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

Abstract

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.

Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications

“…More recently, 2 new agents have been approved by the Food and Drug Administration (FDA) for the treatment of advanced HER2+ breast cancer: the monoclonal antibody pertuzumab and the antibody-toxin conjugate trastuzumab emtansine (T-DM1; fig. 2B) [21,22]. Despite the efficacy of these agents, HER2+ tumors can acquire treatment resistance either by reactivating the HER pathway or by activating alternative escape pathways that can bypass effective HER inhibition.…”

Developments and Challenges for mAb-Based Therapeutics

“…It is known that P-glycoprotein (P-gp), a drug transporter, is abundantly expressed in tumors and facilitates the elimination of chemotherapeutics, a phenomenon known as multidrug resistance (MDR) [163]. Drug resistance has been observed both for anticancer small molecule drugs [164,165] and mAbs [166,167]. The concept of ADCs as magic bullets was proposed decades ago [168], however only three such drug products have been approved in the US; gemtuzumab (anti-CD33) ozogamicin (Mylotarg®) for acute myeloid leukemia (AML) in 2000 (voluntarily withdrawn from the US market in 2010), brentuximab (anti-CD30) vedotin (Adcetris®) in 2011 for Hodgkin's lymphoma or anaplastic large cell lymphoma, and ado-trastuzumab (anti-HER2) emtansine (Kadcyla®) for HER2-positive metastatic breast cancer in early 2013.…”

“…Indeed, ADCs can be adequately processed to release the active form of the drug in the lysosomes of the target cells, such as mAb-maytansinoid conjugates containing either a disulfide linker or a thioether linker [188]. The superior efficacy and reduced toxicity of a trastuzumab-maytansinoid (mAb-DM1) conjugate eventually led to the approval of T-DM1 this year as the first ADC with a non-reducible thioether linker, following demonstration of both safety and efficacy [167].…”

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

“…Antibody drug conjugates (ADCs) such as T-DM1 are considered to be sophisticated drug delivery systems that provide one of the most promising approaches to improve the therapeutic window of existing cytotoxic agents such as tubulin-targeting agents (19–21). Trastuzumab emtansine (T-DM1), approved as a second-line monotherapy for the treatment of relapsed HER2 positive metastatic breast cancer, includes trastuzumab covalently linked with a non-cleavable linker to the antimitotic agent emtansine (DM1) (22, 23). Once the ADC is internalized into tumor cells by receptor-mediated endocytosis and processed, DM1 is released and binds to tubulin and inhibits microtubule assembly and causes apoptosis in dividing tumor cells (24–27).…”