival

Shaded areas show 95% CIs of the curves.

Figure 3:. Overall survival

Shaded areas show 95% CIs of the curves.