Abstract

The human epidermal growth factor receptor-2 (HER2)-targeted therapies have improved clinical outcomes for patients at any stage of HER2-positive breast cancer (BC). Trastuzumab, a monoclonal antibody that targets the HER2 receptor on BC cells, showed improved survival in metastatic BC (MBC). However, resistance to therapy arises in the majority of patients with advanced disease. Antibody drug conjugate (ADC) is a relatively new development to deliver cytotoxic drugs specifically to cancer cells. Trastuzumab emtansine (T-DM1) is a HER2-targeted ADC, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent, emtansine (DM1, derivative of maytansine). T-DM1 has been approved for use in patients with MBC who have failed prior therapy with trastuzumab and a taxane. Dose finding Phase I study established the maximum tolerated dose at 3.6 mg/kg every 3 weeks. Phase I and II studies of T-DM1 have shown clinical activity and a favorable safety profile in HER2-positive MBC patients. The Phase III randomized EMILIA and TR3RESA trials demonstrated that T-DM1 significantly improves progression-free and overall survival in pretreated HER2-positive MBC patients. Nausea and fatigue are most commonly reported adverse drug reactions with T-DM1 and cardiac toxicity comparable with standard of care therapies. The drug is well tolerated in most patients, with a predictable pharmacokinetic profile and minimal systemic exposure to free cytotoxic DM1. T-DM1 has emerged as an effective therapeutic option for the management of patients with HER2-positive MBC.

Keywords

Drug conjugate - human epidermal growth factor receptor-2 - metastatic breast cancer - Trastuzumab emtansine

Introduction

Breast cancer (BC) is the second most common cancer worldwide and second leading cause of cancer-related death in women.[1] Research over the past 3 decades has led to a better insight into multifaceted molecular heterogeneity of the disease. The discovery of human epidermal growth factor receptor 2 (HER2) (also known as epidermal growth factor receptor or Erb-B), a membrane tyrosine kinase and oncogene, was one such important finding.[2],[3] Slamon et al. showed that amplification of HER2 gene occurs relatively infrequently in BC, and that it is associated with disease relapse and reduced overall patient survival.[2] The HER2 proteins are involved in promoting cell growth through activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin and Ras-Raf-MEK-Erk1/2 pathways, resulting in tumor growth and progression.[4],[5]

BC cells can have up to 25 50 copies of the HER2 gene (HER2 amplification) and up to 40 100-fold increase in HER2 protein resulting in two million receptors expressed at the tumor cell surface (HER2 overexpression).[6] HER-2 is amplified in 15 % of human primary BC and is significant predictor of both overall survival (OS) and time to relapse in patients with BC.[7] The identification of HER2 in BC pathogenesis has led to the development of therapies targeting this receptor.[8]

Trastuzumab (Herceptin ; Genentech, South San Francisco, CA, USA), the first monoclonal antibody developed to target HER2, received US Federal Drug Authority approval in 1998 for the treatment of HER2-positive metastatic BC (MBC) in combination with paclitaxel for first-line treatment.[9] Trastuzumab was shown to significantly improve the time to progression and OS of patients with metastatic HER2-positive BC.[10],[11]

Despite the significant efficacy of trastuzumab-based therapy, 50% of patients progress within 1 year.[10],[11] Lapatinib, an orally administered small molecule inhibitor of the HER1 and HER2 tyrosine kinases, was found to be superior in combination with capecitabine compared with capecitabine alone, in the treatment of HER2-positive MBC that had progressed after trastuzumab-based therapy.[12] Although this combination therapy provided patients with trastuzumab-resistant disease, an additional treatment option, only 29% of patients showed clinical benefit (complete response, partial response, or stable disease lasting at least 6 months), and half of patients had disease progression at 6.2 months.[13]

Diarrhea is a well-known side effect and a dose-limiting factor associated with lapatinib plus capecitabine treatment. Despite availability of treatment guidelines for the management of lapatinib capecitabine-associated diarrhea, it still represents a significant limitation in the optimal regimen administration in many patients. This frequently has a negative impact on patients' quality of life and efficacy of drug in daily clinical practice.[14]

In 2013, the FDA approved the first successful HER2-targeted antibody drug conjugate (ADC), trastuzumab emtansine (T-DM1; Kadcyla ; Genentech), for the treatment of HER2-positive trastuzumab-pretreated MBC.[15] In this review, we will discuss the pharmacology, efficacy, and tolerability of T-DM1 in HER2-positive MBC. A search of published medical literature was performed following the principles of evidence-based medicine. The search strategy included a search using the keywords: T-DM1, HER2+ve BC, HER2 targeted therapy, MBC in PubMed, Medscape, ClinicalTrials.gov, in addition to older studies identified by the literature reviews were reviewed.

Trastuzumab Emtansine-Human Epidermal Growth Factor Receptor-2-Targeted Antibody–drug Conjugate

ADCs are relatively new drugs and are designed to deliver cytotoxic drugs specifically into cancer cells,[16] thereby creating a more favorable therapeutic window for cytotoxic agents than that would be achieved by a free cytotoxic agent.[17] The key components of an ADC are the cytotoxic agent, a monoclonal antibody targeting a tumor-enriched or tumor-specific antigen, and a linker; covalently binding these components together.[18]

T-DM1, first ADC targeting the HER2 receptor, is a conjugate of trastuzumab through a non-reducible thioether linker (N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate [SMCC]) and a cytotoxic moiety (emtansine, derivative of maytansine [DM1]).[19]

Trastuzumab

Trastuzumab component of T-DM1 binds to subdomain 4 of HER2 receptor and exerts its own antitumor effects. The HER2-DM1 complex is then endocytosed and ultimately fused with a lysosome where it undergoes proteolytic degradation with release of the active DM1.[20]

Derivative of maytansine

DM1 is the derivative of maytansine (C34H46 ClN3O10), a benzoansamacrolide collected from plants and mosses. Maytansine is a potent microtubule-targeted compound, considered to have a high affinity for tubulin located at the ends of microtubules. The suppression of microtubule dynamics causes cells to arrest in the G2/M phase of the cell cycle, ultimately resulting in cell death by apoptosis.[21] In vitro studies demonstrate that on a molar basis across a range of cancer cell lines, DM1 is 24- to 270-fold more potent than paclitaxel, 180- to 4000-fold more potent than doxorubicin, and 100 fold more potent than vincristine (Vinca alkaloids).[22],[23],[24]

Maytansine had been extensively evaluated in Phase I and II clinical trials in humans, but side effects mainly gastrointestinal and neurologic toxicities and lack of tumor specificity have prevented its successful clinical development.[25],[26],[27] However, DM1, a derivative of maytansine, was selected for use in T-DM1, owing to high potency, excellent stability, in addition to the acceptable solubility of maytansine in aqueous solutions.[22],[26]

Thioether linker

The linker should stabilize the ADC in circulation, and once the compound enters the cell, it should liberate the cytotoxic agent either in a pH-dependent manner or by disulfide reaction.[28] T-DM1 is the first clinically developed ADC that uses the noncleavable linker. The advantage of noncleavable linker is that it undergoes proteolytic degradation once internalized and has better stability while in circulation.[19]

The conjugation of linker to trastuzumab is multistep process, first step is reaction of SMCC with the amino side chain of a lysine residue to form an amide bond at pH 7 9. Subsequently, the maleimide moiety undergoes a Michael-type addition with thiols at pH 6.5 7.5 to form thioether bonds with the cytotoxic agent resulting in an average 3.5 molecules per trastuzumab antibody (different drug antibody ratio).[21]

Trastuzumab Emtansine - mechanisms of Action

The mechanism of action (MOA) of T-DM1 is twofold [Figure 1].

| Figure.1Trastuzumab emtansine - mechanism of action

First, T-DM1 has been shown to retain the MOA of unconjugated trastuzumab including inhibition PI3K/AKT pathway, inhibition of HER-2 shedding, and Fc receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity.[23] Moreover, trastuzumab-mediated effect should not be underestimated and is particularly of importance, when target cells do not undergo rapid apoptotic death caused by DM1.[18]

Second, binding of T-DM1 to HER2 triggers entry of the HER2-T-DM1 complex into the cell through receptor-mediated endocytosis and ultimately fused with a lysosome where it undergoes proteolytic degradation.[29],[30],[31] As nonreducible linker is stable in the circulation and the tumor microenvironment, conjugates are efficiently degraded in lysosomes to yield metabolites consisting of the intact maytansinoid drug and linker attached to lysine.[19],[31] Subsequent to release from lysosome, microtubule assembly is inhibited by DM1-containing metabolites, finally causing cell death.[32] The primary active metabolite, lysine SMCC DM1, is a charged molecule, and relatively membrane impermeable, reducing the possibility that the DM1 entering a neighboring cell.[22]

Trastuzumab Emtansine Pharmacokinetics

T-DM1 appears quite stable in circulation, as very low levels of free DM1 were reported to be present in plasma samples from patients treated with T-DM1.[32]

Lu et al. evaluated s erum samples collected from 671 patients with HER2-positive locally advanced or MBC who received single-agent T-DM1 in five Phase I to Phase III studies. The results from the study showed terminal half-life of 3.94 days, with clearance of 0.676 L/day and a central volume of 3.127 L. Age, race, region, and renal function had no influence on pharmacokinetic of T-DM1.[33] In Phase I study of HER2-positive MBC patients with normal or reduced hepatic function, Li et al. reported that no increase in the systemic concentration of DM1 was observed in patients with mild or moderate hepatic impairment, compared to patients with normal hepatic function.[34] T-DM1 is neither an inducer nor inhibitor of CYP isoform. There was no accumulation or tissue retention by day 14 and 80% of the drug was excreted in feces and a small fraction in urine.[35]

Clinical Efficacy

Dose finding studies

T-DM1 was initially evaluated as a single agent in a Phase I dose escalation study in patients with trastuzumab-refractory HER2-positive advanced BC. Both weekly and 3-weekly schedules were tested. The 3-weekly dosing cohort was enrolled first. A total of 24 patients received intravenous T-DM1 doses at 0.3 mg/kg to 4.8 mg/kg every 3 weeks.[18] Grade IV thrombocytopenia was dose limiting at 4.8 mg/kg. The investigators deemed the maximum tolerated dose (MTD) to be 3.6 mg/kg. Response rate in these heavily pretreated patients with measurable disease at MTD was 44%.[18]

Phase II studies

Burris et al. conducted a Phase II clinical trial (TDM 4258 g) [Table 1] in 112 patients with HER2-positive MBC with tumor progression after prior HER2-directed therapy. By independent review, the objective response rate (ORR) was 26%.[32]{Table 1}

|?Figure.1Trastuzumab emtansine - mechanism of action

References