Drug Evaluation

Trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer

1.

Introduction

2.

Chemistry

3.

Preclinical activity studies

Tom Van den Mooter, Laure-Anne Teuwen, Annemie Rutten & Luc Dirix†

4.

Preclinical toxicology and

Sint-Augustinus Cancer Center, Department of Medical Oncology, Antwerp, Belgium

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

pharmacokinetics 5.

Clinical PKs

6.

Clinical efficacy

7.

Safety and tolerability

8.

Predictive biomarkers

9.

Conclusion

10.

Expert opinion

Introduction: Ado-trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine; mertansine). T-DM1 retains the mechanisms of action of trastuzumab, but also acts as a, selectively delivered, tubulin inhibitor. Following antigen-mediated binding to the tumor cell, T-DM1 is endocytosed and intracellularly catabolized resulting in the release of its cytotoxic moiety. Areas covered: T-DM1 has completed Phase III development and compared favorably with the lapatinib/capecitabine combination with a superior response rate (objective response rate [ORR]) and duration of response, longer duration of disease control (progression-free survival [PFS]), prolonged overall survival and improved tolerability and quality of life in patients with prior treatment with trastuzumab and a taxane. In a separate Phase III, T-DM1 was compared with any other chosen regimen in patients who had at least received two prior HER2-directed therapies. T-DM1 nearly doubled PFS. Expert opinion: T-DM1 (Kadcyla) has become the treatment of choice in second-line and beyond for patients with advanced HER2-expressing breast cancer. Keywords: human epidermal growth factor receptor 2, metastatic breast cancer, pertuzumab, trastuzumab emtansine, trastuzumab Expert Opin. Biol. Ther. (2015) 15(5):749-760

1.

Introduction

Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 15 -- 20% of patients with breast cancer [1,2]. This results in overexpression of the HER2 protein on the cellular membrane with on average > 1 million HER2 molecules per cell. HER2-amplified breast cancer is characterized by a more aggressive course and a worse outcome [2-4]. The introduction of trastuzumab, a humanized monoclonal antibody directed at the domain IV of the HER2 protein, has resulted in a paradigm shift. Adding trastuzumab to existing chemo- or endocrine therapy leads to a clinically significant improved outcome in the metastatic, the adjuvant and the neo-adjuvant context [5-8]. Trastuzumab has single-agent activity [9]. Dual anti-HER2 strategies, combining trastuzumab with either a different anti-HER2 antibody such as pertuzumab, directed at the domain II of HER2 protein, or in combination with the dual HER-1/2-directed tyrosine kinase inhibitor, lapatinib, results in improved efficacy [10,11]. In order to obtain maximal efficacy, current HER2-directed agents need to be combined with chemotherapy or hormonal agents. 10.1517/14712598.2015.1036026 © 2015 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

749

T. Van den Mooter et al.

Box 1. Drug summary.

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

Drug name Phase Indication

Trastuzumab emtansine (T-DM1) Launched Human epidermal growth factor receptor 2-positive breast cancer Pharmacology Antibody drug conjugate, description microtubuline inhibitor Route of administration Intravenous Chemical structure cfr infra Pivotal trials EMILIA Phase III: T-DM1 after trastuzumab and taxanes compared to lapatinib-capecitabine [39] TH3RESA Phase III: T-DM1 after tratuzumab and lapatinib compared with physician’s choice treatment [40]

Antibody-drug conjugates (ADCs) combine a tumor antigen-specific targeting antibody linked to a cytotoxic agent [12]. ADCs aim for an improved therapeutic index because they are designed to restrict the delivery of the cytotoxic cargo to the tumor cells, thus limiting collateral damage. This appealing approach implies that several prerequisites are met. The antigen must either be tumor specific or the differential expression of the target antigen between tumor cells and other tissues needs to be substantial. The degree of expression of the target antigen needs to be abundant. The binding sites on the antigen must be accessible to the monoclonal antibody. The presence and the degree of the expression of the antigen are preferentially homogeneous within a particular tumor and between tumor sites [13]. Furthermore, in order to avoid or limit systemic toxicity, the conjugated drug needs to remain firmly attached to the antibody prior to its binding of the ADC to its target. This requires a stable linking between the antibody and the cytotoxic agent. The conjugated drug needs to be released from the antibody after binding to the antigen and its internalization. The cytotoxic activity of both the antibody and the cytotoxic agent should at least be additive or preferentially synergistic. The cytotoxic compound needs to possess substantial in vivo potency with IC50 values in the picomolar range. If these criteria can be met, an ADC ought be both more effective and significantly less toxic. 2.

Chemistry

HER2 is highly expressed on HER2-amplified breast tumor cells (1 -- 2 million copies per cell). Consideration needs to be given to normal tissues that also express HER2 albeit at a much lower level, for example, cardiac muscle tissue. In general, HER2 amplification and protein overexpression in breast tumors are relatively homogeneous. The clinical efficacy of trastuzumab is in accordance with this. Both preclinical and clinical studies have confirmed that trastuzumab combines synergistically with cytoskeleton-directed agents [5,14]. Trastuzumab emtansine (T-DM1) (Box 1) is an ADC directed at the 750

domain IV of the HER2 extracellular domain (ECD). T-DM1 is composed of the microtubule polymerization inhibitor, DM1, conjugated to trastuzumab via a stable thioether linker, MCC [15]. Given the mechanism of action and potency of DM1, it was thought of as a particularly attractive cytotoxic agent to conjugate with trastuzumab. Maytansinoids bind directly to the vinca-binding domain of tubulin. Efforts to link maytansine to monoclonal antibodies led to the development of DM1, which has an impressive in-vitro cytotoxic potency which is 11- to 25-fold greater than maytansine and 24- to 270-fold compared to taxanes [16]. T-DM1 contains on average 3.5 DM1 molecules/antibody. The most important consideration for target-independent cytotoxicity in an ADC is the chemical nature of the linker moiety. ADCs containing maytansinoids were originally designed with linkers that contained disulfide bonds. Different observations guided the choice of incorporating a thioether linker containing a cyclohexane carboxylate spacer into the trastuzumab ADC. The thioether linker results in improved extracellular stability [17,18]. Furthermore, the principal intracellular catabolite of T-DM1 is lysine-MCC-DM1 [15]. This is considered to be a hydrophilic compound with poor cell permeability, which supposedly does not cross the plasma membrane, limiting its access to other cells, which likely contributes to the overall safety profile of T-DM1 [15,17]. 3.

Preclinical activity studies

The in-vitro cytotoxicity of T-DM1 was investigated against a broad panel of cell lines with different levels of expression of HER2 and varying sensitivity to trastuzumab [15-21]. These were not limited to breast cancer cell lines. In HER2-negative tumor models T-DM1 is invariably inactive. In all HER2expressing model systems, T-DM1 proved to be more potent than trastuzumab. In breast cancer cells insensitive to lapatinib, T-DM1 remains to be effective [20]. Similarly, in models of lapatinib resistance based on phosphatase and tensin homolog deletion or activating PIK3CA mutations, cells remained to be sensitive to T-DM1 while being resistant to both lapatinib and trastuzumab [20]. The in-vivo antitumor activity of T-DM1 was evaluated in different HER2-positive models in mice. In breast tumor xenograft models, administration of T-DM1 often led to complete and lasting tumor regression. This activity is considered to be the result of DM1-based cytotoxicity and is critical for T-DM1 becoming an effective treatment in patients with disease progressing on available HER2-directed therapies. Treatment with a control, IL-8 binding conjugate, had no activity, demonstrating the HER2-antigen specificity of the activity of T-DM1. In addition to being a cytotoxic agent, T-DM1 has been shown to retain all the functional activities of unconjugated trastuzumab, including the binding affinity to HER2, the antibodydependent cell-mediated cytotoxicity and the inhibition PI3K pathway with similar levels of inhibition of AKT phosphorylation [20]. Preclinical studies suggest a similar activity of

Expert Opin. Biol. Ther. (2015) 15(5)

Trastuzumab emtansine

T-DM1 in HER2-positive gastric cancer [19]. 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 metabolites that bind to tubulin [15,18,21-23].

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

4.

Preclinical toxicology and pharmacokinetics

Pharmacokinetic (PK), safety and toxicology studies with T-DM1 were performed in rats and monkeys. Trastuzumab recognizes HER2 in monkeys but does not bind to the rodent antigen [24-26]. Studies in the rat allowed for the assessment of antigen-independent toxicity of T-DM1, whereas monkeys allowed evaluation of the combined antigen-mediated effects in addition to antigen-independent toxicity. The acute toxicities in rats were similar between T-DM1 and DM1 and were associated with dose-dependent effects in bone marrow, lymphoid organs, and liver. These laboratory observations were consistent with histologic findings of the organ toxicities, with maximum tolerated dose (MTD) for DM1 and T-DM1 being 1600 and 4400 µg DM1/sqm. Elevations of serum transaminase levels were in the range of two to fourfold at the MTD of both T-DM1 and DM1, consistent with the histologic findings of liver toxicity. At the tolerated doses, all findings were partially or completely reversed during the recovery period. The terminal half-life of T-DM1 in rats was ~ 3.5 days, and a volume of distribution approximating the plasma volume, characteristic for an antibody-based agent. In rats, DM1 PKs showed a large volume of distribution (> 5000 ml/kg) and rapid clearance (CL), as expected for this small molecule. In rodents there was no difference in PK between tumor-bearing and non-tumor bearing mice. However in trastuzumab-binding species a dose-dependent decrease in CL was associated with increasing dose. Results from a preclinical absorption, distribution, metabolism, and excretion study of T-DM1 in rats suggest that T-DM1 nonspecifically distributes to tissues without accumulation. T-DM1 was well tolerated in monkeys upon repeat dosing at 3-week intervals with four doses of up to 30 mg/kg or with eight doses at 10 mg/kg. Most adverse findings were similar to those described for rats, with liver and bone marrow systems being the primary target organs for toxicity. A minimal to mild decrease in platelets was noted on day 3 after each dose, as was a reversible two to fourfold increase in serum hepatic transaminase levels. However, despite the fact that epithelial cells of many tissues express HER2, the incidence of cellular mitotic arrest in the rat studies was noted to be more widespread than that in monkey, indicating that antigen-independent mechanisms predominate in the uptake and intracellular catabolism of T-DM1 and that antigendependent binding and uptake by a normal tissue may not be a major safety concern. That antigen-mediated uptake does occur in monkeys was clearly demonstrated by the nonlinear PKs, with the CL in animals treated at 3 mg/kg being

50% faster than those in the higher dose groups. There was no accumulation of T-DM1 upon repeat dosing at 3-week intervals. As in the rat, free DM1 concentrations were always at least 50-fold lower than conjugated DM1 at any time point. Also as observed in rats, the CL of the intact T-DM1 conjugate was faster than that of total trastuzumab. In 4 of 36 monkeys (11%) given repeated doses of T-DM1, antiproduct antibodies were detected, although there were no apparent effects on the toxicokinetic profiles in these animals. Dose-dependent axonal degeneration was observed in the repeat-dose monkey studies, although these findings were without any clinical observations of neurologic deficit. These findings were not reversible within the 6-week recovery period. Neuropathy is a common toxicity finding with microtubule-acting agents such as taxanes and the Vinca alkaloids, especially with the longer exposures of repeat dose schedules of administration. There were no cardiovascular safety signals in the monkey studies. The overall conclusions of the toxicity evaluation of T-DM1 were that the mechanism of toxicity is consistent with the pharmacology of DM1 as a microtubule-acting compound and that the observed toxicities were primarily through antigen-independent mechanisms of T-DM1 catabolism. The impact of different linkers on PK/pharmacodynamics validated the importance of a non-reducible linker on ensuring low plasma-free DM1 levels. The DM1 component of T-DM1 is primarily metabolized through the biliary route, mainly by CYP3A4 and, to a lesser extent, by CYP3A5 [27]. T-DM1 is neither an inducer nor an inhibitor of major CYP isoforms, which is consistent with the lack of evidence of drug--drug interactions. 5.

Clinical PKs

A consistent PK profile of T-DM1 has been observed in different clinical studies. In the lower dosing in the Phase I study, a twofold increase in dose from 1.2 to 2.4 mg/kg resulted in a fourfold increase in Cmax and an eightfold increase in the AUC [28,29]. This nonlinearity is considered to be consistent with a concentration-dependent target-mediated CL, which predominates at the lower dose [28]. In the dose range from 2.4 to 3.6 mg/kg T-DM1 displays linear PKs. Mean CL ranged between 21.2 and 27 ml/d/kg at doses of 0.3 -- 1.2 mg/kg, whereas CL decreased to 6.9 -- 12.9 ml/d/kg for dosages > 1.2 mg/kg, consistent with a longer half-life. At the 3.6 mg/kg/q3 weekly regimen T-DM1 terminal half-life is between 3.5 and 3.96 days. Plasma DM1 concentrations are consistently low, with no observed accumulation over treatment cycles with the three-weekly regimen [30-33]. The average Cmax of DM1 ranged from 5.36 ng/ml to in cycle 1 -- 5.97 ng/ml in cycle 4. The systemic CL of T-DM1 was thus much more rapid than the CL of total trastuzumab. Gupta et al. presented a population-PK model [32]. This model which was recently updated by Lu et al. using data from 671 patients using 9934 T-DM1 conjugate serum

Expert Opin. Biol. Ther. (2015) 15(5)

751

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

T. Van den Mooter et al.

concentration time points to determine the effects of covariates on the PK of T-DM1 and to identify clinical factors affecting T-DM1 exposure in individual patients [34]. This was externally validated with an additional dataset of 505 concentration-time data points. The estimated CL for T-DM1 is 0.676 L/day, volume of distribution in the central compartment (Vc) is 3.127 L and terminal half-live is 3.94 days. Age, race, renal function did not have an influence on PK. The inter-individual variability in T-DM1 CL was limited; for the CL it was 25.6% and for the Vc 17.5%. After adjusting for covariates, interindividual variability was even lower (< 20%): 19.1% for CL and 11.7% for Vc. Body weight, HER2-ECD (HER2 shed ECD), serum albumin, tumor burden, serum aspartate aminotransferase levels and baseline trastuzumab concentration were all statistically significant covariates accounting for some of the inter-individual variability in T-DM1 exposure and/or CL. Patients with a higher body weight, lower albumin, higher tumor burden, higher HER2-ECD, higher apartate aminotransaminase (AST), and lower trastuzumab concentration had a more rapid CL. At the extreme value for any single covariate the result on CL would differ < 10% from a typical patient. The magnitude of their effect on T-DM1 exposure is thus expected to be clinically insignificant. These results suggest that no dose adjustments for the evaluated covariates are necessary. Overall, 4.3% of patients developed an antibody response to T-DM1 after repeated T-DM1 doses. The significance of antibody development against T-DM1 is unknown, but there were no obvious changes in the PKs, safety profiles, or efficacy outcomes of patients who developed an antibody response to T-DM1. PKs and renal dysfunction T-DM1 is converted intracellularly to a number of different DM1-containing catabolites. These are excreted via the biliary route, with minimal renal elimination in preclinical studies. A priori, renal impairment is not thought to affect T-DM1 PKs substantially. A population PKs evaluation of patients with mild or moderate kidney function impairment confirmed these predictions [34]. PKs in patients with mild (creatinine clearance (CLcr) 60 -- 89 ml/min, n = 254) or moderate (CLcr 30 -- 59 ml/min, n = 53) renal impairment were similar to those in patients with normal renal function (CLcr ‡ 90 ml/min, n = 361). However, no data are available on patients with severe or end-stage renal dysfunction [34]. 5.1

PKs and hepatic dysfunction In a Phase I study in patients with Child A and B hepatic impairment (patients with Child C liver dysfunction were not eligible) three cycles of T-DM1 3.6 mg/kg were administered every 3 weeks. T-DM1, total trastuzumab, DM1, MCC-DM1, and Lys-MCC-DM1 were measured. Compared with the normal cohort, T-DM1 CL at cycle 1 was ~ 1.9- and 3.3-fold faster in the mild and moderate cohorts, respectively. The trend of faster CL was less apparent for cycle 3 after repeated dosing, with similar T-DM1 5.2

752

exposures across the three cohorts. Plasma concentrations of DM1 and DM1-containing catabolites were largely comparable across the three cohorts. No new safety signals were seen relative to the known safety profile of T-DM1. The slightly more rapid CL is most likely related to demographic and pathophysiological covariates such as tumor burden, albumin, and body weight, although more rapid CL was also associated as an independent factor in the population PK-study. No increase in the systemic concentration of DM1 was observed in patients with mild or moderate hepatic impairment versus those with normal hepatic function and no additional safety concerns were observed [34,35]. 6.

Clinical efficacy

T-DM1 was evaluated in a dose escalation Phase I trial in patients with HER2-positive metastatic breast cancer (MBC) who previously received a trastuzumab-containing regimen. T-DM1 was given at various doses on a weekly or every three-weekly schedule by intravenous infusion > 30 -- 90 min. For the three-weekly schedule 24 patients received T-DM1 starting at 0.3 mg/kg up to 4.8 mg/kg [28]. The starting dose level of T-DM1 in three-weekly regimen for the first-inhuman Phase I clinical trial was 0.3 mg/kg based on 1/12 of the highest non-severely toxic dose in cynomolgus monkeys. Dose-limiting toxicity was observed at the 4.8 mg/kg dose with grade 4 thrombocytopenia in two of three patients. The MTD was defined as 3.6 mg/kg every 3 weeks. The most common adverse events (AEs) were thrombocytopenia (54.2%), elevated transaminases (41.7%), fatigue (29.2%), and nausea (25%). Most AEs were mild. Some decline in the platelet count occurred in almost all patients receiving T-DM1 at doses in excess of 1.2 mg/kg. The confirmed response rate (RR) in nine patients treated at MTD and with measurable disease was 44%. In a group of 15 patients receiving 3.6 mg/kg every 3 weeks, the clinical benefit rate (CBR) (RR plus stable disease at 6 months) was 73% (Table 1). The starting dose for the T-DM1 once weekly was 1.2 mg/ kg, a third of the MTD of the three-weekly regimen. Twentyeight patients have received T-DM1 at five dose levels (1.2 mg/kg, 3 pts; 1.6 mg/kg, 3 pts; 2.0 mg/kg, 3 pts; 2.4 mg/kg, 16 pts; 2.9 mg/kg, 3 pts) on a weekly schedule [29]. In two of three patients at 2.9 mg/kg a dose limiting toxicity occurred on day 8 of the first cycle: a grade 3 thrombocytopenia and a grade 3 elevated aspartate aminotransferase (AST/ALT). The MTD was 2.4 mg/kg resulting in a cumulative dose of 7.2 mg/kg in a 21-day cycle. In total 9 out of 28 patients experienced a grade 3/4 AE considered drugrelated, most frequent were an increase in AST/ALT and thrombocytopenia. PKs were dose proportional at a dose > 1.2 mg/kg with some accumulation for T-DM1 and trastuzumab. Objective responses were reported in 13 (46.4%) patients with a median response duration of 18.6 months. The CBR was 57% (16 of 28 patients). Based

Expert Opin. Biol. Ther. (2015) 15(5)

Trastuzumab emtansine

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

Table 1. Summary of efficacy and selected toxicity data from different clinical trials with T-DM1. Clinical trial selection

N

RR (%)

PFS months

DOR months

OS months

AST all grades

Thrombocytopenia all grades

Neutropenia all grades

Ref.

Phase I weekly Phase I 3-weekly Phase II Phase II Randomized Phase II First line T-DM1 Trast + docetaxel Phase III Second line after T + Tax T-DM1 Lap + xeloda Phase III Third line and beyond T-DM1 Physician’s choice

28 24 112 110 137 67 70

46.4 25 26 34.5

NR NR 4.6 6.9

NR NR 9.4 7.2

NR NR NR NR

42.9 41.7 NR 26.4

42.9 54.2 NR 38.2

10.7 4.3 NR NR

[29] [28] [36] [37] [38]

64.2 58

14.2 9.2

Not reached 9.5

NR NR

39.1 6.1

26.1 6.1

15.9 63.6

991

[39]

495 496 602

43.6 30.8

404 198

31 9

9.6 6.4

12.6 6.5

30.9 25.1

22.4 9.4

28 2.5

5.9 8.6 [40]

6.2 3.3

9.7 Not reached

NE 14.9

8 5

15 3

10 22

AST: Apartate aminotransaminase; DOR: Duration of response; NR: Not reported; OS: Overall survival; PFS: Progression-free survival; RR: Response rate; T: Tratuzumab; Tax: Taxane; T-DM1: Trastuzumab emtansine.

on its clinical activity, PK-profile and dosing convenience, T-DM1 3.6 mg/kg every 3 weeks was selected for further development. Two multicenter, single-arm, Phase II studies evaluating single-agent T-DM1 3.6 mg/kg every 3 weeks in pretreated patients with locally assessed HER2-positive MBC following progression on previous chemotherapy and HER2-directed therapy have been reported [36,37]. In the first study, 112 patients were treated with 3.6 mg/kg every three weeks. An objective response was reported in 29 patients by an independent review (25.9%) and in 42 patients by investigator assessment (37.5%), including four complete responses. By independent review either response or stable disease was observed in 84 of 112 patients; this represents a CBR of 75%. The median progression-free survival (PFS) was 4.6 months (3.9 -- 8.6 months). In the second study, 110 patients had been previously treated with an anthracycline, a taxane, and capecitabine, as well as lapatinib and trastuzumab with a median of 8.5 agents (5 -- 19) in all settings and 7.0 agents (3 -- 17) for metastatic disease [28]. The RR was 34.5% and the CBR was 48.2% by independent review. The median PFS was 6.9 months (4.2 -- 8.4 months). Both these studies and the efficacy seen in the Phase I trial, corroborated the preclinical data obtained with T-DM1 as an agent capable of tumor cell killing by an additional mechanism beyond those effected by trastuzumab alone. A randomized, open-label Phase II study has investigated single-agent T-DM1 compared with trastuzumab-plus-docetaxel as a first-line treatment of patients with HER2-positive advanced breast cancer [38]. A total of 137 patients with centrally confirmed HER2 overexpression and RECIST 1.0 measurable disease were randomized to either T-DM1 3.6 mg/kg q3w or trastuzumab-plus-docetaxel, with docetaxel

at respectively 6 mg/kg (after a loading dose of 8 mg/kg) and 75 or 100 mg/m2. The majority of patients (74.2%) received docetaxel at 75 mg/m2. The RR by investigator assessment was 64.2% with T-DM1 and 58% for trastuzumab-plus-docetaxel. There were seven complete responses (10.3%) and three complete responses (4.3%), respectively. The primary endpoints were investigator-assessed PFS and safety. The median PFS was 14.2 months for T-DM1 versus 9.2 months in the trastuzumab-plus-docetaxel arm (hazard ratio [HR] 0.59; 0.36 -- 0.97; p = 0.035). With regard to safety the number of grade 3/4 events was reduced by nearly 50% in the T-DM1 treated group. In the trastuzumab-plus-docetaxel arm 89.4% of patients suffered such an event compared to 46.4% of the T-DM1 treated patients. The number of grade 4 events was reduced from 56 to 9%. Similarly, serious AEs numbered up to 25.8 versus 18.8% for T-DM1. In more detail the risk for alopecia was nearly eliminated from 66.7 to 4.3%. Significant neutropenia (i.e., grade 3 and 4) was reduced from 60.6 to 5.8%. The most significant toxicities for T-DM1 were increased AST, which occurred in a grade intensity in 8.7% of patients. Thrombocytopenia of all grades occurred in 33.4% for T-DM1 and in 9.1% of patients in trastuzumabplus-docetaxel arm. Five patients (7.2%) treated with T-DM1 had a grade 3/4 thrombocytopenia versus two patients (3.0%) in the control arm. These results and the preclinical synergy between T-DM1 and pertuzumab led to the inititation of the MARIANNE study. This is a threearm, Phase III study in previously untreated patients with locally advanced or metastatic HER2+ breast cancer comparing T-DM1 plus placebo, T-DM1 plus pertuzumab, and trastuzumab with a taxane. Preliminary, unpublished results have been reported showing the three regimens affected PFS for a similar amount of time, meeting its non-inferiority endpoint

Expert Opin. Biol. Ther. (2015) 15(5)

753

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

T. Van den Mooter et al.

as assessed by an IRC. However, neither T-DM1-containing treatment arm significantly improved PFS compared to trastuzumab and taxane-based chemotherapy. AEs observed in the two experimental arms of the study were generally consistent with those seen in previous studies of T-DM1 and/or pertuzumab. More detailed analysis is obviously needed, but suggests at least, even in the context of the Cleopatra data (on the remarkable efficacy of the combination of docetaxel, trastuzumab and pertuzumab), that T-DM1 is a good option for patients unable to receive a taxane. T-DM1 was compared with the standard second-line treatment of HER2-positive advanced breast cancer in the EMILIA trial [39]. Eligible patients had documented progression of HER2-positive breast cancer previously treated with a taxane and trastuzumab. Progression of disease had to occur during or after the most recent treatment for MBC (84%) or within 6 months after treatment for early breast cancer (16%). Patients were randomly assigned to either 3.6 mg/kg T-DM1 or lapatinib-plus-capecitabine (L 1250 mg daily, C 2000 mg/sqm on days 1 -- 14) of each 21-day treatment cycle. The primary endpoints were PFS, overall survival (OS) and safety. T-DM1 significantly improved PFS from a median 6.4 to 9.6 months (HR 0.65; 0.55 -- 0.77; p < 0.001). OS was significantly increased from 25.1 to 30.9 months (HR 0.68; 0.55 -- 0.85; p < 0.001). The objective RR was higher in the T-DM1 (43.6%; 95% CI 38.6 -- 48.6) than in the lapatinib-plus-capecitabine (30.8%; 26.3 -- 35.7; p < 0.001). No unexpected safety signal emerged from this study with thrombocytopenia (12.9%) and elevated AST/ALT (7.1%) as the most commonly reported grade 3 or 4 events for T-DM1. The efficacy of T-DM1 compared with a regimen of physician’s choice was also evaluated in the lapatinib pretreated setting in the TH3RESA Phase III study [40]. All patients had previously received both trastuzumab and lapatinib in the advanced setting. The median number of previous regimens for advanced disease was four with nearly one out of three patients having received > 5 prior regimens. Randomization of treatment was in a 2:1 ratio between either open-label standard dosed T-DM1 (3.6 mg/kg) or the treatment of choice. In 68% of cases this consisted of a trastuzumab and chemotherapy combination and in 10% of trastuzumab combined with lapatinib. The co-primary endpoints were investigator-assessed PFS and OS in the intention-to-treat population. The PFS was significantly improved from 3.3 months (2.89 -- 4.14) to 6.2 months (5.59 -- 6.87) with a stratified hazard ratio of 0.528 (0.422 -- 0.661; p < 0.0001). The improvement in PFS onT-DM1 was independent on whether the treatment of choice contained tratuzumab or not. The interim OS analysis showed a trend favoring T-DM1. In patients with measurable disease 108/345 (31%) had an objective response with T-DM1 compared with 14/163 (9%) in the control group. Only 36 (9%) of the 403 patients required dose reductions of T-DM1 and in 30/36 reduction by one dose level sufficed. The number of serious AEs was 18% for the T-DM1 group and 21% in 754

the physician’s choice group. Grade 3 or worse thrombocytopenia was reported in 4% of T-DM1-treated patients versus 2% in the control arm. The reverse was observed for neutropenia: 2% for T-DM1 therapy compared to 16% with the chosen regimen. The consistent gain obtained both in objective response rate, PFS and OS paralleled with an improvement in tolerability, even in heavily pretreated patients, render T-DM1 the preferred second-line regimen in patients with advanced HER2+ breast cancer. Similarly T-DM1 should be the treatment of choice in those patients having received numerous prior therapies including both lapatinib and trastuzumab. Brain metastasis Patients suffering from HER2-positive MBC are at an increased risk for developing CNS relapse. The CNS continues to be considered as a sanctuary site for metastatic disease at least in the context of an intact blood--brain barrier (BBB). Patients with uncontrolled CNS disease have been excluded T-DM1 clinical trials. A retrospective analysis from the EMILIA study suggests that the rate of CNS progression on study was similar for T-DM1 and the lapatinibcapecitabine arms, irrespective of the baseline CNS status [41]. These data suggest that T-DM1 is a valuable option for patients with progressive MBC in the context of controlled CNS disease. Moreover, different authors have reported on single-agent activity of T-DM1 in patients with progressive CNS disease [42]. Bartsch et al. have administered T-DM1 at the standard dose as a single agent to nine patients with both pretreated and unpretreated CNS disease [43]. In seven evaluable patients a partial response was observed in three out these seven, and in two other patients disease remained controlled for 5 and 10 months. These and other data suggest at least that T-DM1 might have the ability to cross the BBB in the context of CNS metastases. 6.1

7.

Safety and tolerability

Thrombocytopenia In the weekly schedule both grade 3 transaminitis and thrombocytopenia were dose-limiting at 2.9 mg/kg/wk. In the Phase I study of the weekly administration, grade 3 or 4 thrombocytopenia was reported in 10.7% of patients [29]. Thrombocytopenia is the most frequent and the dose-limiting toxicity of the three-weekly administration of T-DM1 [44]. Here thrombocytopenia is observed as early as 1 day after T-DM1 treatment. In most patients, platelet counts reach a nadir by day 8 and recover by day 18. This pattern persists over time but sometimes recovery is incomplete and a downward drift in platelet counts can be observed with repeated cycles. All grade thrombocytopenia was reported in 32.2% in an analysis on 884 T-DM1 treated patients [45]. Low platelet count of grade 3 (12.2%) and grade 4 (2.2%) intensity was observed in 128 patients (14.4%). Asian patients demonstrated a higher incidence of grade 3 -- 4 thrombocytopenia. 7.1

Expert Opin. Biol. Ther. (2015) 15(5)

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

Trastuzumab emtansine

Thrombocytopenia was not typically associated with clinically meaningful bleeding events. Grade 3 -- 4 bleeding events and grade 3 or 4 thrombocytopenia concurred in only two patients. The T-DM1-related thrombocytopenia is the consequence of decreased platelet production rather than accelerated platelet destruction. This decreased platelet production is the direct effect of DM1 on the cytoskeletal organization of maturing megakaryocytes (MK). A live-cell imaging assay demonstrated that T-DM1 is taken up by both mouse MK and mouse/human platelets [46]. This uptake was reported to be both HER2 and Fc gamma RIIa receptor independent, suggesting that T-DM1 is endocytosed through an alternative pathway. Uppal et al. confirmed most of these findings with the exception that they found the uptake of T-DM1 by MK to be HER2-independent, but clearly Fc gamma RIIa dependent [47]. These date confirm the hypothesis that the T-DM1-related thrombocytopenia is DM1 mediated, most likely due to internalization via the Fc gamma receptor in differentiating MKs. The cyclical nature of the thrombocytopenia might be explained by the lower affinity of the IgG1 for Fc gamma RIIa resulting in limited and transient uptake during the period of the highest T-DM1 concentration. Even at Cmax the occupancy of the Fc gamma receptor is estimated to be ~ 35%. These observations are clearly important for the development of other ADC, because this mechanism is independent of HER2. Alopecia Hair loss is minimal or absent with T-DM1. In the first-line Phase II study 3 out of 69 patients (4.3%) reported some degree of hair loss compared to 66.7% for the trastuzumabplus-docetaxel arm [38]. This relative low number for docetaxel might be related to the dose of 75 mg/sqm that was given to most patients. 7.2

Cardiotoxicity Cardiotoxicity is an adverse event linked to all HER2-directed agents. It is of particular interest in the T-DM1 studies as continued deposition of DM1 to the myocardium might have long-term implications. On the other hand cardiomyocytes are in general non-proliferating cells and thus might not be affected by DM1. Treatment with T-DM1 leads a 40% decrease in the amount of trastuzumab being delivered during each treatment cycle. In the single-arm studies of single-agent T-DM1 no dose-limiting cardiotoxicities were observed [36,37]. In the randomized comparative Phase II study, T-DM1 did not increase the risk of cardiotoxicity relative to trastuzumab plus docetaxel [38]. Grade cardiac dysfunction rates appeared to be lower in the T-DM1 arm than in the control arm (2.9 vs 12.1%). However, in all T-DM1 studies, a baseline left ventricular ejection fraction (LVEF) of ‡ 50% was required for study entry. In both the EMILIA and the TH3RESA Phase III studies LVEF drop to below 50% and a drop > 15% from baseline occurred in 8 (1.7%) 7.3

and 2 (1%), respectively. In the integrated safety analysis 4 patients (0.5%) had a post-baseline LVEF < 40% and 16 patients (1.8%) had a LVEF decline of 15% or more from baseline to < 50% [45]. In addition a separate study on the cardiac safety of T-DM1 after the administration of doxorubicin plus cyclophosphamide (AC) or 5-fluorouracil plus epirubicin and cyclophosphamide (FEC) in patients with early-stage HER2-positive breast cancer was very reassuring [48]. In 148 patients with a baseline LVEF > 55%, after a median follow-up was 24.6 months no prespecified cardiac events or symptomatic congestive heart failure were reported. Four (2.7%) patients had asymptomatic LVEF declines (10% from baseline to a LVEF < 50%), leading to T-DM1 discontinuation in one patient. The effect of T-DM1 (3.6 mg/kg q3w) on the QT interval was evaluated in a separate study [49]. Single-agent T-DM1 was administered to 51 patients and evident data and time-matched PK samples were collected at different time points. No patient exhibited an average change in the Fridericia’s corrected QT interval (QTcF) interval from baseline exceeding 30 ms at any of the protocol-specified time points. Whereas there appears to be a trend between T-DM1 drug concentration and its effect on QT interval, there is reasonable assurance that the true increase in mean baseline-adjusted average QTcF does not exceed 5 ms. Moreover, because T-DM1, total trastuzumab, and DM1 achieve steady-state levels by Cycle 3, the likelihood of progressively longer QTcF with repeated T-DM1 dosing is low. Overall, the statistical analysis of evident data and concentration--QTc analysis indicate that single-agent T-DM1 given 3.6 mg/kg q3w does not have a clinically meaningful effect on the QTc interval in patients with HER2-positive MBC. Transaminitis In the Phase I study of T-DM1 on a three-weekly schedule, 42% of patients experienced transaminitis, but no grade 3 or 4 events were observed. Weekly administration of T-DM1 resulted in grade 3 transaminitis in 7.1% of patients [28]. In the Phase II comparative first-line study, grade 3 or higher transaminitis was seen in 8.7% of patients in the T-DM1 arm compared with 0% of patients in the trastuzumab plus docetaxel arm [38]. In an integrated safety analysis among 884 T-DM1 exposed patients reported all-grade increases in serum AST and ALT in 23.5 and 15.7%, respectively [45]. Increases to grade 3 or more were observed in 4.3% for AST and 3.1% for ALT. Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver and some with a fatal outcome due to drug-induced liver injury, have been observed. This might have been confounded by comorbidities and/or other hepatoxic agents, for example, alcoholic-induced liver damage. The liver function needs to be monitored prior to initiation of treatment and each dose. Three cases of NRH of the liver have been identified in patients treated with T-DM1 [50]. NRH is a rare liver condition characterized by widespread small regenerative nodules; 7.4

Expert Opin. Biol. Ther. (2015) 15(5)

755

T. Van den Mooter et al.

it may lead to non-cirrhotic portal hypertension. Diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, T-DM1 treatment must be permanently discontinued. Neuropathy Patients who receive T-DM1 for prolonged periods do experience some degree of sensory neuropathy, which is Vinca-like. This is predicted with preclinical toxicology data in monkeys [25]. In the weekly Phase I study grade 1 -- 2 sensory neuropathy was reported in 3 of 28 patients (10.7%) [29]. In the integrated analysis a total 257/884 (29.1%) of T-DM1-treated patients suffered from any degree of peripheral neuropathy, mainly grade 1 events. Grade 3 (21/884) and grade 4 (1/884) neuropathy occurred in 2.4% (22/884) [45]. These patients were nearly all (19/22) pretreated with taxanes.

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

7.5

Pneumonitis Pneumonitis as an adverse event is rarely reported in patients treated with T-DM1 with 10 reported events in 884 treated patients (1.1%). Seven cases were of grade 1 and 2 severity [45].

They further suggest that tumor response to T-DM1 may be dependent on HER2 quantity. T-DM1 activity was not correlated with PI3K-mutational status and phosphatase and tensin homolog expression in different Phase II studies [52]. In the EMILIA biomarker analysis PI3K mutational status was associated with a decreased PFS in the lapatinib/capecitabine-treated patients, but did not affect the outcome in T-DM1-treated patients [54]. Different neoadjuvant studies with HER2 directed non-T-DM1 regimens have reported lower pCR rates in patients with tumors harboring PI3K mutations [55]. Preclinical data suggest that neuregilin-HER3 signaling affected T-DM1 cytotoxicity [56]. This effect was reversed by the addition of pertuzumab [57]. T-DM1 and pertuzumab can safely be combined, with both agents used at their standard dose [58]. These observations supported the design of the MARIANNE study, which apparently failed to prove any benefit from combining T-DM1 with pertuzumab. Recently, intriguing in vitro data suggest that the sequential use of pertuzumab followed after 1 h by T-DM1 seems to be antagonistic in comparison to the simultaneous treatment of cell lines with both agents [59].

7.6

Quality of life The Phase II comparative trial, which compared T-DM1 to trastuzumab-docetaxel as first-line therapy in the metastatic setting, included quality of life as assessed by the FACT-B Trial Outcome Index [38]. The questionnaire assesses physical and functional wellbeing as well as breast cancer-specific symptoms. The T-DM1 arm was associated with an improved quality of life when compared with trastuzumab plus docetaxel. A secondary endpoint of the EMILIA study was time to symptomatic worsening as measured by the Trial Outcome Index Physical/Functional/Breast (TOI-PFB) subset of the Functional Assessment of Cancer Therapy-Breast questionnaire [51]. Time to symptom worsening was delayed in the T-DM1 arm versus the capecitabine/lapatinib arm (7.1 vs 4.6 months, HR = 0.796; p = 0.0121). 7.7

8.

Predictive biomarkers

Clinically confirmed HER2-positive status was associated with a better efficacy of T-DM1 than HER2-normal status. Analysis by qRT-PCR showed that levels of HER2 mRNA expression equal to or above the median were also associated with a higher ORR than levels below the median [36,37,52]. These observations support the specificity of T-DM1 for HER2-positive MBC. These results were confirmed in the randomized first-line study and the EMILIA trial [53,54]. 756

9.

Conclusion

T-DM1, an ADC for the treatment of HER2-positive breast cancer, is well both well-tolerated and effective as a single agent dosed at 3.6 mg/kg every 3 weeks. T-DM1 has demonstrated clinical superiority in trastuzumab-pretreated and trastuzumab- and lapatinib-pretreated patients. In untreated patients with advanced disease T-DM1 seems to be noninferior to the combination of a taxane and trastuzumab. With the impressive data of the first-line trastuzumab-pertuzumab-docetaxel data, it seems unlikely at this point in time to consider a role for T-DM1 in first line, with the obvious exception of these patients not able to tolerate taxane-based chemotherapy. T-DM1 is now been recognized as the preferred treatment option in second and third line for patients with advanced HER2-positive breast cancer. T-DM1 is clearly distinct from trastuzumab; it is a cytotoxic agent, albeit one with an exceptional tolerability profile. The difference with trastuzumab is reflected in the dosing and PK (3.6 mg/kg every 3 weeks for T-DM1 vs 6 mg/kg every 3 weeks for trastuzumab) and half-life (~ 4 days for conjugated T-DM1 vs ~ 3 -- 4 weeks for trastuzumab). Unlike trastuzumab, T-DM1 undergoes deconjugation, proteolytic degradation, and cytochrome P450-mediated metabolism of DM1 metabolites, which explains the faster CL of T-DM1 compared with trastuzumab and a potential for drug-drug interaction. Finally T-DM1 is active in trastuzumab- and lapatinib-insensitive disease in preclinical studies and Phase III clinical studies. The improved efficacy of T-DM1 in patients with higher HER2 expression seems well established as seems the independence of its activity in patients

Expert Opin. Biol. Ther. (2015) 15(5)

Trastuzumab emtansine

PI3K-mutated tumors. This is different from what is observed with all other, currently available HER2 directed therapies.

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

10.

Expert opinion

T-DM1 is an antibody drug conjugate for the treatment of HER2-positive breast cancer. It is both well-tolerated and remarkably effective as a single agent dosed at 3.6 mg/kg every 3 weeks in patients with HER2-overexpressing advanced breast cancer. The weekly dosing regimen should not be used. Currently data in other HER2 overexpressing malignancies are lacking. Similarly, T-DM1 should not be considered in patients with advanced breast cancer and more moderate HER2 expression. There are no convincing data that combination therapy with T-DM1 results in a superior outcome. The use of T-DM1 following anthracycline-based chemotherapy and following or concomitantly with radiotherapy seems a safe approach in patients with early breast cancer. T-DM1 is now the preferred option for patients with advanced HER2-positive breast cancer in second line and beyond. In first-line T-DM1 seems to be as effective as the taxane trastuzumab combination, with most likely a superiority for T-DM1 regarding side effects. This superiority over standard of care in second line and beyond is clear for all the classical end points, including patient safety. However long-term safety data for patients receiving T-DM1 for extensive periods of time are still limited. With the updated results from the Cleopatra study, it seems clear that the combination of trastuzumab, pertuzumab and a taxane remains the first-line regimen of choice. The preliminary results from the Marianne study do not suggest that T-DM1 with or without pertuzumab are likely to change this in the first line. But obviously for these patients who are Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: An erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 1984;312:513-16

2.

Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82

3.

Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-52

4.

Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses

not considered candidate for this taxane, trastuzumab plus pertuzumab regimen, T-DM1 is clearly an excellent alternative. The reassuring results obtained with T-DM1 in patients with liver function impairment are important. The potential role for T-DM1 in patients presenting with brain metastasis should be further explored. The preliminary results on, admittedly very few patients, suggests a potential role for T-DM1 in these patients. The lack of impact on the effectiveness of T-DM1 in patients with tumors harboring PIK3CA mutations similarly suggests a preference for T-DM1 above other HER2-directed regimens, if these data from the EMILIA study can be confirmed in other studies, including neoadjuvant trials. The apparent lack of additive or synergistic effects of pertuzumab and T-DM1 deserve further study and the aspect of timing and sequence is one possible explanation for this lack of benefit of the combination. These questions are critical for the development of the optimal adjuvant regimens. With the insight in the predictive role of tumor infiltrating lymphocytes in HER2-positive breast cancer and the potential for increasing treatment benefit with combination of HER2targeted agents and immune checkpoint modulators, the future new treatment options for patients with HER2-positive breast cancer seems to be bright.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

with clinical implications. Proc Natl Acad Sci USA 2001;98:10869-74 5.

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;344:783-92

6.

Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014;32:3744-52

7.

Gianni L, Dafni U, Gelber RD, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011;12:236-44

Expert Opin. Biol. Ther. (2015) 15(5)

8.

Gianni L, Pienkowsky 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 randomized multicenter, open-label, phase 2 trial. Lancet Oncol 2012;13:25-32

9.

Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26

10.

Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71

757

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

T. Van den Mooter et al.

11.

Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010;28(7):1124-30

12.

Teicher BA, Chari RVJ. Antibody conjugate Therapeutics: challenges and potential. Clin Cancer Res 2011;17:6389-97

13.

Kovtun YV, Audette CA, Ye Y, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 2006;66:3214-21

14.

15.

.

16.

17.

..

18.

19.

758

Pegram MD, Lopez A, Konecny G, Slamon DJ. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 2000;27(6 Suppl 11):21-5; discussion 92-100 Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linkerdependent intracellular processing. Cancer Res 2006;66:4426-33 Describes the cellular uptake and mode of action of antibodymaytansoid conjugates. Lambert JM, Chari RVJ. Ado-trastuzumab emtansine (T-DM1); an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem 2014;57:6949-64 Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008;68:9280-90 Extensive preclinical study of different trastuzumab-based antibody-drug conjugate with disulfide and thioether linkers. Junutula JR, Flagella KM, Graham RA, et al. Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer. Clin Cancer Res 2010;16:4769-78 Barok M, Tanner M, Konicke K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett 2011;306:171-9

20.

.

21.

Junttila TT, Li G, Parsons K, et al. 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;128:347-56 Preclinical studies on the antitumor activity of the trastuzumab moiety of trastuzumab emtansine (T-DM1) and effect in lapatinib-resistant models. Barok M, Tanner M, K€oninki K, Isola J. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res 2011;13:R46

22.

Oroudjev E, Lopus M, Wilson L, et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther 2010;9:2700-13

23.

Austin CD, Wen X, Gazzard L, et al. Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. Proc Natl Acad Sci USA 2005;102:17987-92

24.

Erickson HK, Philips GDL, Leipold DD, et al. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Res 2012;11:1133-42

25.

Poon KA, Flagella K, Beyer J, et al. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability. Toxicol Appl Pharmacol 2013;273(2):298-313

26.

Jumbe NL, Xin Y, Leipold DD, et al. Modeling the efficacy of trastuzumabDM1 an antibody drug conjugate, in mice. J Pharmacokinet Pharmacodyn 2010;37:221-42

27.

Shen B-Q, Bumbaca D, Saad O, et al. Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine: an emphasis on preclinical and clinical catabolism. Curr Drug Metab 2012;13:901-10

28.

Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, a HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2positive metastatic breast cancer. J Clin Oncol 2010;28:2698-704

Expert Opin. Biol. Ther. (2015) 15(5)

29.

Beeram M, Krop IE, Burris HA, et al. A phase I study of weekly dosing of trastuzumab Emtansin (T-DM1) in patients with advanced Human epidermal growth factor 2-positive breast cancer. Cancer 2012;118:5733-40

30.

Girish S, Gupta M, Wang B, et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): a unique antibodydrug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 2012;69:1229-40 Extensive review on the pharmacokinetics (PKs) of T-DM1.

.

31.

Chudasama VL, Schaedeli Stark F, Harrold JM, et al. Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer. Clin Pharmacol Ther 2012;92:520-7

32.

Gupta M, LoRusso PM, Wang B, et al. Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab-DM1, a HER2-targeted antibody--drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Pharmacol 2012;52:691-703

33.

Lu D, Joshi A, Wang B, et al. An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer. Clin Pharmacokinet 2013;52:657-72

34.

Lu D, Girish S, Gao Y, et al. Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody--drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of various covariates. Cancer Chemother Pharmacol 2014;74:399-410 PK evaluation on serum samples from 671 patients receiving T-DM1 in clinical studies.

.

35.

LI C, Agarwal P, Dent S, et al. Phase 1 study of trastuzumab emtansine in HER2-positive metastatic breast cancer patients with normal or reduced hepatic function. SABCS 2014;P4-15-09

36.

Burris HA III, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the

Trastuzumab emtansine

.

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

37.

.

38.

39.

..

40.

..

41.

42.

treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011;29:398-405 First large Phase II demonstrating the activity and safety of T-DM1 in pretreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Krop I, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor 2- positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane and capecitabine. J Clin Oncol 2012;30:3234-41 Phase II in well-defined group of pretreated patients with HER2-positive MBC, confirming the preclinical activity of T-DM1 in trastzumab and lapatinib-resistant MBC models in patients. Hurvitz SA, Dirix L, Kocsis J, et al. Trastuzumab emtansine versus trastuzumab plus docetaxel for HER2positive metastatic breast cancer. J Clin Oncol 2013;31:1157-63 Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2positive advanced breast cancer. N Engl J Med 2012;367:1783-91 The Emilia study, resulting T-DM1 being recognized as the preferred second-line regimen for patients with HER2 metastatic disease. Kropp IE, Kim S-B, Gonzalez-Martin A, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:689-99 T-DM1 is shown to be more effective than other third line and later line options. Kropp IE, Lin NU, Blackwell K, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol 2015;26:113-19 Kalsi R, Feigenberg S, Kwok Y, et al. Brain metastasis and response to ado-

a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer 2014;120:642-51

trastuzumab emtansine: a case-report and literature review. Clin Breast Cancer 2015;15(2):e163-6 43.

44.

45.

..

46.

Bartsch R, Berghoff AS, Vogl U, et al. Activity of T-DM1 in HER2-positive breast cancer brain metastases. SABCS 2014;P6-16-10 Bender BC, Schaedeli-Stark F, Koch R, et al. A population pharmacokinetic/ pharmacodynamics model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmavol 2012;70:591-601 Dieras V, Harbeck N, Budd GT, et al. Trastuzumab emtansine in human epidermal growth factor receptor 2-positive breast cancer: an integrated safety analysis. J Clin Oncol 2014;32:2750-7 Extensive analysis of the most relevant toxicities of T-DM1 on 884 patients treated with T-DM1. Thon JN, Devine MT, Begonja AJ, et al. High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)-mediated inhibition of platelet production. Blood 2012;120:1975-84

47.

Uppal H, Doudement E, Mahapatra K, et al. Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1). Clin Cancer Res 2015;21:123-33

48.

Krop IE, Suter TM, Dang CT, et al. Feasibility and cardiac safety of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as (Neo) adjuvant therapy for human epidermal growth factor receptor 2--positive early-stage breast cancer. J Clin Onc 2015; In press

49.

50.

51.

Gupta M, Wang B, Carrothers TJ, et al. Effects of trastuzumab emtansine (T DM1) on QT interval and safety of pertuzumab plus T - DM1 in patients with previously treated human epidermal growth factor receptor 2--positive metastatic breast cancer. Clin Pharmacol Drug Dev 2013;2:11-24 Force J, Saxena R, Schneider BP, et al. Nodular regenerative hyperplasia after treatment with trastuzumab emtansine. J Clin Oncol 2014;32:1-4 Welslau M, Dieras V, Sohn JH, et al. Patient-reported outcomes from EMILIA, Expert Opin. Biol. Ther. (2015) 15(5)

52.

LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positiive cancer. Clin Cancer Res 2011;17:6437-47

53.

Perez EA, Hurvitz SA, Lukas C Amler LC, et al. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res 2014;16:R50

54.

Baselga J, Verma S, Ro J, et al. Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC). AACR 2013;LB-63

55.

Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 2015. pii: JCO.2014.55.2158

56.

Phillips GD, Fields CT, Li G, et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res 2014;20:456-68

57.

Gwin WR, Spector NL. Pertuzumab protects the achilles’ heel of trastuzumab--emtansine. Clin Cancer Res 2014;20:278-80

58.

Miller KD, Dieras V, Harbeck N, et al. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol 2014;32:1437-44

59.

Korkola JE, Liu M, Liby T, Heiser L. Detrimental effects of sequential compared to concurrent treatment of pertuzumab plus T-DM1 in HER2+

759

T. Van den Mooter et al.

breast cancer cell lines. SABCS 2014;S6-07

Affiliation

Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by Kainan University on 04/12/15 For personal use only.

Tom Van den Mooter MD, Laure-Anne Teuwen MD, Annemie Rutten MD & Luc Dirix† MD PhD † Author for correspondence Sint-Augustinus Cancer Center, Department of Medical Oncology, Sint-Augustinus, Oosterveldlaan 24, 2610 Wilrijk-Antwerp, Belgium Tel: +003234433737; E-mail: [email protected]

760

Expert Opin. Biol. Ther. (2015) 15(5)