Skip to main content
SpringerLink
Log in

Targeting the Epidermal Growth Factor Receptor in Solid Tumor Malignancies

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

The epidermal growth factor receptor (EGFR) is over-expressed, as well as mutated, in many types of cancers. In particular, the EGFR variant type III mutant (EGFRvIII) has attracted much attention as it is frequently and exclusively found on many tumor cells, and hence both EGFR and EGFRvIII have been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Table II
Table III

Similar content being viewed by others

References

  1. Burgess AW. EGFR family: structure physiology signalling and therapeutic targets. Growth Factors 2008 Oct; 26 (5): 263–74

    Article  PubMed  CAS  Google Scholar 

  2. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005 May; 5 (5): 341–54

    Article  PubMed  CAS  Google Scholar 

  3. Ullrich A, Coussens L, Hayflick JS, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 1984; 309 (5967): 418–25

    Article  PubMed  CAS  Google Scholar 

  4. Cohen S, Ushiro H, Stoscheck C, et al. A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles. J Biol Chem 1982 Feb; 257 (3): 1523–31

    PubMed  CAS  Google Scholar 

  5. Lax I, Johnson A, Howk R, et al. Chicken epidermal growth factor (EGF) receptor: cDNA cloning, expression in mouse cells, and differential binding of EGF and transforming growth factor alpha. Mol Cell Biol 1988 May; 8 (5): 1970–8

    PubMed  CAS  Google Scholar 

  6. Lax I, Burgess WH, Bellot F, et al. Localization of a major receptor-binding domain for epidermal growth factor by affinity labeling. Mol Cell Biol 1988 Apr; 8 (4): 1831–4

    PubMed  CAS  Google Scholar 

  7. Carpenter G, Lembach KJ, Morrison MM, et al. Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts. J Biol Chem 1975 Jun; 250 (11): 4297–304

    PubMed  CAS  Google Scholar 

  8. Marquardt H, Hunkapiller MW, Hood LE, et al. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science 1984 Mar; 223 (4640): 1079–82

    Article  PubMed  CAS  Google Scholar 

  9. Shoyab M, Plowman GD, McDonald VL, et al. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 1989 Feb; 243 (4894 Pt 1): 1074–6

    Article  PubMed  CAS  Google Scholar 

  10. Lax I, Bellot F, Howk R, et al. Functional analysis of the ligand binding site of EGF-receptor utilizing chimeric chicken/human receptor molecules. EMBO J 1989 Feb; 8 (2): 421–7

    PubMed  CAS  Google Scholar 

  11. Watanabe T, Shintani A, Nakata M, et al. Recombinant human betacellulin: molecular structure, biological activities, and receptor interaction. J Biol Chem 1994 Apr; 269 (13): 9966–73

    PubMed  CAS  Google Scholar 

  12. Komurasaki T, Toyoda H, Uchida D, et al. Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4. Oncogene 1997 Dec; 15 (23): 2841–8

    Article  PubMed  CAS  Google Scholar 

  13. Higashiyama S, Abraham JA, Miller J, et al. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 1991 Feb; 251 (4996): 936–9

    Article  PubMed  CAS  Google Scholar 

  14. Bajaj M, Waterfield MD, Schlessinger J, et al. On the tertiary structure of the extracellular domains of the epidermal growth factor and insulin receptors. Biochim Biophys Acta 1987 Nov; 916 (2): 220–6

    Article  PubMed  CAS  Google Scholar 

  15. Weber W, Bertics PJ, Gill GN. Immunoaffinity purification of the epidermal growth factor receptor: stoichiometry of binding and kinetics of self-phosphorylation. J Biol Chem 1984 Dec; 259 (23): 14631–6

    PubMed  CAS  Google Scholar 

  16. Zhang X, Gureasko J, Shen K, et al. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006 Jun; 125 (6): 1137–49

    Article  PubMed  CAS  Google Scholar 

  17. Ferguson KM. Structure-based view of epidermal growth factor receptor regulation. Annu Rev Biophys 2008; 37: 353–73

    Article  PubMed  CAS  Google Scholar 

  18. Lu C, Mi LZ, Grey MJ, et al. Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor. Mol Cell Biol 2010 Nov; 30 (22): 5432–43

    Article  PubMed  CAS  Google Scholar 

  19. Chung I, Akita R, Vandlen R, et al. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature 2010 Apr; 464 (7289): 783–7

    Article  PubMed  CAS  Google Scholar 

  20. Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002 Nov; 277 (48): 46265–72

    Article  PubMed  CAS  Google Scholar 

  21. Honegger AM, Dull TJ, Felder S, et al. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 1987 Oct; 51 (2): 199–209

    Article  PubMed  CAS  Google Scholar 

  22. Honegger AM, Szapary D, Schmidt A, et al. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol Cell Biol 1987 Dec; 7 (12): 4568–71

    PubMed  CAS  Google Scholar 

  23. Chen WS, Lazar CS, Poenie M, et al. Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor. Nature 1987 Aug; 38 (6133): 820–3

    Article  Google Scholar 

  24. Reinehr R, Haussinger D. Epidermal growth factor receptor signaling in liver cell proliferation and apoptosis. Biol Chem 2009 Oct; 390 (10): 1033–7

    Article  PubMed  CAS  Google Scholar 

  25. Schneider MR, Sibilia M, Erben RG. The EGFR network in bone biology and pathology. Trends Endocrinol Metab 2009 Dec; 20 (10): 517–24

    Article  PubMed  CAS  Google Scholar 

  26. Wong RW. Transgenic and knock-out mice for deciphering the roles of EGFR ligands. Cell Mol Life Sci 2003 Jan; 60 (1): 113–8

    Article  PubMed  CAS  Google Scholar 

  27. Zandi R, Larsen AB, Andersen P, et al. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal 2007 Oct; 19 (10): 2013–23

    Article  PubMed  CAS  Google Scholar 

  28. Herbst RS, Langer CJ. Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers. Semin Oncol 2002 Feb; 29 (1 Suppl. 4): 27–36

    Article  PubMed  CAS  Google Scholar 

  29. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002 Mar; 94 (5): 1593–611

    Article  PubMed  CAS  Google Scholar 

  30. Petrides PE, Bock S, Bovens J, et al. Modulation of pro-epidermal growth factor, pro-transforming growth factor alpha and epidermal growth factor receptor gene expression in human renal carcinomas. Cancer Res 1990 Jul; 50 (13): 3934–9

    PubMed  CAS  Google Scholar 

  31. Yao M, Shuin T, Misaki H, et al. Enhanced expression of c-myc and epidermal growth factor receptor (C-erbB-1) genes in primary human renal cancer. Cancer Res 1988 Dec; 48 (23): 6753–7

    PubMed  CAS  Google Scholar 

  32. Hirsch FR, Scagliotti GV, Langer CJ, et al. Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer 2003 Aug; 41Suppl. 1: S29–42

    Article  PubMed  Google Scholar 

  33. Ge H, Gong X, Tang CK. Evidence of high incidence of EGFRvIII expression and coexpression with EGFR in human invasive breast cancer by laser capture microdissection and immunohistochemical analysis. Int J Cancer 2002 Mar; 98 (3): 357–61

    Article  PubMed  CAS  Google Scholar 

  34. Wong AJ, Bigner SH, Bigner DD, et al. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A 1987 Oct; 84 (19): 6899–903

    Article  PubMed  CAS  Google Scholar 

  35. Hatanpaa KJ, Burma S, Zhao D, et al. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia 2010 Sep; 12 (9): 675–84

    PubMed  CAS  Google Scholar 

  36. Merlino GT, Ishii S, Whang-Peng J, et al. Structure and localization of genes encoding aberrant and normal epidermal growth factor receptor RNAs from A431 human carcinoma cells. Mol Cell Biol 1985 Jul; 5 (7): 1722–34

    PubMed  CAS  Google Scholar 

  37. Batra SK, Castelino-Prabhu S, Wikstrand CJ, et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 1995 Oct; 6 (10): 1251–9

    PubMed  CAS  Google Scholar 

  38. Sugawa N, Ekstrand AJ, James CD, et al. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A 1990 Nov; 87 (21): 8602–6

    Article  PubMed  CAS  Google Scholar 

  39. Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995 Dec; 55 (23): 5536–9

    PubMed  CAS  Google Scholar 

  40. Wikstrand CJ, Reist CJ, Archer GE, et al. The class III variant of the epidermal growth factor receptor (EGFRvIII): characterization and utilization as an immunotherapeutic target. J Neurovirol 1998 Apr; 4 (2): 148–58

    Article  PubMed  CAS  Google Scholar 

  41. Okamoto I, Kenyon LC, Emlet DR, et al. Expression of constitutively activated EGFRvIII in non-small cell lung cancer. Cancer Sci 2003 Jan; 94 (1): 50–6

    Article  PubMed  CAS  Google Scholar 

  42. Tang CK, Gong XQ, Moscatello DK, et al. Epidermal growth factor receptor vIII enhances tumorigenicity in human breast cancer. Cancer Res 2000 Jun; 60 (11): 3081–7

    PubMed  CAS  Google Scholar 

  43. Olapade-Olaopa EO, Moscatello DK, MacKay EH, et al. Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer. Br J Cancer 2000 Jan; 82 (1): 186–94

    Article  PubMed  CAS  Google Scholar 

  44. Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 2006 Sep; 12 (17): 5064–73

    Article  PubMed  CAS  Google Scholar 

  45. Garcia de Palazzo IE, Adams GP, Sundareshan P, et al. Expression of mutated epidermal growth factor receptor by non-small cell lung carcinomas. Cancer Res 1993 Jul; 53 (14): 3217–20

    PubMed  CAS  Google Scholar 

  46. Wikstrand CJ, McLendon RE, Friedman AH, et al. Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res 1997 Sep; 57 (18): 4130–40

    PubMed  CAS  Google Scholar 

  47. Morinaga R, Okamoto I, Fujita Y, et al. Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer. Cancer Sci 2008 Dec; 9 (12): 2455–60

  48. Ekstrand AJ, James CD, Cavenee WK, et al. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 1991 Apr; 51 (8): 2164–72

    PubMed  CAS  Google Scholar 

  49. Heimberger AB, Hlatky R, Suki D, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 2005 Feb; 11 (4): 1462–6

    Article  PubMed  CAS  Google Scholar 

  50. Liu TF, Tatter SB, Willingham MC, et al. Growth factor receptor expression varies among high-grade gliomas and normal brain: epidermal growth factor receptor has excellent properties for interstitial fusion protein therapy. Mol Cancer Ther 2003 Aug; 2 (8): 783–7

    PubMed  CAS  Google Scholar 

  51. Hall WA, Merrill MJ, Walbridge S, et al. Epidermal growth factor receptors on ependymomas and other brain tumors. J Neurosurg 1990 Apr; 72 (4): 641–6

    Article  PubMed  CAS  Google Scholar 

  52. Heimberger AB, Suki D, Yang D, et al. The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med 2005 Oct 19; 3: 38

    Article  PubMed  CAS  Google Scholar 

  53. Agero AL, Dusza SW, Benvenuto-Andrade C, et al. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006 Oct; 55 (4): 657–70

    Article  PubMed  Google Scholar 

  54. Kawamoto T, Sato JD, Le A, et al. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A 1983 Mar; 80 (5): 1337–41

    Article  PubMed  CAS  Google Scholar 

  55. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995 Nov; 1 (11): 1311–8

    PubMed  CAS  Google Scholar 

  56. Li S, Schmitz KR, Jeffrey PD, et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 2005 Apr; 7 (4): 301–11

    Article  PubMed  CAS  Google Scholar 

  57. Jaramillo ML, Leon Z, Grothe S, et al. Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting. Exp Cell Res 2006 Sep 10; 312 (15): 2778–90

    Article  PubMed  CAS  Google Scholar 

  58. Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007 Mar; 13 (5): 1552–61

    Article  PubMed  CAS  Google Scholar 

  59. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004 Jul; 351 (4): 337–45

    Article  PubMed  CAS  Google Scholar 

  60. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009 Apr; 360 (14): 1408–17

    Article  PubMed  Google Scholar 

  61. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011 May; 29 (15): 2011–9

    Article  PubMed  CAS  Google Scholar 

  62. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009 Feb; 27 (5): 663–71

    Article  PubMed  CAS  Google Scholar 

  63. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011 Jul; 22 (7): 1535–46

    Article  PubMed  CAS  Google Scholar 

  64. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006 Feb; 354 (6): 567–78

    Article  PubMed  CAS  Google Scholar 

  65. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007 Jun; 25 (16): 2171–7

    Article  PubMed  CAS  Google Scholar 

  66. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008 Sep; 359 (11): 1116–27

    Article  PubMed  CAS  Google Scholar 

  67. Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010 Feb; 28 (6): 911–7

    Article  PubMed  CAS  Google Scholar 

  68. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009 May; 373 (9674): 1525–31

    Article  PubMed  CAS  Google Scholar 

  69. Hasselbalch B, Lassen U, Hansen S, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol 2010 May; 12 (5): 508–16

    PubMed  CAS  Google Scholar 

  70. Yang XD, Jia XC, Corvalan JR, et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999 Mar; 59 (6): 1236–43

    PubMed  CAS  Google Scholar 

  71. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007 May; 25 (13): 1658–64

    Article  PubMed  CAS  Google Scholar 

  72. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008 Apr; 26 (10): 1626–34

    Article  PubMed  CAS  Google Scholar 

  73. Van Cutsem E, Siena S, Humblet Y, et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol 2008 Jan; 19 (1): 92–8

    Article  PubMed  Google Scholar 

  74. Douillard JY, Salvatore S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010; 28 (31): 4697–705

    Article  PubMed  CAS  Google Scholar 

  75. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009 Feb; 27 (5): 672–80

    Article  PubMed  CAS  Google Scholar 

  76. Lammerts van Bueren JJ, Bleeker WK, Bogh HO, et al. Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action. Cancer Res 2006 Aug; 66 (15): 7630–8

    Article  PubMed  CAS  Google Scholar 

  77. Lammerts van Bueren JJ, Bleeker WK, Brannstrom A, et al. The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility. Proc Natl Acad Sci U S A 2008 Apr; 105 (16): 6109–14

    Article  PubMed  CAS  Google Scholar 

  78. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH, et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 2004 Oct; 173 (7): 4699–707

    PubMed  CAS  Google Scholar 

  79. Machiels JP, Subramanian S, Ruzsa A, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol 2011 Apr; 12 (4): 333–43

    Article  PubMed  CAS  Google Scholar 

  80. Li S, Kussie P, Ferguson KM. Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure 2008 Feb; 16 (2): 216–27

    Article  PubMed  CAS  Google Scholar 

  81. Dienstmann R, Tabernero J. Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer. Curr Opin Investig Drugs 2010 Dec; 11 (12): 1434–41

    PubMed  CAS  Google Scholar 

  82. Kuenen B, Witteveen PO, Ruijter R, et al. A phase I pharmacologic study of necitumumab (IMC-11F8), a fully human IgG1 monoclonal antibody directed against EGFR in patients with advanced solid malignancies. Clin Cancer Res 2010 Mar; 16 (6): 1915–23

    Article  PubMed  CAS  Google Scholar 

  83. Dienstmann R, Felip E. Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development. Expert Opin Biol Ther 2011 Sep; 11 (9): 1223–31

    Article  PubMed  CAS  Google Scholar 

  84. Murthy U, Basu A, Rodeck U, et al. Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide. Arch Biochem Biophys 1987 Feb; 252 (2): 549–60

    Article  PubMed  CAS  Google Scholar 

  85. Faillot T, Magdelenat H, Mady E, et al. A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas. Neurosurgery 1996 Sep; 39 (3): 478–83

    PubMed  CAS  Google Scholar 

  86. Wersall P, Fagerberg J, Ohlsson I, et al. Induction of a T- and B-cell response against a unique amino acid sequence of the mouse IgG2A hinge region in a MAb-treated patient. Int J Cancer 1997 Dec; 73 (6): 790–4

    Article  PubMed  CAS  Google Scholar 

  87. Wersall P, Ohlsson I, Biberfeld P, et al. Intratumoral infusion of the monoclonal antibody, mAb 425, against the epidermal-growth-factor receptor in patients with advanced malignant glioma. Cancer Immunol Immunother 1997 May; 44 (3): 157–64

    Article  PubMed  CAS  Google Scholar 

  88. Schmiedel J, Blaukat A, Li S, et al. Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization. Cancer Cell 2008 Apr; 13 (4): 365–73

    Article  PubMed  CAS  Google Scholar 

  89. Takeda Pharmaceutical Company Limited. Takeda discontinues development of matuzumab [media release]. 2008 Feb 18 [online]. Available from URL: http://www.takeda.com/press/article_29042.html [Accessed 2012 Feb 1]

  90. Boland W, Bebb G. The emerging role of nimotuzumab in the treatment of non-small cell lung cancer. Biologics 2010; 4: 289–98

    PubMed  CAS  Google Scholar 

  91. Mateo C, Moreno E, Amour K, et al. Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: recovery of antagonistic activity. Immunotechnology 1997 Mar; 3 (1): 71–81

    Article  PubMed  CAS  Google Scholar 

  92. Diaz Miqueli A, Blanco R, Garcia B, et al. Biological activity in vitro of anti-epidermal growth factor receptor monoclonal antibodies with different affinities. Hybridoma (Larchmt) 2007 Dec; 26 (6): 423–31

    Article  CAS  Google Scholar 

  93. Choi HJ, Sohn JH, Lee CG, et al. A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung Cancer 2011 Jan; 71 (1): 55–9

    Article  PubMed  Google Scholar 

  94. Strumberg D, Schultheis B, Scheulen ME, et al. Phase II study of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer. Invest New Drugs. Epub 2010 Dec 21

  95. Bebb G, Smith C, Rorke S, et al. Phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab with concurrent external thoracic radiotherapy in Canadian patients diagnosed with stage IIb, III or IV non-small cell lung cancer unsuitable for radical therapy. Cancer Chemother Pharmacol 2011 Apr; 67 (4): 837–45

    Article  PubMed  CAS  Google Scholar 

  96. You B, Brade A, Magalhaes JM, et al. A dose-escalation phase I trial of nimotuzumab, an antibody against the epidermal growth factor receptor, in patients with advanced solid malignancies. Invest New Drugs 2011 Oct; 29 (5): 996–1003

    Article  PubMed  CAS  Google Scholar 

  97. Garrido G, Tikhomirov IA, Rabasa A, et al. Bivalent binding by intermediate affinity of nimotuzumab: a contribution to explain antibody clinical profile. Cancer Biol Ther 2011 Feb; 11 (4): 373–82

    Article  PubMed  CAS  Google Scholar 

  98. Pedersen MW, Jacobsen HJ, Koefoed K, et al. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Research 2010 Jan; 70 (2): 588–97

    Article  PubMed  CAS  Google Scholar 

  99. Skartved NJ, Jacobsen HJ, Pedersen MW, et al. Preclinical pharmacokinetics and safety of Sym004: a synergistic antibody mixture directed against epidermal growth factor receptor. Clin Cancer Res 2011 Sep; 17 (18): 5962–72

    Article  PubMed  CAS  Google Scholar 

  100. Mamot C, Drummond DC, Greiser U, et al. Epidermal growth factor receptor (EGFR)-targeted immunoliposomes mediate specific and efficient drug delivery to EGFR- and EGFRvIII-overexpressing tumor cells. Cancer Res 2003 Jun; 63 (12): 3154–61

    PubMed  CAS  Google Scholar 

  101. Mamot C, Ritschard R, Kung W, et al. EGFR-targeted immunoliposomes derived from the monoclonal antibody EMD72000 mediate specific and efficient drug delivery to a variety of colorectal cancer cells. J Drug Target 2006 May; 14 (4): 215–23

    Article  PubMed  CAS  Google Scholar 

  102. Yang L, Mao H, Wang YA, et al. Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. Small 2009 Feb; 5 (2): 235–43

    Article  PubMed  CAS  Google Scholar 

  103. Brady LW, Markoe AM, Woo DV, et al. Iodine125 labeled anti-epidermal growth factor receptor-425 in the treatment of malignant astrocytomas: a pilot study. J Neurosurg Sci 1990 Jul–Dec; 34 (3–4): 243–9

    PubMed  CAS  Google Scholar 

  104. Li L, Quang TS, Gracely EJ, et al. A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. J Neurosurg 2010 Aug; 113 (2): 192–8

    Article  PubMed  Google Scholar 

  105. Drexel University. Access protocol for MAB-425 radiolabeled with I-125 for high grade gliomas [ClinicalTrials.gov identifier NCT01317888]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2012 Feb 1]

  106. Torres LA, Perera A, Batista JF, et al. Phase I/II clinical trial of the humanized anti-EGF-r monoclonal antibody h-R3 labelled with 99mTc in patients with tumour of epithelial origin. Nucl Med Commun 2005 Dec; 26 (12): 1049–57

    Article  PubMed  CAS  Google Scholar 

  107. Casaco A, Lopez G, Garcia I, et al. Phase I single-dose study of intracavitary-administered Nimotuzumab labeled with 188 Re in adult recurrent high-grade glioma. Cancer Biol Ther 2008 Mar; 7 (3): 333–9

    Article  PubMed  CAS  Google Scholar 

  108. Crombet T, Torres L, Neninger E, et al. Pharmacological evaluation of humanized anti-epidermal growth factor receptor, monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer. J Immunother 2003 Mar–Apr; 26 (2): 139–48

    Article  PubMed  CAS  Google Scholar 

  109. Crombet T, Torres O, Rodriguez V, et al. Phase I clinical evaluation of a neutralizing monoclonal antibody against epidermal growth factor receptor in advanced brain tumor patients: preliminary study. Hybridoma 2001 Apr; 20 (2): 131–6

    Article  PubMed  CAS  Google Scholar 

  110. Crombet T, Torres O, Neninger E, et al. Phase I clinical evaluation of a neutralizing monoclonal antibody against epidermal growth factor receptor. Cancer Biother Radiopharm 2001 Feb; 16 (1): 93–102

    Article  PubMed  CAS  Google Scholar 

  111. Allen C, Vongpunsawad S, Nakamura T, et al. Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity. Cancer Res 2006 Dec; 66 (24): 11840–50

    Article  PubMed  CAS  Google Scholar 

  112. Phuong LK, Allen C, Peng KW, et al. Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res 2003 May; 63 (10): 2462–9

    PubMed  CAS  Google Scholar 

  113. Myers R, Harvey M, Kaufmann TJ, et al. Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas. Hum Gene Ther 2008 Jul; 19 (7): 690–8

    Article  PubMed  CAS  Google Scholar 

  114. Paraskevakou G, Allen C, Nakamura T, et al. Epidermal growth factor receptor (EGFR)-retargeted measles virus strains effectively target EGFR- or EGFRvIII expressing gliomas. Mol Ther 2007 Apr; 15 (4): 677–86

    PubMed  CAS  Google Scholar 

  115. Mayo Clinic. Viral therapy in treating patients with recurrent glioblastoma multiforme [ClinicalTrials.gov identifier NCT00390299]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2012 Feb 1]

  116. Mathew M, Verma RS. Humanized immunotoxins: a new generation of immunotoxins for targeted cancer therapy. Cancer Sci 2009 Aug; 100 (8): 1359–65

    Article  PubMed  CAS  Google Scholar 

  117. Pastan I. Targeted therapy of cancer with recombinant immunotoxins. Biochim Biophys Acta 1997 Oct; 1333 (2): C1–6

    PubMed  CAS  Google Scholar 

  118. Pastan I, Hassan R, Fitzgerald DJ, et al. Immunotoxin therapy of cancer. Nat Rev Cancer 2006 Jul; 6 (7): 559–65

    Article  PubMed  CAS  Google Scholar 

  119. Kounnas MZ, Morris RE, Thompson MR, et al. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem 1992 Jun; 267 (18): 12420–3

    PubMed  CAS  Google Scholar 

  120. Ogata M, Chaudhary VK, Pastan I, et al. Processing of Pseudomonas exotoxin by a cellular protease results in the generation of a 37,000-Da toxin fragment that is translocated to the cytosol. J Biol Chem 1990 Nov; 265 (33): 20678–85

    Google Scholar 

  121. Iglewski BH, Liu PV, Kabat D. Mechanism of action of Pseudomonas aeruginosa exotoxin Aiadenosine diphosphate-ribosylation of mammalian elongation factor 2 in vitro and in vivo. Infect Immun 1977 Jan; 15 (1): 138–44

    PubMed  CAS  Google Scholar 

  122. Duke University. Study of Immunotoxin, MR1-1 [ClinicalTrials.gov identifier NCT01009866]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2012 Feb 1]

  123. Kuan CT, Wikstrand CJ, Archer G, et al. Increased binding affinity enhances targeting of glioma xenografts by EGFRvIII-specific scFv. Int J Cancer 2000 Dec 15; 88 (6): 962–9

    Article  PubMed  CAS  Google Scholar 

  124. Humphrey PA, Wong AJ, Vogelstein B, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A 1990 Jun; 87 (11): 4207–11

    Article  PubMed  CAS  Google Scholar 

  125. Beers R, Chowdhury P, Bigner D, et al. Immunotoxins with increased activity against epidermal growth factor receptor vIII-expressing cells produced by antibody phage display. Clin Cancer Res 2000 Jul; 6 (7): 2835–43

    PubMed  CAS  Google Scholar 

  126. Sampson JH, Akabani G, Archer GE, et al. Progress report of a phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 2003 Oct; 65 (1): 27–35

    Article  PubMed  Google Scholar 

  127. Sampson JH, Reardon DA, Friedman AH, et al. Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study. Neuro Oncol 2005 Jan; 7 (1): 90–6

    Article  PubMed  Google Scholar 

  128. Sampson JH, Akabani G, Archer GE, et al. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro Oncol 2008 Jun; 10 (3): 320–9

    Article  PubMed  CAS  Google Scholar 

  129. Yu JS, Wheeler CJ, Zeltzer PM, et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 2001 Feb; 61 (3): 842–7

    PubMed  CAS  Google Scholar 

  130. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 2005 Aug; 11 (15): 5515–25

    Article  PubMed  CAS  Google Scholar 

  131. Wheeler CJ, Black KL, Liu G, et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 2008 Jul; 68 (14): 5955–64

    Article  PubMed  CAS  Google Scholar 

  132. De Vleeschouwer S, Fieuws S, Rutkowski S, et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 2008 May; 14 (10): 3098–104

    Article  PubMed  Google Scholar 

  133. Mackensen A, Herbst B, Chen JL, et al. Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34 (+) hematopoietic progenitor cells. Int J Cancer 2000 May; 86 (3): 385–92

    Article  PubMed  CAS  Google Scholar 

  134. Caruso DA, Orme LM, Neale AM, et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro Oncol 2004 Jul; 6 (3): 236–46

    Article  PubMed  CAS  Google Scholar 

  135. Mitchell DA, Cui X, Schmittling RJ, et al. Monoclonal antibody blockade of IL-2 receptor a during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood 2011 Sep; 118 (11): 3003–12

    Article  PubMed  CAS  Google Scholar 

  136. Sampson JH, Archer GE, Mitchell DA, et al. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 2008 Oct; 20 (5): 267–75

    Article  PubMed  CAS  Google Scholar 

  137. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 2010 Nov; 28 (31): 4722–9

    Article  PubMed  Google Scholar 

  138. Schmittling RJ, Archer GE, Mitchell DA, et al. Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods 2008 Nov; 339 (1): 74–81

    Article  PubMed  CAS  Google Scholar 

  139. Pfizer Inc. Notice of 2011 Annual Meeting of Shareholders and Proxy Statement. 2011 Mar 22 [online]. Available from URL: http://www.pfizer.com/files/annualreport/2010/proxy/proxyfinancial2010.pdf [Accessed 2012 Feb 1]

  140. Hartmann JT, Haap M, Kopp HG, et al. Tyrosine kinase inhibitors: a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009 Jun; 10 (5): 470–81

    Article  PubMed  CAS  Google Scholar 

  141. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009 Jan; 9 (1): 28–39

    Article  PubMed  CAS  Google Scholar 

  142. El-Rayes BF, LoRusso PM. Targeting the epidermal growth factor receptor. Br J Cancer 2004 Aug; 91 (3): 418–24

    Article  PubMed  CAS  Google Scholar 

  143. Giaccone G, Wang Y. Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitors. Cancer Treat Rev 2011 Oct; 37 (6): 456–64

    PubMed  CAS  Google Scholar 

  144. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003 Jun; 21 (12): 2237–46

    Article  PubMed  CAS  Google Scholar 

  145. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003 Oct; 290 (16): 2149–58

    Article  PubMed  CAS  Google Scholar 

  146. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366 (9496): 1527–37

    Article  PubMed  CAS  Google Scholar 

  147. Comis RL. The current situation: erlotinib (Tarceva) and gefitinib (Iressa) in non-small cell lung cancer. Oncologist 2005 Aug; 10 (7): 467–70

    Article  PubMed  CAS  Google Scholar 

  148. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009 Sep; 361 (10): 947–57

    Article  PubMed  CAS  Google Scholar 

  149. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004 May; 350 (21): 2129–39

    Article  PubMed  CAS  Google Scholar 

  150. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 Jun; 304 (5676): 1497–500

    Article  PubMed  CAS  Google Scholar 

  151. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial — INTACT 1. J Clin Oncol 2004 Mar; 22 (5): 777–84

    Article  PubMed  CAS  Google Scholar 

  152. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial — INTACT 2. J Clin Oncol 2004 Mar; 22 (5): 785–94

    Article  PubMed  CAS  Google Scholar 

  153. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009 Apr; 27 (11): 1864–71

    Article  PubMed  CAS  Google Scholar 

  154. Vieitez JM, Valladares M, Pelaez I, et al. A randomized phase II study of raltitrexed and gefitinib versus raltitrexed alone as second line chemotherapy in patients with colorectal cancer. (1839IL/0143). Invest New Drugs 2011 Oct; 29 (5): 1038–44

    Article  PubMed  CAS  Google Scholar 

  155. Ciardiello F, Troiani T, Caputo F, et al. Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer. Br J Cancer 2006 Jun; 94 (11): 1604–9

    PubMed  CAS  Google Scholar 

  156. Dennison SK, Jacobs SA, Wilson JW, et al. A phase II clinical trial of ZD1839 (Iressa) in combination with docetaxel as first-line treatment in patients with advanced breast cancer. Invest New Drugs 2007 Dec; 25 (6): 545–51

    Article  PubMed  CAS  Google Scholar 

  157. Baselga J, Albanell J, Ruiz A, et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 2005 Aug; 23 (23): 5323–33

    Article  PubMed  CAS  Google Scholar 

  158. Cristofanilli M, Valero V, Mangalik A, et al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 2010 Mar; 16 (6): 1904–14

    Article  PubMed  CAS  Google Scholar 

  159. Bernsdorf M, Ingvar C, Jorgensen L, et al. Effect of adding gefitinib to neo-adjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial. Breast Cancer Res Treat 2011 Apr; 126 (2): 463–70

    Article  PubMed  CAS  Google Scholar 

  160. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005 Jul; 353 (2): 123–32

    Article  PubMed  CAS  Google Scholar 

  161. Tran HT, Zinner RG, Blumenschein Jr GR, et al. Pharmacokinetic study of the phase III, randomized, double-blind, multicenter trial (TRIBUTE) of paclitaxel and carboplatin combined with erlotinib or placebo in patients with advanced Non-small Cell Lung Cancer (NSCLC). Invest New Drugs 2011 Jun; 29 (3): 499–505

    Article  PubMed  CAS  Google Scholar 

  162. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005 Sep; 23 (25): 5892–9

    Article  PubMed  CAS  Google Scholar 

  163. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007 Apr; 25 (12): 1545–52

    Article  PubMed  CAS  Google Scholar 

  164. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010 Jun; 11 (6): 521–9

    Article  PubMed  CAS  Google Scholar 

  165. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 2011 May; 377 (9780): 1846–54

    Article  PubMed  CAS  Google Scholar 

  166. Moore MJ, Goldstein D, Hamm J, 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 May; 25 (15): 1960–6

    Article  PubMed  CAS  Google Scholar 

  167. Wood ER, Truesdale AT, McDonald OB, et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004 Sep; 64 (18): 6652–9

    Article  PubMed  CAS  Google Scholar 

  168. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New Engl J Med 2006 Dec; 355 (26): 2733–43

    Article  PubMed  CAS  Google Scholar 

  169. Burris 3rd HA. Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 2004; 9Suppl. 3: 10–5

    Article  PubMed  CAS  Google Scholar 

  170. Castellino S, O’Mara M, Koch K, et al. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab Dispos 2012 Jan; 40 (1): 139–50

    Article  PubMed  CAS  Google Scholar 

  171. Wong KK, Fracasso PM, Bukowski RM, et al. A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin Cancer Res 2009 Apr; 15 (7): 2552–8

    Article  PubMed  CAS  Google Scholar 

  172. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol 2010 Jun; 28 (18): 3076–83

    Article  PubMed  CAS  Google Scholar 

  173. Metro G, Crino L. The LUX-Lung clinical trial program of afatinib for non-small-cell lung cancer. Expert Rev Anticancer Ther 2011 May; 11 (5): 673–82

    Article  PubMed  CAS  Google Scholar 

  174. Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol 2001 Oct; 28 (5 Suppl. 16): 80–5

    Article  PubMed  CAS  Google Scholar 

  175. Rixe O, Franco SX, Yardley DA, et al. A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother Pharmacol 2009 Nov; 64 (6): 1139–48

    Article  PubMed  CAS  Google Scholar 

  176. Janne PA, von Pawel J, Cohen RB, et al. Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non small-cell lung cancer. J Clin Oncol 2007 Sep; 25 (25): 3936–44

    Article  PubMed  CAS  Google Scholar 

  177. Campos S, Hamid O, Seiden MV, et al. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J Clin Oncol 2005 Aug; 23 (24): 5597–604

    Article  PubMed  CAS  Google Scholar 

  178. Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002 Dec; 62 (24): 7284–90

    PubMed  CAS  Google Scholar 

  179. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002 Aug; 62 (16): 4645–55

    PubMed  CAS  Google Scholar 

  180. Ciardiello F, Caputo R, Damiano V, et al. 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 2003 Apr; 9 (4): 1546–56

    PubMed  CAS  Google Scholar 

  181. Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010 Jul; 11 (7): 619–26

    Article  PubMed  CAS  Google Scholar 

  182. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011 Mar; 29 (8): 1059–66

    Article  PubMed  CAS  Google Scholar 

  183. de Boer RH, Arrieta O, Yang CH, et al. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011 Mar; 29 (8): 1067–74

    Article  PubMed  CAS  Google Scholar 

  184. Soria JC, Cortes J, Massard C, et al. Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors. Ann Oncol 2012 Feb; 23 (2): 463–71

    Article  PubMed  Google Scholar 

  185. Wong NS, Fernando NH, Nixon AB, et al. A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer. Anticancer Res 2011 Jan; 31 (1): 255–61

    PubMed  CAS  Google Scholar 

  186. Spigel DR, Greco FA, Waterhouse D, et al. Phase II trial of FOLFOX6, bevacizumab, and cetuximab in the first-line treatment of metastatic colorectal cancer. Clin Adv Hematol Oncol 2010 Jul; 8 (7): 480–5, 98

    PubMed  Google Scholar 

  187. Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells — perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006 Oct; 66 (19): 9339–44

    Article  PubMed  CAS  Google Scholar 

  188. Van Meir EG, Hadjipanayis CG, Norden AD, et al. Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 2010 May–Jun; 60 (3): 166–93

    Article  PubMed  Google Scholar 

  189. Goldman B, DeFrancesco L. The cancer vaccine roller coaster. Nat Biotechnol 2009 Feb; 27 (2): 129–39

    Article  PubMed  CAS  Google Scholar 

  190. Salemi S, D’Amelio R. Could autoimmunity be induced by vaccination? Int Rev Immunol 2010 Jun; 29 (3): 247–69

    Article  PubMed  CAS  Google Scholar 

  191. Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 2005 Aug; 54 (8): 721–8

    Article  PubMed  CAS  Google Scholar 

  192. Khoruts A, Fraser JM. A causal link between lymphopenia and autoimmunity. Immunol Lett 2005 Apr; 98 (1): 23–31

    Article  PubMed  CAS  Google Scholar 

  193. Krupica Jr T, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 2006 Aug; 120 (2): 121–8

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

The authors would like to thank Marie-Thérése Stockhausen for her editorial support in the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiation Biology, the Finsencenter, Copenhagen University Hospital, Section 6321, Blegdamsvej 9, DK-2100, Rigshospitalet, Copenhagen, Denmark

    Mette K. Nedergaard, Chris J. Hedegaard &  Hans S. Poulsen

Authors
  1. Mette K. Nedergaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chris J. Hedegaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans S. Poulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans S. Poulsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nedergaard, M.K., Hedegaard, C.J. & Poulsen, H.S. Targeting the Epidermal Growth Factor Receptor in Solid Tumor Malignancies. BioDrugs 26, 83–99 (2012). https://doi.org/10.2165/11599760-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11599760-000000000-00000

Keywords

Search

Navigation