Trastuzumab emtansine: the first targeted chemotherapy for treatment of breast cancer

Parvin F Peddi, Sara A Hurvitz, Parvin F Peddi, Sara A Hurvitz

Abstract

Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate, comprised of a potent cytotoxic drug connected via a stable linker to the anti-HER2 antibody, trastuzumab, thereby primarily targeting chemotherapy delivery to cells overexpressing the HER2 receptor. A Phase II randomized trial of T-DM1 in the front-line metastatic breast cancer setting revealed promising activity and improved safety compared with standard chemotherapy plus trastuzumab. Subsequently, a Phase III trial in patients with trastuzumab-pretreated metastatic breast cancer showed T-DM1 to be associated with prolonged progression-free and overall survival compared with lapatinib plus capecitabine. T-DM1 represents a major shift in the treatment of patients with breast cancer as it replaces traditional nontargeted chemotherapy with a 'smart' medication that directs the cytotoxic therapy to cancer cells by using a known biomarker.

Figures

Figure 1. Structure of trastuzumab emtansine and…
Figure 1. Structure of trastuzumab emtansine and mechanisms of action
After T-DM1 binds HER2, the HER2–T-DM1 complex undergoes internalization, followed by lysosomal degradation. This process results in the intracellular release of DM1-containing catabolites that bind to tubulin and prevent microtubule polymerization, as well as suppress microtubule dynamic instability. T-DM1 has also been shown to retain mechanisms of action of trastuzumab, including disruption of the HER3/PI3K/AKT signaling pathway and FCγ receptor-mediated engagement of immune effector cells that leads to antibody-dependent cellular cytotoxicity. ADCC: Antibody-dependent cellular cytotoxicity; Lys: Lysine; T-DM1: Trastuzumab emtansine.

References

    1. Slamon DJ, Gary CM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–182.
    1. Arteaga CL, Sliwkowski MX, Osborne CK, et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 2012;9(1):16–32.
    1. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 2011;365(14):1273–1283.
    1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 2001;344:783–792.
    1. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 1999;17(9):2639–2648.
    1. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2006;355(26):2733–2743.
    1. Johnston S, Pippen J, Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J. Clin. Oncol. 2009;27(33):5538–5546.
    1. Gomez HL, Doval DC, Chavez MA, et al. Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J. Clin. Oncol. 2008;26(18):2999–3005.
    1. Burris HA, 3rd, Hurwitz HI, Dees EC, et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J. Clin. Oncol. 2005;23(23):5305–5313.
    1. Burstein HJ, Storniolo AM, Franco S, et al. A Phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann. Oncol. 2008;19(6):1068–1074.
    1. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 2010;28(7):1124–1130.
    1. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5(4):317–328.
    1. Gradishar WJ. HER2 therapy – an abundance of riches. N. Engl. J. Med. 2012;366(2):176–178.
    1. Cortés J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 2012;30(14):1594–1600.
    1. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J. Clin. Oncol. 2010;28(7):1138–1144.
    1. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 2012;366(2):109–119.
    1. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, Phase 2 trial. Lancet Oncol. 2012;13(1):25–32.
    1. Nahta R, Yu D, Hung M-C, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol. 2006;3(5):269–280.
    1. Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin. Cancer Res. 2007;13(16):4909–4919.
    1. Chandarlapaty S, Sakr RA, Giri D, et al. Frequent mutational activation of the PI3K–AKT pathway in trastuzumab-resistant breast cancer. Clin. Cancer Res. 2012;18(24):6784–6791.
    1. Eichhorn PJA, Gili M, Scaltriti M, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68(22):9221–9230.
    1. Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127.
    1. Kupchan SM, Komoda Y, Court WA, et al. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J. Am. Chem. Soc. 1972;94(4):1354–1356.
    1. Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumor inhibitor maytansine. Science. 1975;189(4207):1002–1005.
    1. Cassady JM, Chan KK, Floss HG, Leistner E. Recent developments in the maytansinoid antitumor agents. Chem. Pharm. Bull. (Tokyo) 2004;52(1):1–26.
    1. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat. 2011;128(2):347–356.
    1. Venter DJ, Tuzi NL, Kumar S, Gullick WJ. Overexpression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistological assessment correlates with gene amplification. Lancet. 1987;2(8550):69–72.

    1. Phillips GDL, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody–cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280–9290. ▪▪ Describes the rational design and first preclinical data of trastuzumab emtansine (T-DM1).

    1. Hudis CA. Trastuzumab – mechanism of action and use in clinical practice. N. Engl. J. Med. 2007;357(1):39–51.
    1. Erickson HK, Park PU, Widdison WC, et al. Antibody–maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66(8):4426–4433.
    1. Xie H, Audette C, Hoffee M, Lambert JM, Blättler WA. Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J. Pharmacol. Exp. Ther. 2004;308(3):1073–1082.
    1. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15(5):429–440.
    1. Girish S, Gupta M, Wang B, et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother. Pharmacol. 2012;69(5):1229–1240.
    1. Gupta M, Lorusso PM, Wang B, et al. Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer. J. Clin. Pharmacol. 2012;52(5):691–703.
    1. Shen B-Q, Bumbaca D, Saad O, et al. Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism. Curr. Drug Metab. 2012;13(7):901–910.

    1. Krop IE, Beeram M, Modi S, et al. 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. 2010;28(16):2698–2704. ▪▪ First in-human use of T-DM1 and trial identifying dose used in subsequent studies.

    1. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. 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. 2011;29(4):398–405.

    1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012;367(19):1783–1791. ▪▪ Landmark EMILIA trial establishing superiority of T-DM1 to lapatinib–capecitabine in previously treated HER2-amplified patients.

    1. Wong S, Bumbaca D, Yue Q, et al. Nonclinical disposition, metabolism, and in vitro drug–drug interaction assessment of DM1, a component of trastuzumab emtansine (T-DM1) Mol. Cancer Ther. 2011;10(Suppl. 1):A136–A136. (Abstract A136)
    1. Beeram M, Krop IE, Burris HA, et al. A Phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer. 2012;118(23):5733–5740.
    1. Krop IE, LoRusso P, Miller KD, et al. 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. 2012;30(26):3234–3241.

    1. Hurvitz SA, Dirix L, Kocsis J, et al. Trastuzumab emtansine (T-DM1) versus trastuzumab + docetaxel in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label Phase II study (TDM4450g/BO21976) Eur. J. Cancer. 2011;47(Suppl. 1):330. (Abstract 5001) ▪▪Only reported randomized trial examining T-DM1 in the first-line setting.

    1. Hurvitz SA, Dirix L, Kocsis J, et al. A Phase 2 randomized study of trastuzumab emtansine (T-DM1) versus trastuzumab + docetaxel in patients with HER2-positive metastatic breast cancer. J. Clin. Oncol. 2013 (Epub ahead of print)
    1. Blackwell KL, Miles D, Gianni L, Krop IE, Welslau M. 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. 2012;30(15S):5S. (Abstract LBA1)
    1. Bender BC, Schaedeli-Stark F, Koch R, et al. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother. Pharmacol. 2012;70(4):591–601.
    1. Thon JN, Devine MT, Jurak Begonja A, Tibbitts J, Italiano JE., Jr High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1) – mediated inhibition of platelet production. Blood. 2012;120(10):1975–1984.
    1. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5(7):953–962.
Websites
    1. . A study of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer and normal or reduced hepatic function. 2012 .
    1. . A study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab [Herceptin] plus a taxane in patients with metastatic breast cancer (MARIANNE) 2010 .
    1. . A combination study of trastuzumab emtansine and capecitabine in patients with breast cancer or gastric cancer. 2012 .
    1. . A study of trastuzumab emtansine, paclitaxel, and pertuzumab in patients with HER2-positive, locally advanced or metastatic breast cancer. 2009 .
    1. . A study of trastuzumab emtansine (T–DM1) in combination with docetaxel, and potentially pertuzumab, in patients with advanced breast cancer. 2009 .
    1. . A study of trastuzumab emtansine (T-DM1) sequentially with anthracycline-based chemotherapy, as adjuvant or neoadjuvant therapy for patients with early stage HER2-positive breast cancer. 2010 .

Source: PubMed

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