Erlotinib Improves Chemotherapy Response Rates for Patients with Advanced Biliary Tract Cancers

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a Phase 3 trial including 268 patients with advanced biliary tract cancers, response rates were improved in patients receiving erlotinib with chemotherapy (gemcitabine/oxaliplatin) compared to chemotherapy alone. However, progression-free survival was not enhanced except for the subset with cholangiocarcinoma.

Source: Lee J, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary tract cancer: A multicenter, open label, randomized, phase 3 trial. Lancet Oncology 2012;13:181-188.

For carcinomas arising in the biliary tract, including gall bladder, ampullary of Vater, or cholangiocarinoma, long-term survival hinges on complete surgical resection.1 However, the majority of patients present with advanced disease and for these patients treatment has offered only modest success. Combination chemotherapy with gemcitabine and a platinum-based agent is currently regarded as a standard treatment,1 although a number of other drugs and combinations have been evaluated in this setting.2 Results of several Phase 2 studies have shown that the combination of gemcitabine and oxaliplatin is equivalent in efficacy and less toxic than gemcitabine/cisplatin and is more tolerable.2-4

Results of Phase 2 trials of single-agent erlotinib in biliary-tract cancer5,6 and of gemcitabine plus erlotinib in pancreatic cancer7 have shown modest benefits. Thus, in an effort to enhance treatment responses for patients with advanced biliary tract cancers, Lee and colleagues throughout South Korea performed an open-label, randomized, Phase 3 trial comparing gemcitabine/oxaliplatin with or without erlotinib. A total of 268 patients were randomly assigned to receive either first-line treatment with chemotherapy alone (gemcitabine 1000 mg/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2) or the same drugs plus erlotinib (100 mg daily, orally). Treatment was repeated every 2 weeks until disease progression or unacceptable toxic effects. The primary endpoint was progression-free survival.

Median progression-free survival was 4.2 months (95% confidence interval [CI] 2.7-5.7) in the chemotherapy alone group and 5.8 months (95% CI 4.6-7.0) in the chemotherapy plus erlotinib group (hazard ratio [HR] 0.80, 95% CI 0.61-1.03; P = 0.087). A significantly higher number of patients had an objective response in the chemotherapy plus erlotinib group than in the chemotherapy alone group (40 patients vs 21 patients; P = 0.005), but median overall survival was the same in both groups (9.5 months). The most common grade 3-4 adverse event was febrile neutropenia (eight [6%] patients in the chemotherapy alone group and six [4%] in the chemotherapy plus erlotinib group) and there was treatment-related mortality during the study. Subgroup analyses by primary site of disease showed that for patients with cholangiocarcinoma, the addition of erlotinib to chemotherapy significantly prolonged median progression-free survival (5.9 months [95% CI 4.7-7.1] for chemotherapy plus erlotinib vs 3.0 months [1.1-4.9] for chemotherapy alone; P = 0.049).


This is the first Phase 3 trial to add a targeted agent to the combination of gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer, although Phase 2 studies have been reported using bevacizumab plus erlotinib5,8 erlotinib alone,6 or gemcitabine/oxaliplatin with cetuximab.8 Although the current trial resulted in no significant difference in progression-free survival for the group of advanced biliary tract cancer as a whole, the addition of erlotinib to gemcitabine and oxaliplatin showed antitumor activity as indicated by a higher objective response rate. Furthermore, for the subset with cholangiocarcinoma, prolonged progression-free survival was observed, a finding that warrants confirmatory studies.

A few caveats are worth noting. First, this study was conducted exclusively in South Korea and all patients were Asian. Whether other ethnic groups would have similar responses remains to be established. Furthermore, additional studies are required to determine if responses correlate with EGFR overexpression or KRAS mutation, as might be expected from the larger experience with non-small cell lung cancer. Also, inasmuch as progression-free survival was comparable, it would be important to establish the effect of added erlotinib on quality of life. Despite these concerns, it is encouraging to see even a small step forward in the treatment of advanced biliary tract cancer, a disease with projected survival measured in months.


1. NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers Version 2.2012. 2012.

2. Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist 2008;13:415-423.

3. Harder J, et al. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer 2006;95:848-852.

4. Jang JS, et al. Gemcitabine and oxaliplatin in patients with unresectable biliary cancer including gall bladder cancer: A Korean Cancer Study Group phase II trial. Cancer Chemotherapy Pharmacol 2010;65:641-647.

5. Lubner SJ, et al. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: A phase II Consortium study. J Clin Oncol 2010;28:3491-3497.

6. Philip PA, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 2006;24:3069-3074.

7. Moore MJ, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-1966.

8. Gruenberger B, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: A phase 2 study. Lancet Oncol 2010;11:1142-1148.