Molecular Medicine

, Volume 18, Issue 11, pp 1473–1479 | Cite as

Trastuzumab-DM1: A Clinical Update of the Novel Antibody-Drug Conjugate for HER2-Overexpressing Breast Cancer

  • Myra F. Barginear
  • Veena John
  • Daniel R. Budman
Invited Review Article


Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-(3-mercapto-1-oxopropyl)-L-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.


  1. 1.
    Bross PF, et al. (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 7:1490–6.PubMedGoogle Scholar
  2. 2.
    Gopal AK, et al. (2012) Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012.120:560–8.CrossRefGoogle Scholar
  3. 3.
    Pro B, et al. (2012) Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J. Clin. Oncol. 30:2190–6.CrossRefGoogle Scholar
  4. 4.
    Mylotarg (gemtuzumab ozogamicin): market withdrawal [Internet]. Silver Spring (MD): FDA; [updated 2010 Jun 21; cited 2013 Jan 11]. Available from:
  5. 5.
    Senter PD. (2009) Potent antibody drug conjugates for cancer therapy. Curr. Opin. Chem. Biol. 13:235–44.CrossRefGoogle Scholar
  6. 6.
    Ducry L, Stump B. (2010) Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug. Chem. 21:5–13.CrossRefGoogle Scholar
  7. 7.
    Carter PJ, Senter PD. (2008) Antibody-drug conjugates for cancer therapy. Cancer J. 14:154–69.CrossRefGoogle Scholar
  8. 8.
    Higashide E, et al. (1977) Ansamitocin, a group of novel maytansinoid antibiotics with antitumour properties from Nocardia. Nature. 270:721–2.CrossRefGoogle Scholar
  9. 9.
    Yu TW, et al. (2002) The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum. Proc. Natl. Acad. Sci. U. S. A. 99:7968–73.CrossRefGoogle Scholar
  10. 10.
    Wang L, Amphlett G, Blattler WA, Lambert JM, Zhang W. (2005) Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Sci. 14:2436–46.CrossRefGoogle Scholar
  11. 11.
    Beeram M, et al. (2008) A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC). J. Clin. Oncol. 26(15 Suppl [May 20, 2008]). Abstr nr 1028.Google Scholar
  12. 12.
    Burris HA, et al. (2008) A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC). Abstract presented at: ASCO 2008 Breast Cancer Symposium. Abstr nr 155.Google Scholar
  13. 13.
    Carter P, Smith L, Ryan M. (2004) Identification and validation of cell surface antigens for antibody targeting in oncology. Endocr. Rel. Cancer. 11:659–87.CrossRefGoogle Scholar
  14. 14.
    Slamon DJ. (1987) Proto-oncogenes and human cancers. N. Engl. J. Med. 317:955–7.CrossRefGoogle Scholar
  15. 15.
    Sjogren S, Inganas M, Lindgren A, Holmberg L, Bergh J. (1998) Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J. Clin. Oncol. 16:462–9.CrossRefGoogle Scholar
  16. 16.
    Arteaga CL, et al. (2012) Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9:16–32.CrossRefGoogle Scholar
  17. 17.
    Piccart-Gebhart MJ, et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353:1659–72.CrossRefGoogle Scholar
  18. 18.
    Romond EH, et al. (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353:1673–84.CrossRefGoogle Scholar
  19. 19.
    Slamon DJ, Eiermann W, Robert N, et al. (2006) Second interim analysis phase III randomized trial comparing doxorubicin and cyclophos-phamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2neu positive early breast cancer patients. Breast Cancer Res. Treat. 100(1 Suppl). Abstr nr LBA 53. 94.Google Scholar
  20. 20.
    Joensuu H, et al. (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl. J. Med. 354:809–20.CrossRefGoogle Scholar
  21. 21.
    Tubbs RR, et al. (2007) Fluorescence in situ hybridization (FISH) as primary methodology for the assessment of HER2 status in adenocarcinoma of the breast: a single institution experience. Diagn. Mol. Path. 16:207–10.CrossRefGoogle Scholar
  22. 22.
    Ohlschlegel C, Zahel K, Kradolfer D, Hell M, Jochum W. (2011) HER2 genetic heterogeneity in breast carcinoma. J. Clin. Path. 64:1112–6.CrossRefGoogle Scholar
  23. 23.
    Yang YL, et al. (2012) Genetic heterogeneity of HER2 in breast cancer: impact on HER2 testing and its clinicopathologic significance. Breast Cancer Res. Treat. 134:1095–102.CrossRefGoogle Scholar
  24. 24.
    Drugs [Internet]. Silver Spring (MD): FDA; [updated 2013 Jan 10; cited 2013 Jan 11]. Available from:
  25. 25.
    Yamauchi C, et al. (2011) E-cadherin expression on human carcinoma cell affects trastuzumab-mediated antibody-dependent cellular cytotoxicity through killer cell lectin-like receptor G1 on natural killer cells. Int. J. Cancer. 128:2125–37.CrossRefGoogle Scholar
  26. 26.
    Miller TW, Rexer BN, Garrett JT, Arteaga CL. (2011) Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 13:224.CrossRefGoogle Scholar
  27. 27.
    Nahta R. (2012) Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance. Curr. Med. Chem. 19:1065–75.CrossRefGoogle Scholar
  28. 28.
    von Minckwitz G, et al. (2011) Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur. J. Cancer. 47:2273–81.CrossRefGoogle Scholar
  29. 29.
    von Minckwitz G, et al. (2009) Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03–05 study. J. Clin. Oncol. 27:1999–2006.CrossRefGoogle Scholar
  30. 30.
    Geyer CE, et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355:2733–43.CrossRefGoogle Scholar
  31. 31.
    Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J. (1998) Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 58:2825–31.PubMedGoogle Scholar
  32. 32.
    Pegram M, et al. (1999) Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 18:2241–51.CrossRefGoogle Scholar
  33. 33.
    Schechter AL, et al. (1984) The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 312:513–6.CrossRefGoogle Scholar
  34. 34.
    Lewis Phillips GD, et al. (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68:9280–90.CrossRefGoogle Scholar
  35. 35.
    Girish S, et al. (2012) Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother. Pharmacol. 69:1229–40.CrossRefGoogle Scholar
  36. 36.
    Erickson HK, et al. (2012) The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol. Cancer Ther. 11:1133–42.CrossRefGoogle Scholar
  37. 37.
    Holden SN, et al. (2008) A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients (pts) with advanced HER2+ breast cancer (BC). J. Clin. Oncol. 26(15 Suppl [May 20, 2008]). Abstr nr 1029.Google Scholar
  38. 38.
    LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. (2011) Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin. Cancer Res. 17:6437–47.CrossRefGoogle Scholar
  39. 39.
    Wong S, et al. (2011) Abstract A136: Nonclinical disposition, metabolism, and in vitro drug-drug interaction assessment of DM1, a component of trastuzumab emtansine (T-DM1). Mol. Cancer Ther. 2011;10(11 Suppl 1).Google Scholar
  40. 40.
    Dieras V, et al.(2010) Abstract P3-14-01: A phase Ib/II trial of trastuzumab-DM1 with pertuzumab for patients with HER2-positive, locally advanced or metastatic breast cancer: interim efficacy and safety results. Cancer Res. 70(24 Suppl 2).Google Scholar
  41. 41.
    Krop IE, et al. (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J. Clin. Oncol. 28:2698–704.CrossRefGoogle Scholar
  42. 42.
    Burris HA 3rd, et al. (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J. Clin. Oncol. 29:398–405.CrossRefGoogle Scholar
  43. 43.
    Krop IE, et al. (2012) A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J. Clin. Oncol. 30:3234–41.CrossRefGoogle Scholar
  44. 44.
    Dang C, et al. (2012) Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as adjuvant or neoadjuvant therapy for early-stage HER2-positive breast cancer. J. Clin. Oncol. 30(15 Suppl [May 20, 2012]). Abstr nr 532.Google Scholar
  45. 45.
    Telli ML, Hunt SA, Carlson RW, Guardino AE. (2007) Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J. Clin. Oncol. 25:3525–33.CrossRefGoogle Scholar
  46. 46.
    Seidman A, et al. (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 20:1215–21.CrossRefGoogle Scholar
  47. 47.
    Guglin M, Hartlage G, Reynolds C, Chen R, Patel V. (2009) Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study J. Card. Fail. 15:651–7.CrossRefGoogle Scholar
  48. 48.
    Hurvitz S, et al. (2011) Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously-untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g/B021976). Eur. J. Cancer. 47 Suppl 1:S330. Abstr nr 5001.CrossRefGoogle Scholar
  49. 49.
    Perez EA, et al. (2010) Efficacy and safety of trastuzumab-DM1 versus trastuzumab plus doxetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a randomized, multicenter, open-label phase 2 study (TDM4450G). Ann. Oncol. 21 Suppl 8:viii2. Abstr nr LBA3.Google Scholar
  50. 50.
    Blackwell KL, et al. (2012) Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. J. Clin. Oncol. 30(15 Suppl [May 20, 2012]). Abstr nr LBA1.Google Scholar
  51. 51.
    Ellis PA, et al. (2011) MARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC). J. Clin. Oncol. 29(15 Suppl [May 20, 2011]). Abstr nr TPS102.Google Scholar
  52. 52.
    A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-Positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-Directed Therapy (TH3RESA) [Internet]. Bethesda (MD): NIH; [study updated 2012 Dec 3; cited 2013 Jan 11]. Available from:
  53. 53.
    Elderly Metastatic Breast Cancer: Pertuzumab-Herceptin vs Pertuzumab-Herceptin-Metronomic Chemotherapy, Followed by T-DM1 [Internet]. Bethesda (MD): NIH; [study updated 2012 Jun 1; cited 2013 Jan 11]. Available from:
  54. 54.
    ImmunoGen, Inc. announces development of trastuzumab emtansine for early stage HER2-positive breast cancer [Internet]. 2012 Jun 3. Waltham (MA): ImmunoGen, Inc.; [cited 2013 Jan 11]. Available from:
  55. 55.
    Roche provides update on FDA application for T-DM1: Roche expects a global regulatory submission mid 2012 [Internet]. 2010 Aug 10. Basel: F. Hoffmann-La Roche Ltd.; [cited 2013 Jan 18]. Available from:–27.htm

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Authors and Affiliations

  • Myra F. Barginear
    • 1
  • Veena John
    • 1
  • Daniel R. Budman
    • 1
  1. 1.Monter Cancer Center of the North Shore-Long Island Jewish (LIJ) Cancer InstituteHofstra North Shore-LIJ School of MedicineLake SuccessUSA

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