The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies

Abstract

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.

Keywords

breast cancer HER2-positive T-DM1 trastuzumab emtansine

Introduction: HER2 positive breast cancer

Despite advances in early diagnosis and treatment, breast cancer remains the leading cause of cancer-related deaths among women worldwide [Jemal et al. 2011; Desantis et al. 2011]. Molecular analyses have revealed that one subtype of breast cancer characterized by amplification of the gene encoding for human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase receptor, is associated with decreased overall survival (OS) and shorter time to relapse compared with HER2-normal tumors [Perou et al. 2000; Slamon et al. 1987, 1989; Sorlie et al. 2001]. The development of targeted therapies for HER2-positive (HER2+) breast cancer has dramatically improved clinical outcomes for these patients. Trastuzumab (Herceptin; Genentech^®, South San Francisco, CA), a humanized monoclonal body directed against the extracellular domain of HER2, was the first HER2-targeted agent to receive regulatory approval based on a phase III randomized study that showed an improved time to progression (TTP) and OS with the addition of trastuzumab to chemotherapy [Slamon et al. 2001]. Subsequently, trastuzumab became the standard of care treatment in combination with chemotherapy for nonmetastatic HER2+ breast cancer based on several large randomized adjuvant studies showing improved disease free and OS for patients treated with trastuzumab-based therapy [Piccart-Gebhart et al. 2005; Romond et al. 2005; Slamon et al. 2011].

While use of single-agent HER2-targeted therapy is extremely well tolerated, cross-trial comparisons suggest that combination with chemotherapy results in improved clinical outcomes. For example, approximately a quarter of patients with first-line HER2+ metastatic breast cancer (MBC) treated with single-agent trastuzumab will achieve an objective response [Vogel et al. 2002] compared with 50% of patients treated with combination chemotherapy and trastuzumab in the pivotal trial [Slamon et al. 2001]. Unfortunately, the addition of chemotherapy to HER2-targeted agents also results in increased toxicity [Slamon et al. 2001; Vogel et al. 2002]. Furthermore, approximately 50% of patients with previously untreated HER2+ MBC do not achieve an objective response to HER2-targeted therapy indicating de novo resistance to targeted therapy [Slamon et al. 2001] and the vast majority of patients treated with currently available HER2-targeted agents will experience disease progression, underscoring the need for more active and less toxic therapies for this disease.

With the development and approval of therapeutic monoclonal antibodies for the treatment of cancer over the past several decades, a notion has emerged that antibodies may be used to target cytotoxic therapy directly to cancer cells. Delivery of a cytotoxic agent specifically to cancer cells while relatively sparing normal cells promises to improve the therapeutic index for patients. The first antibody–drug conjugate (ADC) to receive United States Federal Drug Administration (FDA) approval was gemtuzumab ozogamicin (Mylotarg^®), an anti-CD33 monoclonal IgG4 antibody linked to a semisynthetic derivative of calicheamicin, a potent DNA-binding antibiotic [Bross et al. 2001; Ricart, 2011]. The accelerated approval of this novel therapy in 2000 was based on phase II data showing efficacy for acute myeloid leukemia. However, in 2010, the drug was withdrawn from the market based on phase III data showing lack of benefit and increased toxicity compared with standard chemotherapy [Petersdorf et al. 2009]. A major problem with this particular molecule, leading to its substantial toxicity, is that calicheamicin is released prematurely prior to being internalized in the cancer cell. Subsequently, scientists focused on developing stable linker technology that does not allow release of the cytotoxic agent until inside the cancer cell.

Trastuzumab emtansine (T-DM1, Genentech^®, South San Francisco, CA, USA), is a first-in-class antibody drug conjugate composed of trastuzumab linked to a highly potent cytotoxic derivative of maytansine (DM1). In contrast to first-generation molecules, T-DM1 utilizes a stable linker that releases the cytotoxic agent only when internalized. Phase I and II clinical trials of T-DM1 in HER2+ advanced breast cancer have been reported and published showing interesting clinical activity and impressive safety results. Multiple later phase studies are ongoing, some of which are close to reporting. This paper will review the mechanism of action, preclinical evidence, clinical trial results and ongoing studies for T-DM1.

T-DM1 preclinical data

Early studies of maytansine, an antibiotic isolated from the Maytenus plant, demonstrated it to be a potent inhibitor of cell division [Remillard et al. 1975; Cassady et al. 2004]. In vitro, it binds tubulin, inhibiting its polymerization as well as resulting in its depolymerization, thus preventing the assembly of microtubules [Cassady et al. 2004]. Treatment of sea urchin and clam eggs with maytansine leads to the disappearance of the mitotic apparatus [Remillard et al. 1975]. Although it binds to the same site on tubulin as the Vinca alkaloids, it has been demonstrated to be 100 times more potent in vitro [Remillard et al. 1975; Cassady et al. 2004]. While highly active in vitro, phase I and II clinical studies in cancer patients demonstrated an unacceptable systemic toxicity profile and the development of this agent was halted [Widdison et al. 2006]. With the emergence of monoclonal antibodies and the subsequent development of technology that allows the cytotoxic to be stably linked to the antibody, the potential for the use of maytansine or its derivatives (maytansinoids) has been revived.

Trastuzumab conjugated with a derivative of maytansine (DM1) is one such ADC that is currently being investigated. Early in its development, studies were conducted to identify the optimal linker to conjugate trastuzumab to DM1 [Lewis Phillips et al. 2008]. This is arguably the most critical work conducted as it led to the development of a conjugated molecule that did not allow the release of the chemotherapy until cellular internalization had occurred. In a series of preclinical experiments, it was shown that linking DM1 to trastuzumab via a nonreducible thioether (SMCC) yielded superior activity, improved pharmacokinetics, and less toxicity compared with trastuzumab linked to a maytansinoid via a disulfide linker. Furthermore, the trastuzumab–SMCC–DM1 conjugate (trastuzumab–MCC–DM1, hereafter T-DM1) was shown to be selective for HER2+ cells, displayed enhanced potency compared with trastuzumab alone in vitro and retained activity against trastuzumab-resistant cells in vitro and in vivo [Lewis Phillips et al. 2008]. Single doses of T-DM1 in rats showed toxicities of transient transaminitis and reversible thrombocytopenia at 20 mg/kg but not 6 mg/kg. This initial clinical work identified T-DM1 as the molecule to take forward into clinical testing.

Other important preclinical work subsequently demonstrated that T-DM1 is active not only in trastuzumab-naïve tumors, but also has significant activity in preclinical models of trastuzumab- and lapatinib-resistant disease. Barok and colleagues reported that T-DM1 significantly inhibited the growth of nine HER2+ cell lines, three of which were resistant to both trastuzumab and lapatinib [Barok et al. 2011]. In their in vivo trastuzumab-resistant xenograft model, T-DM1 had a partial but significant tumor growth inhibition compared with trastuzumab and lapatinib (p < 0.05) [Barok et al. 2011]. Histologic examination revealed a significantly higher number of cells with aberrant mitotic morphology and giant multinucleated cells, both of which are consistent with mitotic catastrophe, as well as apoptotic cells in T-DM1-treated compared with trastuzumab-treated xenografts [Barok et al. 2011].

A unique feature of T-DM1 is that it appears to maintain the antitumor activity of the monoclonal antibody. Barok and colleagues performed an in vitro antibody-dependent cellular cytotoxicity (ADCC) assay and showed that T-DM1 maintains a similar ability to evoke ADCC as trastuzumab, indicating that conjugation of the antibody does not alter its ability to mediate an immune response [Barok et al. 2011]. Junttila and colleagues further evaluated the mechanisms of action of T-DM1 and showed through in vitro molecular analyses that T-DM1 binds HER2 with an affinity similar to that of trastuzumab and retains all of the mechanisms of action of trastuzumab including inhibition of the PI3K/AKT signaling pathway, inhibition of HER2 shedding, and Fcγ receptor-mediated engagement of immune cells [Junttila et al. 2011]. Further analysis showed that T-DM1 retains activity against cell lines with activated PI3K mutations and lapatinib-resistant cell lines. The ability of T-DM1 to circumvent trastuzumab resistance has been explored in other preclinical models, including a set of experiments aimed at evaluating whether T-DM1 is able to augment natural killer (NK)-cell-mediated tumor cell lysis or inhibit the induction of cancer stem cells [Honig et al. 2011] which are inherently treatment resistant. In this preclinical work, T-DM1 appeared to interfere with the NK-cell-dependent induction of the epithelial-to-mesenchymal transition (EMT), thus possibly preventing the induction of the stem cell phenotype.

T-DM1 clinical data

Phase I studies

Clinical evaluation of T-DM1 for the treatment of HER2+ breast cancer has largely corroborated the promising findings of the preclinical studies described above (Table 1). In the first-in-human phase 1 clinical trial (TDM3569g) evaluating T-DM1, successive cohorts of patients with HER2+ MBC who had progressed on trastuzumab-based therapy received escalating doses of T-DM1 starting at 0.3 mg/kg, up to 4.8 mg/kg every 3 weeks [Krop et al. 2010a]. Twenty-four patients who had received a median of four prior chemotherapy regimens for metastatic disease were treated on this study. The dose-limiting toxicity (DLT) was transient grade 4 thrombocytopenia at 4.8 mg/kg, and the maximum tolerated dose (MTD) was established at 3.6 mg/kg. The half-life at this dose was 3.5 days. The most common adverse events (AEs) were thrombocytopenia (54.2%), elevated transaminases (41.7%), fatigue (37.5%), anemia (29.2%), and nausea (25.0%). Interestingly, there were no reports of greater than grade 1 nausea, vomiting, alopecia, or neuropathy despite the use of a cytotoxic agent. Although grade 3 and 4 thrombocytopenia was reported in 4.2% and 8.3% of patients, respectively, at the MTD, it was generally grade 1 or 2. One patient experienced grade 3 pulmonary hypertension at the MTD. For the 15 patients treated with the MTD, the clinical benefit rate (CBR) at 6 months was 73%, and the objective response rate (ORR) for the 9 patients with measurable disease was 44%.

Table 1.

Summary of clinical trials of trastuzumab emtansine (T-DM1).

Study	Phase	Patient Characteristics	N	Treatment	Outcomes
Krop et al (2010a) ²²	I	Pretreated HER2+ MBC	24	T-DM1 every 3 weeks	CBR: 73%
Krop et al (2010a) ²²	I	Pretreated HER2+ MBC	24	T-DM1 every 3 weeks	ORR: 44%
Krop et al (2008) ²³	I	Pretreated HER2+ MBC	28	T-DM1 every week	Confirmed ORR: 46%
Aogi et al (2011) ²⁴	I	Pretreated HER2+ MBC	10	T-DM1 every 3 weeks	PR: 20%
Krop et al (2010b) ²⁸	Ib	Pretreated HER2+ MBC	14	T-DM1 every 3 weeks with weekly paclitaxel	Unconfirmed ORR: 43%
Krop et al (2010c) ³¹	Ib	Pretreated HER2+ MBC	65	T-DM1 every 3 weeks with GDC-0941 daily on days 14-21	Unreported to date
Diéras et al (2010) ³²	Ib/II	First-line or pretreated HER2+ MBC	67	T-DMI1 and pertuzumab every 3 weeks	ORR (pretreated): 42%
Diéras et al (2010) ³²	Ib/II	First-line or pretreated HER2+ MBC	67	T-DMI1 and pertuzumab every 3 weeks	ORR (first line): 41%
Burris et al (2011) ²⁵	II	Pretreated HER2+ MBC	112	T-DM1 3.6 mg/kg every 3 weeks	ORR: 25.9% (95% CI: 18.4-34.4%)
Burris et al (2011) ²⁵	II	Pretreated HER2+ MBC	112	T-DM1 3.6 mg/kg every 3 weeks	PFS: 4.6 months (95% CI: 3.9-8.6 months)
Krop et al (2009) ²⁶	II	Pretreated HER2+ MBC	110	T-DM1 3.6 mg/kg every 3 weeks	ORR: 32.7% (95% CI: 24.1-42.1%)
Krop et al (2009) ²⁶	II	Pretreated HER2+ MBC	110	T-DM1 3.6 mg/kg every 3 weeks	PFS: 7.3 months
Hurvitz et al (2011) ³⁴	II	First-line HER2+ MBC	137	T-DM1 versus trastuzumab plus docetaxel	ORR: 64% versus 58% PFS: 14.2 versus 9.2 months (HR 0.594, p = 0.035)

HER2, human epidermal growth factor receptor 2; HER2+, HER2 positive; MBC, metastatic breast cancer; CBR, clinical benefit rate; ORR, objective response rate; PR, partial response; PFS, progression-free survival.

Another phase I dose escalation study examined the safety of weekly administration of T-DM1 in 28 patients with advanced HER2-positive MBC pretreated with trastuzumab [Krop et al. 2008]. Patients were heavily pretreated, having received a median of five prior regimens for MBC. The most common AEs were similar to those seen with every 3-week dosing and included fatigue, nausea, thrombocytopenia, transaminitis, and anorexia. Of the reported AEs, 10% were grade 3 and 0.4% were grade 4. Alopecia was not listed as an adverse event. The study reported a DLT of thrombocytopenia at 2.9 mg/kg, and thus concluded the weekly MTD to be 2.4 mg/kg. Interestingly, the exposure to T-DM1 was two times higher at steady state with weekly dosing compared with every 3 weeks dosing. It is unclear why weekly dosing has not been evaluated in subsequent studies, although patient convenience of every 3 weeks dosing may have been a factor. Of the 28 patients enrolled in the study, 27 had measurable disease at baseline and 26 were evaluable for response. ORR was seen in 15 (57.6%) and confirmed in 12 (46%).

A third phase I study sought to determine the MTD in 10 Japanese patients with trastuzumab-pretreated HER2+ MBC [Aogi et al. 2011]. Patients received T-DM1 every 3 weeks at a dose of 1.8, 2.4, or 3.6 mg/kg. One patient in the 2.4 mg/kg group experienced a DLT of grade 3 transaminitis. No other DLTs were observed. Therefore, the MTD was established at 3.6 mg/kg. Although generally mild, the most frequently reported AEs were nausea, fatigue, arthralgia, and pyrexia. Recurrent lab value changes included thrombocytopenia and transaminitis. A partial response was observed in 2 patients. Promising efficacy results with ORRs of 40–50% and manageable toxicity profiles in these phase I trials quickly led to phase II and III trials of T-DM1.

Phase II single-arm studies

Based on the promising phase I results, a phase II proof-of-concept single-arm trial (TDM4258g) was conducted and enrolled 112 patients with HER2+ MBC who had received prior HER2-directed therapy and chemotherapy [Burris et al. 2011]. T-DM1 was administered at 3.6 mg/kg every 3 weeks. The ORR was 25.9% by independent review (95% confidence interval [CI]: 18.4–34.4%) and 37.5% by investigator review (95% CI: 28.6–46.6%). Median duration of response (DR) was not reached due to insufficient events (lower limit of 95% CI: 6.2 months) and median PFS was 4.6 months by both independent and investigator review (95% CI for independent review: 3.9–8.6 months). In 66 patients who had received prior trastuzumab and lapatinib therapy, ORR was 24.2% by independent review and 34.8% by investigator review. T-DM1 was well tolerated with no dose-limiting cardiotoxicity observed. The most frequent AEs were fatigue, nausea, and headache. Although most AEs were grade 1 or 2, grade 3 and 4 toxicities included hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). Retrospective analysis confirmed 74 out of 95 assessable patients as having HER2+ tumors by immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH). In these patients, ORR was 33.8% compared with 4.8% in patients with HER2-normal tumors. HER2 positivity was further quantified by PCR. In 25 patients whose degree of HER2 positivity was greater than or equal to the median, the ORR was 36% and median PFS was not reached. Comparatively, in 25 patients whose degree of HER2-positivity was less than the median, ORR was 28.0% and median PFS was 4.2 months.

A confirmatory single-arm phase II (TDM4374g) study enrolled 110 patients with HER2+ MBC previously treated with an anthracycline, a taxane, capecitabine, lapatinib, and trastuzumab, and two HER2-directed regimens [Krop et al. 2009]. Again, T-DM1 was administered at a dose of 3.6mg/kg every 3 weeks. The median number of prior agents used in the metastatic setting was 7 (1-15), and 99% of patients had been given five agents prior to the study. Frequent AEs included fatigue (59.1%), nausea (37.3%), and thrombocytopenia (29.1%). A serious AE occurred in 23% of patients, and 42% experienced grade 3 or 4 AEs. The most common grade 3 and 4 toxicities included thrombocytopenia (5.4%), back pain (3.6%), fatigue (2.7%), and transaminitis (2.7%). T-DM1 use was not associated with significant cardiotoxicity. No patients had a left ventricular ejection fraction (EF) <45% at the end of the study, and no patients experienced a decrease ≥25%. ORR was 32.7% (95% CI: 24.1–42.1%) by independent review and 30.0% (95% CI: 22.0–39.4%) by investigator review. Median PFS was 7.3 months. Retrospective analysis confirmed HER2+ disease in 76 patients by IHC 3+ or FISH, and ORR for these patients was 39.5% by independent review. Retrospective analysis also revealed an association between the degree of HER2-positivity and response [LoRusso et al. 2010]. In 26 patients with greater than or equal to the median degree of HER2 expression, ORR was 50%, and in 38 patients with less than the median degree of HER2 positivity, ORR was 32%.

Phase I and II combination studies

TDM4652g is a phase Ib multicenter, open-label, dose-escalation study with a 3 × 3 design, evaluating T-DM1 plus paclitaxel and pertuzumab in patients with HER2+ MBC who previously received HER2-directed therapy [Krop et al. 2010b]. Interim results for 14 patients who received T-DM1 every 3 weeks and weekly paclitaxel were reported. All patients had received prior trastuzumab and 11 had received prior lapatinib therapy. Patients had extremely heavily pretreated disease with a median of 10 prior systemic therapies. At a T-DM1 dose of 2.4 mg/kg and paclitaxel dose of 65 mg/m² administered in six patients, 2 DLTs were observed: grade 3 transaminitis and grade 3 dehydration due to nausea and vomiting. No DLT was observed in three patients when the T-DM1 dose was reduced to 2.0 mg/kg with the same dose of paclitaxel. However, when T-DM1 was dosed at 2.0 mg/kg and the paclitaxel dose was increased to 80 mg/m² in six patients, a DLT of grade 3 neutropenia was observed in one patient. This was established as the MTD. A total of six serious adverse events (SAEs) were reported in three patients: grade 2 vomiting (considered related), grade 3 dehydration (considered related), grade 3 cellulitis, grade 3 muscular weakness, grade 3 interverterbral disc protrusion, and grade 3 hypersensitivity (considered related). To date, two confirmed objective responses and an additional four unconfirmed partial responses have been observed, and five of these patients remain on study.

BP22572 is another ongoing, phase Ib, multistage study evaluating the combination of T-DM1 and docetaxel in patients with HER2-positive advanced breast cancer [Lu et al. 2011]. Although the results of the study are pending, pharmacokinetic analysis has been conducted for both phase Ib combination studies to evaluate for possible drug–drug interaction between T-DM1 and taxanes. The pharmacokinetics of T-DM1 were not altered when administered with paclitaxel [Lu et al. 2010] and were within historical range when administered with docetaxel [Lu et al. 2011]. The pharmacokinetics of paclitaxel and docetaxel were also not altered when administered with T-DM1. Furthermore, paclitaxel and docetaxel did not alter the exposure of DM1 as measured by the maximum concentration after T-DM1 administration. This data suggests T-DM1 and taxanes can be administered together without clinically significant drug–drug interaction. The larger question of whether or not optimal treatment outcomes require the addition of taxane (or other) chemotherapy to T-DM1 remains unanswered as of yet.

Activation of the PI3K pathway has been hypothesized to reduce the efficacy of trastuzumab. GDC4627g is a phase Ib, open-label, 3 × 3 design, dose escalation study of GDC-0941, a PI3K inhibitor, and T-DM1 in 65 trastuzumab pretreated patients with advanced HER2-positive cancer [Krop et al. 2010c]. Results have been reported on 13 patients. Starting doses were T-DM1 3.6 mg/kg administered every 3 weeks and GDC-0941 80 mg administered orally daily on days 14–21. When T-DM1 was administered at 3.6 mg/kg and GDC-0941 was administered at 80 mg, one DLT of grade 4 thrombocytopenia was observed. No additional DLTs were observed in the cohort, and dose escalation continued. At a T-DM1 dose of 3.6 mg/kg and GDC-0941 dose of 115 mg, one patient experienced grade 4 thrombocytopenia and another experienced grade 3 fatigue. Therefore, the T-DM1 dose was reduced to 3.0 mg/kg and GDC-0941 was reduced to 100 mg. No DLTs were observed, and dose escalation continues. Pharmacokinetic and efficacy data has not yet been reported.

TDM4373g is a phase Ib/II study evaluating the combination of T-DM1 with pertuzumab, a monoclonal antibody that binds to the extracellular domain of HER2 at a different epitope than trastuzumab, and prevents dimerization of HER2 with HER3. In this study, 67 patients with HER2+ MBC in the first-line (n = 22) or relapsed setting (n = 45) [Diéras et al. 2010] were enrolled. Of the first-line patients, 19 had received trastuzumab, and 2 had received lapatinib in the adjuvant setting. All of the relapsed patients had been treated with trastuzumab, 34 had been treated with lapatinib, and the median number of prior systemic agents was 7. T-DM1 was administered at 3.6 mg/kg every 3 weeks, and pertuzumab was administered at a loading dose of 840 mg followed by 420 mg every 3 weeks thereafter. Evaluation of the volume of distribution and clearance of T-DM1 in the setting or pertuzumab did not vary significantly when compared with T-DM1 monotherapy, indicating that pertuzumab does not alter the pharmacokinetics of T-DM1 [Burris et al. 2010]. The most frequently reported AEs were fatigue (53.7%), nausea (44.8%), and thrombocytopenia (31.3%) [Diéras et al. 2010]. Frequently reported grade ≥3 toxicities included thrombocytopenia (11.9%), fatigue (9.0%), increased alanine transaminase (ALT) (7.5%), and increased aspartate transaminase (AST) (6.0%). One grade 5 SAE of pneumonia was reported. A total of 19 responses (42%) in relapsed patients and 9 responses (41%) in first-line patients were reported. TDM4688g (NCT00943670) is a phase II trial also investigating the safety and tolerability of the combination of T-DM1 and pertuzumab in patients with HER2-positive advanced breast cancer with early disease progression while receiving T-DM1 alone. Enrollment is complete, but results are pending. TDM4788g (MARIANNE [ClinicalTrials.gov identifier: NCT01120184] is a phase III study of T-DM1 alone or in combination with pertuzumab compared with trastuzumab plus a taxane as first-line treatment for HER2-positive MBC. This study is still ongoing.

Phase II comparative study

TDM4450g is a randomized, multicenter, open-label, phase II study comparing T-DM1 with trastuzumab plus docetaxel as first line therapy for HER2-positive MBC in 137 patients [Hurvitz et al. 2011]. Trastuzumab had been used in the neoadjuvant or adjuvant setting in 18% of patients in the T-DM1 arm and 27% of patients in the trastuzumab plus docetaxel arm prior to enrollment. Trastuzumab was administered at a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks, docetaxel was administered at a dose of 75 or 100 mg/m² every 3 weeks, and T-DM1 was administered at a dose of 3.6 mg/kg every 3 weeks. Although the ORR was similar in the two groups (64% in the T-DM1 arm compared with 58% in the trastuzumab plus docetaxel arm), median PFS was significantly improved in the T-DM1 arm (14.2 versus 9.2 months; hazard ratio [HR] 0.594, p = 0.035) and duration of response was 9.5 months in the combination arm but had not been reached at the time of reporting in the T-DM1 arm. Moreover, T-DM1 had a better safety profile than the standard therapy with 46% of patients experiencing grade 3/4 AEs in the T-DM1 arm compared with 89% in the control arm. Serious AEs were observed in 19% and 26% of patients, respectively. The most frequent AEs in the standard treatment arm were alopecia (66.7%), neutropenia (63.6%), and fatigue (45.5%), and most frequent grade ≥3 AEs were neutropenia (60.6%), leukopenia (25.8%), and febrile neutropenia (13.6%). In the T-DM1 arm, the most frequent AEs were fatigue (49.3%), nausea (47.8%), and increased AST and pyrexia (both 39.1%). The most frequent grade ≥3 AEs were thrombocytopenia (8.7%), increased AST (8.7%), and increased ALT (8.7%). No significant cardiotoxicity was observed in either arm. Alopecia was reported in 67% of patients in the control arm compared with 4% of patients in the T-DM1 arm. Patients in the control arm were allowed to discontinue one drug (docetaxel or trastuzumab) for toxicity and continue on the other study drug until disease progression or unacceptable toxicity. Patients in the control arm received a median of 8.1 months of trastuzumab and 5.5 months with docetaxel. In contrast, the median duration of treatment with T-DM1 was 10.0 months. Thus, one potential benefit of T-DM1 is that its tolerability may allow patients to continue treatment of the ADC longer than patients are able to receive an unconjugated cytotoxic such as docetaxel.

T-DM1 ongoing studies

Several phase III comparative trials of T-DM1 are currently underway (Table 2). The TDM4370 (EMILIA) study is a randomized, phase III multicenter, open-label trial [ClinicalTrials.gov identifier: NCT00829166] that is comparing the safety and efficacy of T-DM1 with that of capecitabine and lapatinib for HER2+, trastuzumab-pretreated MBC. This study has been powered to show differences in the coprimary endpoints of OS and PFS, with preliminary results expected in 2012. Another randomized phase III study (MARIANNE; [ClinicalTrials.gov identifier: NCT01120184]) is studying T-DM1 alone or in combination with pertuzumab compared with trastuzumab plus a taxane as first-line treatment for HER2+ MBC. The primary endpoint of this study is PFS. Another trial, TH3RESA [ClinicalTrials.gov identifier: NCT01419197] is investigating T-DM1 versus physician’s choice of treatment in patients with HER2-positive MBC previously treated with HER2-directed therapy.

Table 2.

Ongoing phase III clinical trials of trastuzumab emtansine (T-DM1).

Study	Patient population	Study design and treatment regimen	Treatment regimen	N
NCT00829166 “EMILIA”	Pretreated HER2+ MBC	Randomized, open label	T-DM1 versus lapatinib + capecitabine	980
NCT01120184 “MARIANNE”	Untreated HER2+ MBC	Randomized, double blind	T-DM1 +/- pertuzumab versus trastuzumab + taxane	1092
NCT01419197 “TH3RESA”	Pretreated HER2+ MBC	Randomized, open label	T-DM1 versus physician’s choice	795

HER2, human epidermal growth factor receptor 2; HER2+, HER2 positive; MBC, metastatic breast cancer

Toxicity and patient-focused perspectives

The most frequent AEs associated with T-DM1 include thrombocytopenia, transaminitis, and fatigue.

Thrombocytopenia

Early in the clinical development of T-DM1, thrombocytopenia emerged as one of its more concerning AEs. In the first phase I study of T-DM1, a decline in platelet count was reported in almost all patients receiving a dose greater than 1.2 mg/kg [Krop et al. 2010a]. However, this decline was generally transient. At the MTD, thrombocytopenia was generally grade 1 or 2. Furthermore, no clinically significant bleeding events were reported. Future studies of T-DM1 reported a higher incidence of grade 3 or higher thrombocytopenia [Krop et al. 2008; Burris et al. 2011; Krop et al. 2009, 2010c; Diéras et al. 2010]; however, none of these studies reported hemorrhagic complications. In the study of weekly administration of T-DM1, grade 3 or 4 thrombocytopenia was reported in 10.7% of patients [Krop et al. 2008]. A single-arm phase II study reported an incidence of grade 3 or 4 thrombocytopenia of 8% [Burris et al. 2011]. Two patients required dose reduction due to thrombocytopenia, and one patient discontinued treatment due to thrombocytopenia. The study did report six grade 3 hemorrhagic events, and one patient had concurrent grade 3 thrombocytopenia and epistaxis. However, no patients discontinued treatment due to hemorrhage. In the second single-arm phase II study, 3.6% and 1.8% of patients experienced grade 3 and 4 thrombocytopenia, respectively [Krop et al. 2009]. A total of 17 patients required dose reduction due to toxicity, and some of these reductions were due to thrombocytopenia. In a phase Ib combination study of T-DM1 and a P13K inhibitor, DLT of grade 4 thrombocytopenia was seen in the two cohorts with T-DM1 dosed at 3.6mg/kg [Krop et al. 2010c]. In another phase Ib/II study investigating the combination or T-DM1 and pertuzumab, 11.9% of patients experienced grade 3 or higher thrombocytopenia and three patients required dose reductions due to thrombocytopenia [Diéras et al. 2010]. In the only phase II comparative study of T-DM1, 8.7% of patients experienced grade ≥3 thrombocytopenia in the T-DM1 arm compared with 3.0% in the trastuzumab plus docetaxel arm [Hurvitz et al. 2011]. However, no grade 3 or 4 hemorrhagic events and only one grade 2 hemorrhagic event was reported.

A model of platelet development and circulation was generated and analyzed to better understand the thrombocytopenia associated with T-DM1 [Bender et al. 2011]. Data from the phase I dose escalation study (TDM3569g) and phase II study of single-agent T-DM1 (TDM4258g) were used to generate this model, and data from another phase II study (TDM4374g) were used to validate the model. The model accurately predicted the incidence of grade 3 or higher thrombocytopenia in the validation data set. The model also accurately predicted that the downward drifting of the platelet count would eventually stabilize, and there would be a subset of patients who would experience a rapid decline in platelets which would also eventually stabilize. The authors concluded that the model suggests partial depletion of the platelet pool as a mechanism for the thrombocytopenia. This data suggests that that the thrombocytopenia associated with T-DM1 should be transient and well tolerated.

Transaminitis

In the first phase I study of T-DM1 (TDM3569g), 42% of patients experienced transaminitis, but no grade 3 or 4 events were observed [Krop et al. 2010a]. Subsequent studies continued to report grade 3 or higher transaminitis in less than 10% of patients. Weekly administration of T-DM1 resulted in grade 3 transaminitis in 7.1% of patients [Krop et al. 2008]. In a single-arm phase II study, 2.7% of patients experienced a grade 3 elevation in AST and ALT [Krop et al. 2009]. One patient with underlying nonalcoholic fatty liver disease died of grade 5 hepatic dysfunction. A portion of the 17 dose reductions in the study were attributed to transaminitis. In a combination phase Ib study of T-DM1 and paclitaxel, DLT toxicity of grade 3 transaminitis was observed at a T-DM1 dose of 2.4 mg/kg [Krop et al. 2010b]. In another phase Ib/II combination study of T-DM1 and pertuzumab, 7.5% of patients experienced grade 3 or higher elevation in ALT, 6.0% of patients experienced grade 3 or higher elevation in AST, and 5 patients required dose reduction in T-DM1 due to elevation in AST or ALT [Diéras et al. 2010]. In the phase II comparative study of T-DM1, 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.

Quality of life

The phase II comparative trial, TDM4450g, which compared T-DM1 to trastuzumab plus docetaxel as first line therapy in the metastatic setting, included quality of life as assessed by the FACT-B Trial Outcome Index as a secondary end point [Bianchi et al. 2011]. The questionnaire assesses physical and functional wellbeing as well as breast cancer specific symptoms. Worsening, reported as a ≥5-point decrease, was significantly delayed in the T-DM1 arm (7.5 months versus 3.5 months; hazard ratio [HR] = 0.58, p = 0.022). Furthermore, a repeated measures mixed effects model showed a mean difference of 3.65 favoring the T-DM1 arm in FACT-B TOI scores (p = 0.023), attributed to treatment effects. The highest difference was seen in physical wellbeing, but other categories with significant differences included ‘lack of energy’, ‘trouble meeting needs of family’, ‘bothered by side effects’, ‘feeling ill’ and ‘forced to spend time in bed’. Thus, the T-DM1 arm was associated with an improved quality of life when compared with trastuzumab plus docetaxel. These sorts of differences in quality of life are not surprising given the fact that the cytotoxic agent within T-DM1 is delivered relatively specifically to cancer cells, thus improving the tolerability and limiting the toxicity experienced by patients.

Conclusion

Although the treatment of HER2+ breast cancer has dramatically improved since the introduction of targeted therapy, treatment challenges persist including resistance to currently available therapies as well as significant treatment-related toxicity. T-DM1 is a novel ADC consisting of trastuzumab stably linked to a maytansinoid, a potent cytotoxic chemotherapeutic agent. Early preclinical and clinical studies have shown that the agent is well tolerated and efficacious, both in the front-line and pretreated settings. One randomized phase II study demonstrates that T-DM1 is more tolerable than standard trastuzumab plus docetaxel and is associated with improved clinical outcomes including PFS and quality of life. Despite the fact that T-DM1 contains a strong chemotherapeutic agent, the toxicity profile of T-DM1 is relatively mild with self-limited thrombocytopenia and transaminitis emerging as the most common AEs. Preliminary data from phase II studies evaluating T-DM1 in combination with other chemotherapeutic and nonchemotherapeutic agents have also been promising. Several randomized phase III studies of T-DM1 alone and in combination with other targeted agents are nearing completion. Results of these trials will clarify the role of T-DM1 in the treatment of HER2+ breast cancer and will continue to pave the path for future developments. Studies of T-DM1 in the adjuvant/neoadjuvant setting compared with standard trastuzumab-based cytotoxic regimens are on the horizon. As the first ADC, the tolerability and efficacy of T-DM1 has encouraged the development of newer agents. Moreover, its stable linker can be expanded to join other targeted antibodies and cytotoxic agents.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Dr Kakkar has no conflicts of interest. Dr Hurvitz received reimbursement for international travel expenses from Roche to present at an international symposium and has received research grant funding from Genentech/Roche.

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