Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 6, pp 1051–1057

A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer

  • Andrew H. Ko
  • Alan P. Venook
  • Emily K. Bergsland
  • R. Kate Kelley
  • W. Michael Korn
  • Elizabeth Dito
  • Brian Schillinger
  • Janet Scott
  • Jimmy Hwang
  • Margaret A. Tempero
Original Article



No standard of care exists for patients with metastatic pancreatic cancer following progression on first-line chemotherapy. Based on potential for additive or synergistic activity by concurrent inhibition of VEGF and EGFR, we conducted a phase II study evaluating the combination of bevacizumab plus erlotinib in this patient population.


Patients with metastatic pancreatic adenocarcinoma, ECOG performance status 0–1, and previous exposure to 1–3 systemic therapies (at least one gemcitabine-based) were eligible. Treatment consisted of bevacizumab 15 mg/kg every 21 days plus erlotinib 150 mg daily.


Thirty-six patients were enrolled, including eight who had previously received VEGF-targeted therapy and nine prior erlotinib. Median number of treatment cycles was 2 (range, 1–7). Common toxicities included rash (72%), diarrhea (25%), venous thromboembolic events (15%), and hypertension (11%). One patient demonstrated partial response and seven others stable disease for >2 cycles. CA19-9 decline ≥25% was observed in 4/26 patients with baseline levels >2x ULN. Estimated median time to progression was 40 days (95% CI, 35–41 days) and median survival 102 days (95% CI, 74–117 days), with a 6-month survival rate of 22%. Baseline concentration of circulating endothelial cells (CD45/CD34+/CD31+) was inversely associated with overall survival.


The combination of bevacizumab and erlotinib is safe but relatively ineffective in patients with gemcitabine-refractory metastatic pancreatic cancer. Future studies should focus on refining subsets of patients in this challenging population likely to benefit from treatment beyond first-line.


Bevacizumab Circulating endothelial cells Erlotinib Pancreatic cancer Phase II Refractory 


  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249CrossRefPubMedGoogle Scholar
  2. 2.
    Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8:82CrossRefPubMedGoogle Scholar
  3. 3.
    Louvet C, Labianca R, Hammel P et al (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516CrossRefPubMedGoogle Scholar
  4. 4.
    Heinemann V, Quietzsch D, Gieseler F et al (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24:3946–3952CrossRefPubMedGoogle Scholar
  5. 5.
    Moore MJ, Goldstein D, Hamm J et al (2007) 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 25:1960–1966CrossRefPubMedGoogle Scholar
  6. 6.
    Herrmann R, Bodoky G, Ruhstaller T et al (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25:2212–2217CrossRefPubMedGoogle Scholar
  7. 7.
    Schrag D, Archer L, Wang X, Romanus D (2007) A patterns-of-care study of post-progression treatment among patients with advanced pancreas cancer after gemcitabine therapy on Cancer and Leukemia Group B study #80303. J Clin Oncol 25(Suppl): (abstract 4524)Google Scholar
  8. 8.
    Kindler HL, Niedzwiecki D, Hollis D et al (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: a preliminary analysis of Cancer and Leukemia Group B. J Clin Oncol 25(Suppl): (abstract 4508)Google Scholar
  9. 9.
    Vervenne W, Bennouna J, Humblet Y et al (2008) A randomized, double-blind, placebo controlled, multicenter phase III trial to evaluate the efficacy and safety of adding bevacizumab to erlotinib and gemcitabine in patients with metastatic pancreatic cancer. J Clin Oncol 26(Suppl): (abstract 4507)Google Scholar
  10. 10.
    Ciardiello F, Bianco R, Damiano V et al (2000) Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6:3739–3747PubMedGoogle Scholar
  11. 11.
    Jung YD, Mansfield PF, Akagi M et al (2002) Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 38:1133–1140CrossRefPubMedGoogle Scholar
  12. 12.
    Bukowski RM, Kabbinavar FF, Figlin RA et al (2007) Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 25:4536–4541CrossRefPubMedGoogle Scholar
  13. 13.
    Cohen EE, Davis DW, Karrison TG et al (2009) Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 10:247–257CrossRefPubMedGoogle Scholar
  14. 14.
    Dickler MN, Rugo HS, Eberle CA et al (2008) A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res 14:7878–7883CrossRefPubMedGoogle Scholar
  15. 15.
    Herbst RS, O’Neill VJ, Fehrenbacher L et al (2007) Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol 25:4743–4750CrossRefPubMedGoogle Scholar
  16. 16.
    Pelzer U, Kubica K, Stieler J, Schwaner I (2008) A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. J Clin Oncol 26(Suppl): (abstract 4508)Google Scholar
  17. 17.
    Ciardiello F, Caputo R, Damiano V et al (2003) Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 9:1546–1556PubMedGoogle Scholar
  18. 18.
    Hirata A, Ogawa S, Kometani T, Kuwano T, Naito S, Kuwano M, Ono M (2002) ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62:2554–2560PubMedGoogle Scholar
  19. 19.
    Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523–1530PubMedGoogle Scholar
  20. 20.
    Kindler HL, Friberg G, Singh DA et al (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8040CrossRefPubMedGoogle Scholar
  21. 21.
    O’Reilly EM, Niedzwiecki D, Hollis DR et al (2008) A phase II trial of sunitinib in previously-treated pancreas adenocarcinoma, CALGB 80603. J Clin Oncol 26(Suppl): (abstract 4515)Google Scholar
  22. 22.
    Torrisi R, Bagnardi V, Cardillo A et al (2008) Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity. Br J Cancer 99:1564–1571CrossRefPubMedGoogle Scholar
  23. 23.
    Willett CG, Duda DG, di Tomaso E et al (2009) Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27:3020–3026CrossRefPubMedGoogle Scholar
  24. 24.
    Oettle H, Arnold D, Esser M, Huhn D, Riess H (2000) Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma. Anticancer Drugs 11:635–638CrossRefPubMedGoogle Scholar
  25. 25.
    Ulrich-Pur H, Raderer M, Verena Kornek G et al (2003) Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer 88:1180–1184CrossRefPubMedGoogle Scholar
  26. 26.
    Tsavaris N, Kosmas C, Skopelitis H et al (2005) Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: a phase II study. Invest New Drugs 23:369–375CrossRefPubMedGoogle Scholar
  27. 27.
    Burris HA III, Rivkin S, Reynolds R et al (2005) Phase II trial of oral rubitecan in previously treated pancreatic cancer patients. Oncologist 10:183–190CrossRefPubMedGoogle Scholar
  28. 28.
    Boeck S, Weigang-Kohler K, Fuchs M et al (2007) Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial. Ann Oncol 18:745–751CrossRefPubMedGoogle Scholar
  29. 29.
    Kulke MH, Blaszkowsky LS, Ryan DP et al (2007) Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 25:4787–4792CrossRefPubMedGoogle Scholar
  30. 30.
    Ko AH, Dito E, Schillinger B, Venook AP, Bergsland EK, Tempero MA (2008) Excess toxicity associated with docetaxel and irinotecan in patients with metastatic, gemcitabine-refractory pancreatic cancer: results of a phase II study. Cancer Invest 26:47–52CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Andrew H. Ko
    • 1
  • Alan P. Venook
    • 1
  • Emily K. Bergsland
    • 1
  • R. Kate Kelley
    • 1
  • W. Michael Korn
    • 1
  • Elizabeth Dito
    • 1
  • Brian Schillinger
    • 1
  • Janet Scott
    • 1
  • Jimmy Hwang
    • 1
  • Margaret A. Tempero
    • 1
  1. 1.University of California at San Francisco Helen Diller Family Comprehensive Cancer CenterSan FranciscoUSA

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