Skip to main content

Anti-EGFR Therapy in Gallbladder Cancer

  • Chapter
  • First Online:
Gallbladder Cancer

Abstract

The median overall survival in an advanced or metastatic gallbladder cancer (GBC) is less than a year. Attempts have been made to find various drugs to improve survival in these patients but so far the results are far from clinics. Epidermal Growth Factor Receptor (EGFR) is one of the receptors which is expressed in biliary tract cancers (BTCs), including gallbladder cancer (GBC). Various drugs targeting EGFR, i.e. Tyrosine Kinase Inhibitors (TKIs) and Monoclonal Antibodies (MABs), have been tried, mostly in combination with chemotherapy drugs since last decade with limited clinically meaningful outcomes. The previous studies on EGFR inhibitors have been disappointing but some of the new studies are ongoing which may throw some light in this dark tunnel. This chapter aims to provide an outline of anti-EGFR drugs tested in advanced/metastatic BTCs, including GBCs along with the summary of various clinical trials done and the new ones proposed on anti-EGFR drugs in this disease setting.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19:6550–65.

    Article  CAS  Google Scholar 

  2. Xu MJ, Johnson DE, Grandis JR. EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev. 2017;36(3):463–73.

    Article  Google Scholar 

  3. Song X, Hu Y, Li Y, et al. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther. 2020;5:230.

    Article  CAS  Google Scholar 

  4. Barreto SG, Dutt A, Chaudhary A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann Oncol. 2014;25:1086–97.

    Article  CAS  Google Scholar 

  5. Gomes RV, Vidigal PT, Damasceno KA, et al. Epidermal growth factor receptor (EGFR) in biliary tract cancer. HPB. 2016;18(S1):e385–601. E-Poster (No. EP03A-012).

    Google Scholar 

  6. Chen L, Chen C, Yen Y, Tam KW. Chemotherapy for advanced biliary tract carcinoma: a meta-analysis of randomized controlled trials. Medicine (Baltimore). 2016;95(33):e4584.

    Article  CAS  Google Scholar 

  7. Rizzo A, Frega G, Ricci AD, et al. Anti-EGFR monoclonal antibodies in advanced biliary tract cancer: a systematic review and meta-analysis. In Vivo. 2020;34(2):479–88.

    Article  CAS  Google Scholar 

  8. Zhang M, Cai S, Zuo B, et al. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway. Tumor Biol. 2017;39(5):1010428317698359.

    Article  Google Scholar 

  9. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 176870, Erlotinib; https://pubchem.ncbi.nlm.nih.gov/compound/Erlotinib. Accessed 12 Oct 2021.

  10. Kim TE, Murren JR. Erlotinib OSI/Roche/Genentech. Curr Opin Investig Drugs. 2002;3(9):1385–95.

    CAS  Google Scholar 

  11. Laird AD, Cherrington JM. Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs. 2003;12(1):51–64. https://doi.org/10.1517/13543784.12.1.51.

    Article  CAS  Google Scholar 

  12. Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In: Knollmann BC, Brunton LL, Hilal-Dandan R, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill Education; 2018. p. p1205–10.

    Google Scholar 

  13. Abdelgalil AA, Al-Kahtani HM, Al-Jenoobi FI. Erlotinib. Profiles Drug Subst Excip Relat Methodol. 2020;45:93–117. https://doi.org/10.1016/bs.podrm.2019.10.004. Epub 2019 Dec 6.

    Article  CAS  Google Scholar 

  14. Schaefer G, Shao L, Totpal K, Akita RW. Erlotinib directly inhibits HER2 kinase activation and downstream signaling events in intact cells lacking epidermal growth factor receptor expression. Cancer Res. 2007;67(3):1228–38. https://doi.org/10.1158/0008-5472.CAN-06-3493.

    Article  CAS  Google Scholar 

  15. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Erlotinib. https://www.ncbi.nlm.nih.gov/books/NBK548407/. Accessed 28 Jun 2018.

  16. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 123631, Gefitinib; https://pubchem.ncbi.nlm.nih.gov/compound/Gefitinib. Accessed 12 Oct 2021.

  17. Armour AA, Watkins CL. The challenge of targeting EGFR: experience with gefitinib in nonsmall cell lung cancer. Eur Respir Rev. 2010;19(117):186–96. https://doi.org/10.1183/09059180.00005110.

    Article  CAS  Google Scholar 

  18. Motiur Rahman AFM, Korashy HM, Kassem MG. Gefitinib. In: Brittain HG, editor. Profiles of drug substances, excipients and related methodology, vol. 39. London: Academic Press; 2014. p. 239–64.

    Google Scholar 

  19. Modjtahedi H, Cho BC, Michel MC, Solca F. A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer. Naunyn Schmiedebergs Arch Pharmacol. 2014;387(6):505–21. https://doi.org/10.1007/s00210-014-0967-3.

    Article  CAS  Google Scholar 

  20. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343(2):342–50. https://doi.org/10.1124/jpet.112.197756.

    Article  CAS  Google Scholar 

  21. Minkovsky N, Berezov A. BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Investig Drugs. 2008;9(12):1336–46.

    CAS  Google Scholar 

  22. AfatinibDimaleate. https://www.pharmacodia.com/yaodu/html/v1/chemicals/1175defd049d3301e047ce50d93e9c7a.html.

  23. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 10184653, Afatinib; https://pubchem.ncbi.nlm.nih.gov/compound/Afatinib. Accessed 12 Oct 2021.

  24. Shirley M. Dacomitinib: first global approval. Drugs. 2018;78(18):1947–53. https://doi.org/10.1007/s40265-018-1028-x.

    Article  Google Scholar 

  25. Jänne PA, Boss DS, Camidge DR, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011;17(5):1131–9.

    Article  Google Scholar 

  26. Grivas PD, Day KC, Karatsinides A, et al. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med. 2013;19:367–76.

    Article  Google Scholar 

  27. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 11511120, Dacomitinib; https://pubchem.ncbi.nlm.nih.gov/compound/Dacomitinib. Accessed 12 Oct 2021.

  28. Ruiz-Garcia A, Masters JC, Mendes da Costa L, et al. Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers. J Clin Pharmacol. 2016;56(2):223–30.

    Article  CAS  Google Scholar 

  29. Medina PJ, Goodin S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008;30(8):1426–47. https://doi.org/10.1016/j.clinthera.2008.08.008.

    Article  CAS  Google Scholar 

  30. National Center for Biotechnology Information. PubChem Compound Summary for CID 9941095, Lapatinib Ditosylate. 2021. https://pubchem.ncbi.nlm.nih.gov/compound/9941095. Accessed 20 Oct 2021.

  31. Voigtlaender M, Schneider-Merck T, Trepel M. Lapatinib. Recent Results Cancer Res. 2018;211:19–44. https://doi.org/10.1007/978-3-319-91442-8_2.

    Article  CAS  Google Scholar 

  32. Chidharla A, Parsi M, Kasi A. Cetuximab. 2021 Jul 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls; 2021. PMID: 29083635.

    Google Scholar 

  33. Panitumumab. https://www.cancerquest.org/patients/drug-reference/panitumumab.

  34. Chua YJ, Cunningham D. Panitumumab. Drugs Today (Barc). 2006;42(11):711–9. https://doi.org/10.1358/dot.2006.42.11.1032061.

    Article  CAS  Google Scholar 

  35. Commander H, Whiteside G, Perry C. Vandetanib: first global approval. Drugs. 2011;71(10):1355–65. https://doi.org/10.2165/11595310-000000000-00000.

  36. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 3081361, Vandetanib; https://pubchem.ncbi.nlm.nih.gov/compound/Vandetanib. Accessed 12 Oct 2021.

  37. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 42642648, Varlitinib; https://pubchem.ncbi.nlm.nih.gov/compound/Varlitinib. Accessed 12 Oct 2021.

  38. Deeks ED. Neratinib: first global approval. Drugs. 2017;77(15):1695–704. https://doi.org/10.1007/s40265-017-0811-4.

    Article  CAS  Google Scholar 

  39. Mody K, Strauss E, Lincer R, Frank RC. Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene: a case report. BMC Cancer. 2010;10:570. https://doi.org/10.1186/1471-2407-10-570.

    Article  CAS  Google Scholar 

  40. Soni K, Kumar T, Pandey M. Gallbladder cancer with EGFR mutation and its response to GemOx with erlotinib: a case report and review of literature. World J Surg Oncol. 2020;18(1):153. https://doi.org/10.1186/s12957-020-01934-4.

    Article  Google Scholar 

  41. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24:3069–74.

    Article  CAS  Google Scholar 

  42. Lee J, Park SH, Chang H-M, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13:181–8.

    Article  CAS  Google Scholar 

  43. Chiorean EG, Ramasubbaiah R, Yu M, et al. Phase II trial of erlotinib and docetaxel in advanced and refractory hepatocellular and biliary cancers: hoosier oncology group GI06-101. Oncologist. 2012;17(1):13.

    Article  Google Scholar 

  44. Nakajima Y, Takagi H, Kakizaki S, et al. Gefitinib and gemcitabine coordinately inhibited the proliferation of cholangiocarcinoma cells. Anticancer Res. 2012;32(12):5251–62.

    CAS  Google Scholar 

  45. Nam HJ, Kim HP, Yoon YK, et al. The irreversible pan-HER inhibitor PF00299804 alone or combined with gemcitabine has an antitumor effect in biliary tract cancer cell lines. Invest New Drugs. 2012;30(6):2148–60.

    Article  CAS  Google Scholar 

  46. Rubovszky G, Láng I, Ganofszky E, et al. Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study. Eur J Cancer. 2013;49(18):3806–12.

    Article  CAS  Google Scholar 

  47. Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.

    Article  CAS  Google Scholar 

  48. Chen JS, Hsu C, Chiang NJ, et al. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann Oncol. 2014;26:943–9.

    Article  Google Scholar 

  49. Sohal DPS, Mykulowycz K, Uehara T, et al. A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. Ann Oncol. 2013;24:3061–5.

    Article  CAS  Google Scholar 

  50. Ferraro D, Goldstein D, O'Connell RL, et al. Behalf of the Australasian gastro-intestinal trials group. TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer. Cancer Chemother Pharmacol. 2016;78(2):361–7.

    Article  CAS  Google Scholar 

  51. Hezel AF, Noel MS, Allen JN, et al. Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer. Br J Cancer. 2014;111(3):430–6.

    Article  CAS  Google Scholar 

  52. Leone F, Marino D, Cereda S, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122:574–81.

    Article  CAS  Google Scholar 

  53. Amin NEL, Hansen TF, Fernebro E, et al. Randomized phase II trial of combination chemotherapy with panitumumab or bevacizumab for patients with inoperable biliary tract cancer without KRAS exon 2 mutations. Int J Cancer. 2021;149:119–26.

    Article  CAS  Google Scholar 

  54. Peck J, Wei L, Zalupski M, et al. HER2/neu may not be an interesting target in biliary cancers: results of an early phase II study with lapatinib. Oncology. 2012;82(3):175–9.

    Article  CAS  Google Scholar 

  55. Ramanathan RK, Belani CP, Singh DA, et al. DR: a phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol. 2009;64:777–83.

    Article  CAS  Google Scholar 

  56. Santoro A, Gebbia V, Pressiani T, et al. A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: the VanGogh study. Ann Oncol. 2015;26:542–7.

    Article  CAS  Google Scholar 

  57. Kwak EL, Shapiro GI, Cohen SM, et al. Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation. Cancer. 2013;119(16):3043–51.

    Article  CAS  Google Scholar 

  58. Moehler M, Maderer A, Ehrlich A, et al. Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program. BMC Cancer. 2019;19(1):55.

    Article  Google Scholar 

  59. Javle MM, Oh D-Y, Ikeda M, et al. Results from TreeTopp: a randomized phase II study of the efficacy and safety of varlitinib plus capecitabine versus placebo in second-line (2L) advanced or metastatic biliary tract cancer (BTC). J Clin Oncol. 2020;38(15_suppl):4597. DOI: JCO.2020.38.15_suppl.4597.

    Article  Google Scholar 

  60. Harding JJ, Cleary JM, Quinn DI, et al. Targeting HER2 (ERBB2) mutation-positive advanced biliary tract cancers with neratinib: results from the phase II SUMMIT ‘basket’ trial. J Clin Oncol. 2021;39(3_suppl):320. https://doi.org/10.1200/JCO.2021.39.3_suppl.320.

    Article  Google Scholar 

  61. Guo Y, Feng K, Liu Y, et al. Phase I study of chimeric antigen receptor-modified T cells in patients with EGFR-positive advanced biliary tract cancers. Clin Cancer Res. 2018;24(6):1277–86.

    Article  CAS  Google Scholar 

  62. Smit EF, Baas P. Lung cancer in 2015: bypassing checkpoints, overcoming resistance, and honing in on new targets. Nat Rev Clin Oncol. 2016;13(2):75–6. https://doi.org/10.1038/nrclinonc.2015.223.

    Article  CAS  Google Scholar 

  63. Greig SL. Osimertinib: first global approval. Drugs. 2016;76(2):263–73. https://doi.org/10.1007/s40265-015-0533-4.

    Article  CAS  Google Scholar 

  64. Patel HM, Pawara R, Surana SJ. Chapter 2—approved and clinical trial third-generation EGFR inhibitors. In: Patel HM, Pawara R, Surana SJ, editors. Third Generation EGFR Inhibitors. Amsterdam: Elsevier; 2019. p. 25–43.

    Chapter  Google Scholar 

  65. Santarpia M, Liguori A, Karachaliou N, et al. Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy. Lung Cancer (Auckl). 2017;8:109–25. https://doi.org/10.2147/LCTT.S119644.

    Article  CAS  Google Scholar 

  66. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 71496458, Osimertinib; https://pubchem.ncbi.nlm.nih.gov/compound/Osimertinib. Accessed 12 Oct 2021.

  67. Kim ES. Olmutinib: first global approval. Drugs. 2016;76(11):1153–7. https://doi.org/10.1007/s40265-016-0606-z. Erratum in: Drugs 2016 Aug;76(12):1233.

    Article  CAS  Google Scholar 

  68. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem Compound Summary for CID 54758501, Olmutinib; https://pubchem.ncbi.nlm.nih.gov/compound/Olmutinib. Accessed 12 Oct 2021.

  69. Schmid S, Li JJN, Leighl NB. Mechanisms of osimertinib resistance and emerging treatment options. Lung Cancer. 2020;147:123–9. https://doi.org/10.1016/j.lungcan.2020.07.014.

    Article  Google Scholar 

  70. Syed YY. Amivantamab: first approval. Drugs. 2021;81(11):1349–53. https://doi.org/10.1007/s40265-021-01561-7.

    Article  CAS  Google Scholar 

  71. Dhillon S. Lazertinib: first approval. Drugs. 2021;81(9):1107–13. https://doi.org/10.1007/s40265-021-01533-x. Erratum in: Drugs. 2021 Jun 9.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bains, L., Chawla, T. (2023). Anti-EGFR Therapy in Gallbladder Cancer. In: Kumar Shukla, V., Pandey, M., Dixit, R. (eds) Gallbladder Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-19-6442-8_18

Download citation

  • DOI: https://doi.org/10.1007/978-981-19-6442-8_18

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-19-6441-1

  • Online ISBN: 978-981-19-6442-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics