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`Cancer Therapy Vol. 9, page 45
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`Cancer Therapy Vol. 9, 45-54, 2013
`T-DM1: a giant step forwards in HER2 therapeutics
`Research Article
`
`Dey Nandini 1, 2, Carlson Jennifer1, Leyland-Jones Brian 1, 2, and De Pradip 1, 2*
`
`1 Edith Sanford Breast Cancer, Sanford Research/USD 60th Street N, Sioux Falls, SD, 57104
`2 Department of Internal Medicine, University of South Dakota, SD
`__________________________________________________________________________________________________
`*Correspondence: Pradip De, MS, PhD Associate Scientist, Edith Sanford Breast Cancer, Sanford Research/USD 60th Street N, Sioux
`Falls, SD, 57104 Tel: 0030-25510-74622, Fax: 605-312-6071, Email:  Pradip.De@SanfordHealth.org
`Keywords: Breast cancer, HER2, T-DM1, trastuzumab and pertuzumab
`
`
`Received: 15 August 2013; Revised: 17 September 2013
`Accepted: 18 September 2013; electronically published: 19 September 2013
`
`Summary
`
`Despite treatment advances, including the humanized anti-HER2 antibody trastuzumab and the dual EGFR/HER2
`tyrosine kinase small molecule inhibitor lapatinib, HER2+ breast cancer will eventually progress in most patients,
`highlighting the need for novel, alternative therapies. Moreover, HER2-targeted therapies are rarely given as a
`mono-therapy but are generally given in combination with other chemotherapy. It has been known that systemic
`toxicities are often associated with chemotherapies for cancer patients, therefore antibody drug conjugates with
`potential cytotoxic agent(s) are a promising therapeutic approach for HER2+ breast cancer patients. Trastuzumab
`emtansine (T-DM1) is an antibody drug conjugate that optimizes delivery of chemotherapy with an anti-HER2
`monoclonal antibody, trastuzumab. In HER2+ patients, T- DM1 delivers DM1 to the tumor and uses HER2 as the
`address. The mechanism of action does not rely on functional HER2 signaling and only requires high levels of
`HER2 on the cell surface. In addition, the presence of downstream alterations, such as PIK3CA mutation or the
`absence of PTEN, should not matter. T-DM1 has successfully passed through several clinical trials for the targeted
`delivery of chemotherapy and anti-HER2 monoclonal antibody therapy for patients with metastatic, HER2+ breast
`cancer. Recently, FDA gave approval to T-DM1, which will be marketed as Kadcyla, for patients with HER2+, late
`stage (metastatic) breast cancer. This is a novel approach to treating HER2+ breast cancer, the antibody drug
`conjugate (ADC) is seen as a significant advance for patients.
`
`I. Introduction
`The current view of breast cancer is that it is
`segmented into molecular subtypes defined by genomic
`alterations involved in tumor progression which then
`identify patient populations best treated with targeted
`inhibition. One such population is patients with HER2
`gene amplification and/or overexpression (approximately
`20-30% of human breast cancers) (O'Brien, Browne et al.
`2010). Before the development of HER2-targeted therapy,
`HER2-positivity was predictive of poor clinical outcomes
`(Slamon, Clark et al. 1987; Ross and Fletcher 1998). This
`group of proteins is comprised of EGFR (HER1), HER2,
`HER3 and HER4 (Yarden 2001) that are involved in cell
`growth and survival through activation of the PI3K-AKT-
`mTOR and the RAS-RAF-MEK-ERK pathways (Arteaga,
`Sliwkowski et al. 2012). Non-targeted breast cancer
`treatment options may
`include one or more of
`chemotherapy, radiation, and surgery, while HER2
`overexpressing breast cancers will typically involve
`trastuzumab-based therapy, with newer agents such as
`
`
`lapatinib providing a second line of treatment (Geyer,
`Forster et al. 2006; O'Brien, Browne et al. 2010). Single
`agent use of
`trastuzumab, a humanized anti-HER2
`monoclonal antibody, has shown objective responses in
`the range of 15–20% in phase II trials when used in first-
`line or refractory HER2-positive advanced breast cancer
`settings (Baselga, Tripathy et al. 1996; Cobleigh, Vogel et
`al. 1999; Vogel, Cobleigh et al. 2002). This benefit is
`magnified by the concomitant use of trastuzumab with
`traditional chemotherapy (anthracycline or epirubicin plus
`cyclophosphamide),
`leading
`to an
`improvement
`in
`objective response rates that range between 50–84% and
`median survivals that range between 25–37 months
`(Burstein, Kuter et al. 2001; Slamon, Leyland-Jones et al.
`2001; Esteva, Valero et al. 2002; Montemurro, Choa et al.
`2004; Andersson, Lidbrink et al. 2011; Valero, Forbes et
`al. 2011). Based on these and other data, the FDA and
`other regulatory agencies around the world approved the
`use of trastuzumab in the metastatic setting in 1998;
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`Pradip De et al: T-DM1: a giant step forwards in HER2 therapeutics  
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`an expansion of its use to the adjuvant setting was
`approved in 2006.
`Subsequently, two other HER2-targeted agents
`have been approved for the treatment of HER2-positive
`metastatic breast cancer,
`lapatinib and pertuzumab.
`Lapatinib is an oral small molecule dual receptor tyrosine
`kinase inhibitor that binds and inhibits both HER1 and
`HER2. Preclinical data demonstrated that lapatinib plus
`trastuzumab enhanced apoptosis (Konecny, Pegram et al.
`2006),
`improved
`tumor control
`in HER2-positive
`xenograft (Scaltriti, Verma et al. 2009) and resulted in a
`marketed accumulation of inactive HER2 on the cell
`surface in
` conjunction with enhanced cytotoxicity
`(Scaltriti, Verma et al. 2009). It was approved in 2007 for
`use in combination with capecitabine in patients whose
`disease progressed on or after an anthracycline, taxane
`and trastuzumab-based therapy. Data from a phase III trial
`showed an improved time to progression and response
`rate associated with lapatinib plus capecitabine compared
`to capecitabine alone (Geyer, Forster et al. 2006). In 2010,
`lapatinib also received FDA approval in combination with
`an aromatase inhibitor (letrozole) for post menopausal
`ER+/HER2+ metastatic breast cancer patients (Johnston,
`Pippen et al. 2009). The response rate associated with
`lapatinib monotherapy was 24% in trastuzumab-sensitive
`patients but the response rate was less than 10% in
`trastuzumab-resistant settings (Burstein, Storniolo et al.
`2008; Gomez, Doval et al. 2008; Blackwell, Burstein et
`al. 2010). Since each modality (trastuzumab and lapatinib)
`offers clinical benefit, combining
`trastuzumab plus
`lapatinib to target extracellular and intracellular domains
`of HER2 offers an attractive strategy. A phase III EGF
`104900 study demonstrated a 4.5 month median overall
`survival advantage with the lapatinib and trastuzumab
`combination (Blackwell, Burstein et al. 2012). The phase
`III NeoALTTO study randomly assigned 455 patients
`(HER2+ primary breast cancer with tumors greater than 2
`cm in diameter) to receive paclitaxel (T) with trastuzumab
`(TH), with lapatinib (TL), or with both HER2- targeting
`agents (THL). Pathological complete response (pCR) rate
`was significantly higher in the group given lapatinib plus
`trastuzumab plus paclitaxel (THL) (51%) than in the
`group given trastuzumab plus paclitaxel (TH) (29.5%) or
`lapatinib plus paclitaxel (TL) (24.7%) (Baselga, Bradbury
`et al. 2012). Similar results were observed from a
`randomized phase II CHER-LOB study. This is a non-
`comparative, randomized, phase II trial of preoperative
`taxane-anthracycline in combination with trastuzumab,
`lapatinib or combined trastuzumab plus lapatinib in
`patients with HER2-positive, stage II to IIIA operable
`breast cancer. The pCR rates were 25% for chemotherapy
`plus trastuzumab group, 26% for chemotherapy plus
`lapatinib group and 46%
`for chemotherapy plus
`trastuzumab plus
`lapatinib
`treated group (Guarneri,
`Frassoldati et al. 2012).
`In 2012, the third HER2-targeted therapy to
`receive
`regulatory approval was pertuzumab. Like
`trastuzumab, pertuzumab is a humanized monoclonal
`antibody that binds to the extra- cellular domain of HER2
`but binds to a different domain than that of trastuzumab
`(domain II instead of domain IV) (Franklin, Carey et al.
`
`  
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`46
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`2004; Sun Yuliang, Dey Nandini et al. 2013). In the
`NeoSphere study, 46% of
`the women who were
`administrated trastuzumab, pertuzumab, plus docetaxel
`(neoadjuvant) achieved a pCR (49 of 107 patients; 45.8%
`[95% CI 36.1—55.7]) 4 (Gianni, Pienkowski et al. 2012).
`The median progression free survival (PFS) in patients
`receiving trastuzumab, pertuzumab and docetaxel in the
`double-blind CLEOPATRA
`trial (808 patients with
`HER2-positive,
`locally
`recurrent, unresectable or
`metastatic breast cancer) was observed to be 18.5 months,
`as compared to 12.4 months in patients who received
`placebo, trastuzumab and docetaxel (Baselga, Bradbury et
`al. 2012). The results of these trials show that (1) in 54%
`of
`the patients enrolled
`in
`the NeoSphere
`trail,
`trastuzumab plus pertuzumab plus docetaxel combination
`fell short of achieving pCR, and (2) the median PFS in
`metastatic breast cancer patients receiving treatment with
`trastuzumab plus pertuzumab plus docetaxel in the
`CLEOPATRA trial was increased by not more than 6
`months. Given
`the
`limited benefits of
`these
`latter
`treatment regimens, there is clearly a room for additional
`improvement.
`The above
`findings suggest
`that currently
`available HER2-targeted therapies are rarely given as
`mono-therapy but are generally given in combination with
`other chemotherapy or chemotherapies. Since toxicities
`associated with chemotherapy can be a substantial source
`of comorbidity for patients with cancer, tumor cell-
`specific delivery of cytotoxic agents (via antibody drug
`conjugate, ADC) is a promising therapeutic approach for
`HER2-overexpressed patient populations. It is clear that
`HER2 remains an active/key target, even after multiple
`lines of treatment. It has been demonstrated from different
`neoadjuvant studies including GeparQuinto (Untch, Loibl
`et al. 2012), NeoALTTO (Baselga, Bradbury et al. 2012),
`CHER-LOB (Guarneri, Frassoldati et al. 2012) and
`NeoSphere
`(Gianni, Pienkowski et al. 2012)
`that
`continued HER2 targeting therapy works even after
`disease progression.
`II. Antibody Drug Conjugates (ADC)
`
`Antibody-drug conjugates (ADCs) represent a
`promising
`therapeutic modality
`for
`the
`clinical
`management of cancer. ADCs are composed of
`recombinant chimeric, humanized or human antibodies
`covalently bound by synthetic linkers to highly cytotoxic
`drugs. The primary objective
`is
`to combine
`the
`pharmacological potency of small (300 to 1000 Dalton)
`cytotoxic drugs with the high specificity of monoclonal
`antibodies that target tumor-associated antigens (Teicher
`and Chari 2011). Inside the cell, the cytotoxic agent is
`released from the antibody and kills the tumor cells.
`ADCs are designed to minimize the systemic toxicities of
`free drug and to augment the anti-tumor activity of the
`monoclonal antibody
`targeting
`tumor. ADCs offer
`significant advantages over conventional chemotherapy—
`they attach specifically to tumor cells with their target
`receptors while not affecting healthy cells that do not have
`sufficient number of those receptors. Patients would be
`expected to experience fewer and less severe adverse
`events than they would with systemic chemotherapy. The
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`Cancer Therapy Vol. 9, page 47
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`anti-tumor properties of trastuzumab with the cytotoxic
`activity of the microtubule-inhibitory agent DM1; the
`antibody and the cytotoxic agent are conjugated by means
`of a stable linker (Lewis Phillips, Li et al. 2008; Junttila,
`Li et al. 2011). T-DM1 allows HER2-overexpressing
`tumor cell-specific drug delivery, thereby improving
`therapeutic index and minimizing exposure of normal
`tissue to the toxicities of the DM component. The in vitro
`activity of maytansine ((DM part of the T-DM1) was
`highly substantial—100 fold more potent than vinca
`alkaloids (an anti-mitotic and anti-microtubule agent) and
`24 to 270 fold more potent than paclitaxel (Remillard,
`Rebhun et al. 1975; Cassady, Chan et al. 2004; Junttila, Li
`et al. 2011). It has been previously described by others
`that maytansine may bind to tubulin leading to a
`disassembly of microtubules which prevents tubulin
`spiralization (E H 2008). Furthermore, microtubule
`polymerization /depolymerization plays an important role
`in tumor-induced angiogenesis through the HIF1alpha-
`VEGF signaling axis (Mabjeesh, Escuin et al. 2003).
`
`
`
`
`
`
`Figure 1: Schematic illustrations of antibody drug conjugate
`(ADC): ADCs are unique combination of a precise and targeted
`monoclonal antibody, a stable linker and a potent cytotoxic
`agent.
`
`
`2.2 Pre-clinical and clinical efficacy
`Extensive analysis of T-DM1 in preclinical studies
`has shown that T-DM1 combines the distinct mechanisms
`of action of both DM1 and trastuzumab, and has
`antitumor activity in trastuzumab- and lapatinib-refractory
`experimental models (Barok, Tanner et al. 2011; Junttila,
`Li et al. 2011; Sun Yuliang, Dey Nandini et al. 2013).
`This is extremely important because trastuzumab and
`lapatinib are established for the treatment of HER2-
`postitive metastatic
`breast
`cancer
`(MBC). The
`mechanisms of action for trastuzumab include inhibition
`of the PI3K/AKT/mTOR signaling pathway, inhibition of
`HER2 shedding, and Fcγ receptor–mediated engagement
`of immune cells, which may result in antibody-dependent
`cellular cytotoxicity (Spector and Blackwell 2009; De,
`Hasmann et al. 2013).
`
`  
`level of acceptable target expression may depend on the
`target (e.g., HER2 needs high overexpression to serve as a
`good ADC target (Burris, Rugo et al. 2011) while an ADC
`targeting CD19 can be active on cell lines bearing only
`30,000 or so receptors (Blanc, Bousseau et al. 2011).
`However, delivery of a lethal quantity of a tubulin-acting
`payload into cancer cell via antibody-mediated uptake of
`an ADC may be difficult to achieve below ~10,000
`receptors/cell (Lapusan, Vidriales et al. 2012). Hence,
`HER2 protein is an ideal target for ADC as breast cancers
`with the amplification of HER2 gene have up to 1-2
`million receptors expressed per cell (Venter, Tuzi et al.
`1987).
`The leading ADC in the clinical arena is T-DM1, which is
`composed of Genentech/Roche’s HER2
`targeting,
`humanized IgG1 trastuzumab conjugated with DM1 via
`an non-cleavable thioether link formed using the non-
`reducable
`thioether crosslinker using
`ImmunoGen’s
`platform technology (Lewis Phillips, Li et al. 2008). This
`non-cleavable linker means the linker does not separate
`from the cytotoxin (maytansine) but uses a different
`mechanism to activate the cytotoxin inside the cancer
`cells. The rapid development of T-DM1 was greatly aided
`by the fact that trastuzumab was already marketed and
`tests were already in use for patient selection of likely
`better responders, such as those overexpressing HER2. In
`2000, gemtuzumab ozogamicin (Mylotarg) became the
`first ADC to be approved by the U.S. Food and Drug
`Administration
`(FDA)
`for
`the
`treatment of acute
`myelogenous leukemia (AML). However, this ADC was
`withdrawn from the market in 2010 because, in post-
`marketing follow-up clinical trials, it failed to meet
`prospective efficacy targets that were required as a
`condition of its accelerated approval by the FDA. T-DM1
`is not the first effective ADC, that distinction belongs to
`brentuximab vedotin (SGN-35, Adcetris), developed by
`Seattle Genetics, which was granted accelerated approval
`in 2011. Indicated for the treatment of Hodgkin’s
`lymphoma and systemic anaplastic large cell lymphoma,
`Adcetris is a CD30 antibody linked to the cytotoxin
`auristatin, which blocks cell division.
`
`
`
`2.1 T-DM1
`
`Chemistry
`
`Preclinical studies demonstrated synergistic or
`
`additive interactions of trastuzumab with a variety of anti-
`microtubulin agents, including maytansines (Baselga,
`Norton et al. 1998; Pegram, Hsu et al. 1999; Burstein,
`Keshaviah et al. 2007). Because the initial studies with
`maytansine proved to be associated with intolerable
`toxicities such as nausea and peripheral neuropathy,
`laboratory-based translational cancer research was geared
`to the development of various trastuzumab-maytansinoid
`conjugates (Lewis Phillips, Li et al. 2008). This strategy
`culminated in the development of an antibody drug
`conjugate (ADC), trastuzumab linked to DM1 (derivative
`of maytansine) (Figure.1). Trastuzumab emtansine (T-
`DM1) is an ADC that incorporates the HER2-targeted
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`Pradip De et al: T-DM1: a giant step forwards in HER2 therapeutics  
`
`same
`these
`retains
`importance, T-DM1
`Of
`trastuzumab
`mechanisms of action of unconjugated
`(Junttila, Li et al. 2011). The cytotoxic antitubulin agent
`DM1 remains attached to trastuzumab outside the cell
`because of the non- cleavable linker (nonreduciable
`thioether) molecule until the entire ADC is transported
`into the cytoplasm through endocytosis. It is assumed that
`
`intra-lysosomal proteolytic
`then undergoes
`T-DM1
`degradation resulting in the release of nonreduciable
`thioether
`linked-DM1 and consequent antitubulin-
`associated cell death (Lewis Phillips, Li et al. 2008)
`(Figure. 2).
`
`
`
`
`
`
`Figure 2: Schematic representation of mechanism of action of T-DM1: T-DM1 locks onto HER2 receptor in HER2+ breast tumor
`cells with drug in tow. Once internalization, the antibody and receptor begins to break each other. Then antibody breaks into pieces,
`thereby release the drug. The cytotoxic drug begins to disrupt the cell, killing the cell and eventually augments antitumor activity.
`It has been reported that T-DM1 has been shown
`months and the clinical benefit rate (CBR; objective
`to induce apoptotic cell death in a trastuzumab-resistant
`response rate [ORR] plus stable disease at 6 months) was
`xenograft tumor model (Barok, Tanner et al. 2011). In our
`73% (Krop, Beeram et al. 2010). Most commonly
`cell based model systems, we clearly demonstrated that T-
`reported grade 1 or 2 adverse events at MTD were
`DM1 treatment associated cell death is significantly
`thrombocytopenia
`(54.2%),
`elevated
`transaminases
`higher (by annexinV staining) in HER2+/trastuzumab-
`(41.7%), fatigue (37.5%), anemia (29.2%), and nausea
`sensitive,
`trastuzumab-resistant and HER2+/PIK3CA
`(25%). Cardiac toxicity was not reported. This was the
`mutated cells when compared to trastuzumab alone
`first phase I breast cancer trial with T-DM1 and
`treated cells (data not shown).
`established MTD of 3.6 mg/kg every 3 weeks. The
`Initially T-DM1 was evaluated as a single agent
`original phase I study also evaluated a weekly schedule of
`in a dose escalation phase I trial in patients with HER2+
`T-DM1 with 1.2 mg/kg, 1.6 mg/kg, and 2 mg/kg. In this
`metastatic breast cancer (MBC) who previously received
`weekly schedule, partial responses were noted in four
`a trastuzumab- containing chemotherapy. T-DM1 was
`patients (57%). Grade 3 or higher adverse events were
`administered at various doses on a weekly (23 weeks) or
`limited to rapidly reversible thrombocytopenia in one
`every 3 weeks schedule. The maximum tolerated dose
`patient. No dose limiting toxicity was observed (S. N.
`(MTD) was 3.6 mg/kg every 3 weeks, based on the dose-
`Holden, M. Beeram et al. 2008).
`limiting toxicity (DLT) of grade 4 thrombocytopenia at
`A proof-of-concept phase II study by Burris et al
`4.8 mg/kg every 3 weeks (Krop, Beeram et al. 2010). In a
`showed that single agent T-DM1 (3.6 mg/kg given every
`group of 15 patients receiving 3.6 mg/kg every 3 weeks,
`three weeks) in 112 patients with HER2-positive MBC,
`the median progression free survival (PFS) was 10.4
`who had progressed with previous chemotherapy and
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`rates of grade 3 or 4 bleeding events were low in both
`groups (1.4% and 0.8% respectively). In the majority of
`patients, left ventricular ejection fraction of 45% or more
`was maintained during the study treatment (in 97% of
`patients in the T-DM1 group and 93% of patients in the
`lapatinib plus capcetabine group). The incidence of
`diarrhea,
`nausea,
`vomiting
`and
`palmar-planter
`erythrodysesthesia were much higher with lapatinib plus
`capecitabine group. Tumor biomarkers data from the
`EMILIA trial also revealed that PIK3CA mutations in
`HER2-positive
`tumors did not
`compromise
`the
`effectiveness of T-DM1, but led to poorer responses to
`conventional HER2-
`targeted
`therapies
`such
`as
`trastuzumab and lapatinib. T-DM1 patients with mutated
`PIK3CA had 10.9 months progression-free survival, and
`9.8 months for those with wild-type PIK3CA. However,
`PIK3CA status did make a difference for the capecitabine-
`lapatinib treated patients: progression-free survival was
`4.3 months for patients with mutated PIK3CA and 6.4
`months for those with the wild type PIK3CA (Baselga J,
`Verma S et al. 2013). The two major lessons we learned
`from the above mentioned trials with T-DM1 are: a) there
`is a relative lack of side-effects following the treatment
`with T-DM1 and b) T-DM1 obviates the need for
`chemotherapy.
`Trastuzumab-induced
`cardio-toxicity
`(symptomatic or asymptomatic) is a major concern.
`Although, the cardio-toxicity varies according to the
`definition used in different studies, it has been reported to
`be as high as 30% when associated with anthracyclines
`(Telli, Hunt et al. 2007; Guglin, Hartlage et al. 2009).
`T-DM1 had a better safety profile compared to
`trastuzumab in this context and no significant dose-
`limiting cardio-toxicity was observed with T-DM1 in
`heavily pre-treated patients. T-DM1 has exhibited a
`unique capacity to discriminate between cancer cells and
`normal cells in terms of cytotoxic drug delivery. EMILIA
`study also showed that patients receiving T-DM1 whose
`tumors had above-median levels of HER2 had a median
`overall survival of 34.1 months, vs. 26.5 months for
`patients with lower levels. Progression-free survival with
`T-DM1 was 10.6 months for patients with higher HER2
`levels vs. 8.2 months for lower levels (Baselga J, Verma S
`et al. 2013). Data suggest
`that
`the greater
`the
`overexpression of HER2 in a breast tumor, the more
`sensitive the tumor is to anti-HER2 therapy. Overall these
`results take targeted therapy for HER2-positive breast
`cancer to a newer level.
`MARIANNE, is a phase III randomized study of
`T-DM1 with or without pertuzumab (T- DM1 and
`pertuzumab bind to different epitopes of HER2) compared
`with trastuzuamb plus taxane for the first line treatment of
`HER2-positive, progressive or recurrent locally advanced
`or metastatic breast cancer patients. With 1,092 enrolled
`patients, MARIANNE will compare the efficacy of T-
`DM1 plus pertuzumab, T-DM1 plus placebo, and the
`combination of
`trastuzumab plus a
`taxane. The
`independent Data Monitoring Committee which assesses
`safety data has recently recommended continuation of the
`study without any modification. Brisk completion of
`
`  
`HER2-directed therapy, had anti-tumor activity (Burris,
`Rugo et al. 2011). In this study, the overall response rate
`by
`independent review was 25.9% and 37.5% by
`investigator assessment, including 4 complete responses.
`The median PFS was 4.6 months. In the following study,
`Krop and colleagues gave T-DM1
`(3.6 mg/kg
`intravenously every three weeks) to patients (n=110) with
`HER2-positive MBC who had prior treatment with
`trastuzumab, lapatinib, an antracycline, a taxane and
`capecitabine. The overall response rate was 34.5%, CBR
`was 48.2%, median PFS was 6.9 months and median
`duration of response was 7.2 months. In patients with
`confirmed HER2-positivity
`(n=80) by
`retrospective
`central testing, the response rate was 41.3% and median
`PFS was 7.3 months (Krop, LoRusso et al. 2012). Most
`adverse events were grades 1 or 2; the most frequent
`grade 3 events were thrombocytopenia (9%), fatigue
`(4.5%) and cellulitis (4.6%). Sara Hurvitz and group
`recently published (Hurvitz, Dirix et al. 2013) their phase
`II
`randomized study of T-DM1
`(n= 67) versus
`trastuzumab plus docetaxel (n= 70) in patients with
`HER2-positive MBC. The objective response rate was
`64% on T-DM1 arm versus 58% for patients received
`trastuzumab plus docetaxel. Furthermore, the progression
`free survival in the T-DM1 arm was 14.2 months versus
`9.2 months for patients receiving standard- of-care, an
`improvement in favor of T-DM1 that was significant
`despite the relatively small number of patients. T-DM1
`had a favorable safety profile, with fewer grade 3 adverse
`events
`(AEs),
`and AEs
`leading
`to
`treatment
`discontinuations was 7.2% (for T-DM1) versus 40.9%
`(tarstuzumab plus docetaxel).
`The above phase I and II studies led to the
`landmark phase III EMILIA trial, which was published
`recently in New England Journal of Medicine by Verma,
`Blackwell and the EMILIA study group (Verma, Miles et
`al. 2012) and
`subsequently published associated
`biomarker analysis by Baselga and group at the AACR
`2013 annual meeting (Baselga J, Verma S et al. 2013). In
`this trial, 991 patients with advanced HER2-positive
`breast cancer whose disease had progressed through
`treatment with trastuzumab plus taxane were assigned to
`T-DM1 or lapatinib plus capecitabine, an FDA approved
`and standard treatment option in this setting. The median
`PFS as assessed by independent review was 9.6 months
`with T-DM1 versus 6.4 months with lapatinib plus
`capecitabine (p<0.001, HR 0.65) and median overall
`survival at the second interim analysis was significantly
`improved in the T-DM1 arm (30.9 months versus 25.1
`months, HR 90.68). The objective response rate was also
`significantly higher with T-DM1 (43.6%) than lapatinib
`plus capecitabine (30.8%). Rates of grade 3 or 4 AEs were
`higher with lapatinib plus capecitabine than within the T-
`DM1 arm (57% versus 41%). The
`incidences of
`thrombocytopenia were higher
`in
`the T-DM1 arm;
`although the majority of these patients were able to
`continue treatment (2% discontinued T-DM1 due to
`thrombocytopenia). The overall incidence of bleeding
`events was higher with T-DM1 (29.8% versus 15.8%);
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`Pradip De et al: T-DM1: a giant step forwards in HER2 therapeutics  
`
`accrual and data analyses are eagerly awaited (Ellis EA,
`CH et al. 2011). Roche/Genentech also is actively
`recruiting metastatic HER2+ breast cancer patients into
`the TH3RESA
`trial
`(NCT01419197) at 210 sites,
`including 90 within the US. Women entering this trial will
`be randomized at a 2 to 1 ratio to receive T-DM1 (3.6
`mg/kg intravenously for 3 weeks) or treatment of the
`physician's choice. Anticipated time on study treatment is
`until disease progression or unacceptable toxicity occurs.
`A
`randomized, multicenter, open-label phase
`III
`KATHERINE study (NCT01772472) of T-DM1 vs.
`trastuzumab as adjuvant therapy for patients with HER2+
`
`primary breast cancer who have residual tumor present
`pathologically in the breast or axillary lymph nodes
`following preoperative therapy, which was initiated in
`April 2013. Other ongoing phase II trials are currently
`exploring the feasibility and/or antitumor potency of T-
`DM1 in the adjuvant (NCT01196052) and neoadjuvant
`setting (NCT01745965) of HER2-positive BC (see Table
`1).
`
`
`
`
`
`
`Table 1: Ongoing trials with T-DM1 in HER2 + breast cancer
`MBC: Metastatic breast cancer HT: Hormone treatment AEs: Adverse events DLTs: Dose limiting toxicities PFS:
`Progression free survival pCR: Pathological complete response IDFS: Invasive disease free survival
`
`
`
`2.3 Pharmacokinetic and metabolic
`profile of T-DM1
`The pharmacokinetics of T-DM1 has been assessed
`in preclinical and clinical studies. The results showed that
`T-DM1 exhibits dose-proportional pharmacokinetics in
`non– trastuzumab-binding species (i.e., mice and rats)
`(LoRusso, Weiss et al. 2011) and a dose- dependent
`decrease in clearance associated with increasing dose in
`trastuzumab binding species (i.e., cynomolgus monkeys
`and humans) (Girish S, Gupta M et al. 2011). 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. The major elimination routes of DM1-
`containing metabolites are through fecal/biliary (~80%)
`and urine (<10%) (Shen, Bumbaca et al. 2012).
`
`
`
`
`
`
`The clinical PK of T-DM1 shows that while the
`conjugate is quite stable in circulation, it nevertheless
`appears to show a slow rate of maytansiniod loss over
`time (Krop, Beeram et al. 2010; Burris, Rugo et al. 2011)
`and very low levels of free DM1 were reported to be
`present in plasma samples from patients treated with T-
`DM1 (Burris, Rugo et al. 2011). The median half-life of
`T-DM1 is 4.5 days and steady state is achieved in cycle 2
`(Gupta, Lorusso et al. 2012). Pharmacokinetics-based
`drug interactions between T-DM1 and the HER2-targeted
`monoclonal antibody pertuzumab, or T-DM1 and
`paclitaxel showed that the combination had no effect on
`the pharmacokinetics of the individual agents and had a
`low risk for drug interactions (Lu D, Krop I et al. 2010;
`Lu, Burris et al. 2012).
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`2.4 T-DM1 and resistance mechanism
`The design of cancer
`therapy has become
`increasingly sophisticated, yet there is no cancer treatment
`that is 100% effective against disseminated cancer.
`Resistance to treatment with anticancer drugs results from
`a variety of factors including individual variations in
`patients, somatic cell genetic differences in tumors, and
`signaling pathway alteration/upregulation. Frequently,
`resistance is intrinsic to the cancer but as therapy becomes
`more and more effective, acquired resistance has also
`become common. Trastuzumab-containing therapy is now
`an established standard of care across all HER2-positive
`breast cancer disease stages. However, despite the robust
`clinical efficacy of trastuzumab in HER2-positive MBC,
`primary and secondary resistance remains a clinical
`challenge. Alterations of
`signal
`transducers
`lying
`downstream of HER2, which
`facilitate
`signaling
`independently of the HER2 kinase, have been extensively
`studied as potential mechanisms of
`trastuzumab
`resistance. T-DM1 is a relatively new drug in the horizon
`and the EMILIA trial revealed that PI3K pathway
`upregulation (via activating mutation of PIK3CA) did not
`hinder T-DM1’s efficacy. Pegram and group recently
`reported that despite inactivation of the PI3K-AKT
`signaling pathway, HER2 overexpressed
`lapatinib-
`resistant cells exhibited activation of mTORC1 and its
`downstream signaling pathway (Jegg, Ward et al. 2012).
`Recently, Elkabets and group also reported that breast
`cancer cells (containing PIK3CA mutation) that were
`resistant to p110α- isoform-specific inhibitor (BYL719)
`had persistently active pS6 expression, although AKT
`phosphorylation was inhibited (Elkabets, Vora et al.
`2013). Along the same line, our cell-based preclinical data
`showed that T-DM1 blocked AKT activation in HER2-
`positive breast cancer cells (BT474) but failed to block
`downstream
`of mTORC1
`signaling molecule
`(phosphorylation of P70S6K) (Sun, Dey et al. 2013). This
`data suggest that T-DM1 alone may not be sufficient to
`completely inactivate the PI3K-AKT-mTOR signaling
`
`References:
`Andersson, M., E. Lidbrink, et al. (2011). "Phase III
`randomized
`study
`comparing
`docetaxel
`plustrastuzumab
`with
`vinorelbine
`plus
`trastuzumab as first-line therapy of metastatic
`or13locally advanced human epidermal growth
`factor receptor 2-positive breast cancer:
`the
`HERNATA study." J Clin Oncol 29(3): 264-271.
`Arteaga, C. L., M. X. Sliwkowski, et al. (2012).
`"Treatment of HER2-positive breast cancer:
`current status and future perspectives." Nat Rev
`Clin Oncol 9(1): 16-32.
`Barok, M., M. Tanner, et al. (2011). "Trastuzumab-
`DM1 causes tumour growth inhibition by mitotic
`catastrophe in trastuzumab-resistant breast cancer
`cells in vivo." Breast Cancer Res 13(2): R46.
` Barok, M., M. Tanner, et al. (2011). "Trastuzumab-
`DM1 is highly effective in preclinical models of
`
`Cancer Therapy Vol. 9, page 51
`
`
`
`pathway. Literature references suggest that activation of
`the PI3K-AKT-mTOR pathway is one of the major causes
`for drug
`resistance
`including
`chemotherapy
`and
`trastuzumab
`therapy
`in different
`cancer mod