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

Sam J. Lubner, Michelle R. Mahoney, Jill L. Kolesar, Noelle K. LoConte, George P. Kim, Henry Clement Pitot, Philip A. Philip, Joel Picus, Wei Peng Yong, Lisa Horvath, Guy Van Hazel, Charles E. Erlichman, Kyle D. Holen

Research output: Contribution to journalArticle

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Abstract

Purpose: Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods: Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results: Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion: Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Original languageEnglish (US)
Pages (from-to)3491-3497
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number21
DOIs
StatePublished - Jul 20 2010

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Biliary Tract Neoplasms
Epidermal Growth Factor Receptor
Vascular Endothelial Growth Factor A
Gallbladder Neoplasms
Erlotinib Hydrochloride
Bevacizumab
Mutation
Survival
Cholangiocarcinoma
Exanthema
Combination Drug Therapy
Protein-Tyrosine Kinases
Mouth
Genotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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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. / Lubner, Sam J.; Mahoney, Michelle R.; Kolesar, Jill L.; LoConte, Noelle K.; Kim, George P.; Pitot, Henry Clement; Philip, Philip A.; Picus, Joel; Yong, Wei Peng; Horvath, Lisa; Van Hazel, Guy; Erlichman, Charles E.; Holen, Kyle D.

In: Journal of Clinical Oncology, Vol. 28, No. 21, 20.07.2010, p. 3491-3497.

Research output: Contribution to journalArticle

Lubner, SJ, Mahoney, MR, Kolesar, JL, LoConte, NK, Kim, GP, Pitot, HC, Philip, PA, Picus, J, Yong, WP, Horvath, L, Van Hazel, G, Erlichman, CE & Holen, KD 2010, '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', Journal of Clinical Oncology, vol. 28, no. 21, pp. 3491-3497. https://doi.org/10.1200/JCO.2010.28.4075
Lubner, Sam J. ; Mahoney, Michelle R. ; Kolesar, Jill L. ; LoConte, Noelle K. ; Kim, George P. ; Pitot, Henry Clement ; Philip, Philip A. ; Picus, Joel ; Yong, Wei Peng ; Horvath, Lisa ; Van Hazel, Guy ; Erlichman, Charles E. ; Holen, Kyle D. / 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. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 21. pp. 3491-3497.
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abstract = "Purpose: Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods: Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results: Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12{\%}; 95{\%} CI, 6{\%} to 27{\%}) had a confirmed partial response. Stable disease was documented in another 25 patients (51{\%}). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion: Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.",
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N2 - Purpose: Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods: Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results: Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion: Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

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