1.
`
`Introduction
`
`2. Overview of the market
`
`3. Overview of T-DM1
`
`4.
`
`5.
`
`Conclusion
`
`Expert opinion
`
`Drug Evaluation
`
`Trastuzumab emtansine: a novel
`antibody-drug conjugate for
`HER2-positive breast cancer
`
`Howard A Burris III
`Sarah Cannon Research Institute, Nashville, TN, USA
`
`Introduction: Trastuzumab emtansine (T-DM1)
`is an antibody--drug
`conjugate (ADC) that combines intracellular delivery of the potent cytotoxic
`agent, DM1 (a derivative of maytansine) with the antitumor activity of
`trastuzumab. While there are several ADCs in Phase III development,
`T-DM1 is the only one in which the targeting antibody has antitumor proper-
`ties. T-DM1 is also the only ADC that is directed toward the human EGFR 2
`(HER2). Effective therapies are limited in HER2-positive advanced or meta-
`static breast cancer (MBC), particularly following progression on available
`HER2-targeted therapies.
`Areas covered: The mechanisms of action, preclinical efficacy and clinical
`profile of T-DM1 are reported. The latest preclinical and clinical data for
`T-DM1 are examined.
`Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo,
`which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I
`and II trials, T-DM1 provided objective tumor responses and was well toler-
`ated across various lines of therapy in patients with HER2-positive MBC. In
`addition, it showed similar efficacy to trastuzumab plus docetaxel in first-
`line MBC. Ongoing trials (including two Phase III studies) are investigating
`T-DM1 as single-agent therapy or combined with other chemotherapeutic
`or biologic agents, and the results should help to define the place of
`T-DM1 within current treatment algorithms for HER2-positive disease.
`
`Keywords: antibody-drug conjugate, DM1, HER2-positive, metastatic breast cancer, T-DM1,
`trastuzumab emtansine
`
`Expert Opin. Biol. Ther. (2011) 11(6):807-819
`
`1. Introduction
`
`Female breast cancer is a major public health problem, with an estimated
`207,090 cases
`(an incidence rate of 121.8 per 100,000 population) and
`39,840 deaths anticipated in the USA alone during 2010 [1]. Overexpression of
`human EGFR type 2 (HER2) occurs in approximately 20% of all breast cancers [2-4]
`and is predictive of poor prognosis, including reduced survival [3,5], decreased time
`to relapse [6], and increased incidence of metastases [6]. Treatment guidelines recom-
`mend the use of HER2-targeted therapy for patients with HER2-positive early or
`advanced metastatic breast cancer (MBC) [7-9]. However, despite therapeutic advan-
`ces, most patients with HER2-positive MBC will eventually progress. Thus there is
`an unmet need for alternative treatments.
`
`2. Overview of the market
`
`Trastuzumab (HerceptinÒ, Genentech, Inc.), a humanized anti-HER2 monoclonal
`antibody directed against the extracellular domain of HER2, is the standard of care
`for HER2-positive primary breast cancer and first-line MBC (Box 1) [7,8]. In the
`
`10.1517/14712598.2011.580273 © 2011 Informa UK, Ltd. ISSN 1471-2598
`All rights reserved: reproduction in whole or in part not permitted
`
`807
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`Trastuzumab emtansine
`
`Box 1. Drug summary.
`
`Drug name
`Phase
`Indication
`Pharmacology description/
`mechanism of action
`Route of administration
`Pivotal trial(s)
`
`Trastuzumab emtansine (T-DM1)
`III
`Breast cancer
`Antibody--drug conjugate
`
`Intravenous
`Phase II TDM4258g: Single agent T-DM1 for human EGFR2 (HER2)-positive metastatic breast
`cancer (MBC) previously treated with trastuzumab and chemotherapy
`Phase II TDM4374g:
`Single agent T-DM1 for HER2-positive MBC previously treated with chemotherapy,
`trastuzumab and lapatinib
`Phase II TDM4450g: Single agent T-DM1 first-line for HER2-positive locally advanced or
`MBC (comparator arm: trastuzumab plus docetaxel)
`Phase Ib/II TDM4373g: T-DM1 combined with pertuzumab for HER2-positive MBC
`following prior trastuzumab
`Pivotal Phase III TDM4370g (EMILIA): Single agent T-DM1 for HER2-positive locally
`advanced or MBC previously treated with trastuzumab (comparator arm: capecitabine
`plus lapatinib)
`Phase III TDM4788g (MARIANNE): T-DM1 combined with pertuzumab for HER2-positive
`progressive or recurrent, locally advanced or untreated MBC (comparator arms:
`trastuzumab combined with docetaxel or paclitaxel and T-DM1 plus placebo)
`
`adjuvant setting, trastuzumab is approved in combination
`with chemotherapy or as a single agent after multimodality-
`based anthracycline therapy. In the recurrent or metastatic set-
`tings, trastuzumab is approved in combination with chemo-
`therapy or as a single agent after prior chemotherapy for
`MBC [10,11]. The dual tyrosine kinase inhibitor lapatinib
`(TykerbÒ/TyverbÒ, GlaxoSmithKline)
`is
`indicated for
`patients with HER2-positive MBC after prior trastuzumab,
`anthracyclines and taxane therapy, either as monotherapy or
`combined with capecitabine [12,13]. Lapatinib targets the
`ATP binding site within the intracellular domain of HER1/
`EGFR and HER2 [14]. Both trastuzumab and lapatinib are
`recommended by the US National Comprehensive Cancer
`Network (NCCN) breast cancer treatment guidelines in com-
`bination with an aromatase inhibitor for postmenopausal
`women with hormone-receptor--positive, HER2-positive
`MBC; lapatinib is FDA approved in this setting [10-13].
`Treatment guidelines advocate continuing trastuzumab and
`chemotherapy in patients with HER2-positive MBC who
`have progressed on prior trastuzumab [7,8]. In preclinical stud-
`ies of tumor cells selected for lack of response to trastuzumab,
`cells continued to overexpress HER2 [15,16]. Several retrospec-
`tive, observational, and prospective nonrandomized clinical
`studies have reported improved tumor responses and survival
`outcomes with trastuzumab continuation [17-25]. Two ran-
`domized Phase III trials showed that adding trastuzumab to
`the chemotherapy regimen of patients with MBC who have
`progressed on prior trastuzumab-based therapy significantly
`prolonged progression-free survival (PFS) [26,27].
`CNS metastases are a common complication of HER2-
`positive breast cancer [28]. Lapatinib has been investigated as
`a potential treatment because it is a small molecule that could
`penetrate the blood--brain barrier [29]. However, some data
`suggest that access is impaired by efflux transporters in the
`
`blood--brain barrier [30]. Although some promising clinical
`results have been reported for lapatinib in this setting [31],
`supporting evidence is limited from Phase II or Phase III
`trials [32-34].
`
`3. Overview of T-DM1
`
`A novel approach to HER2-targeted breast cancer therapy
`is trastuzumab emtansine (T-DM1; Genentech, Inc.), an
`antibody-drug conjugate (ADC). ADCs are comprised of a
`cytotoxic agent, an antibody targeting an antigen expressed
`on tumor cells, and a linker that covalently binds these com-
`ponents together [35]. ADCs selectively deliver chemotherapy
`to the tumor cell, thus improving the therapeutic index of
`the agent, sparing normal tissues, and allowing the use of
`drugs otherwise too toxic for clinical application [36-40].
`Because of their high antitumor potency but unacceptable
`toxicity as free drugs, the maytansines auristatins, and cali-
`cheamicins are promising agents for ADCs. Several ADCs
`are in clinical development (Table 1) [40,41].
`T-DM1 utilizes DM1, a highly potent cytotoxic derivative
`of maytansine. DM1 causes apoptosis through inhibition of
`microtubule assembly,
`leading to cell cycle arrest at the
`G2/M phase [42-44]. Although DM1 has a similar mechanism
`of action to the vinca alkaloids, it is 20 -- 100 times more
`potent than vincristine [45]. DM1 also is 24 -- 270 times
`more potent than paclitaxel, and two to three times more
`potent than doxorubicin [46]. The antibody component of
`T-DM1,
`trastuzumab,
`is particularly suitable for ADC
`application because it selectively targets HER2, an antigen
`with high expression on tumor cells relative to normal
`cells. In addition, trastuzumab binding to HER2 does not
`downregulate the receptor -- instead, HER2 passively recycles
`to the cell surface by endocytosis [47]. T-DM1 is the first ADC
`
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`Burris
`
`Table 1. ADCs in clinical development, by drug class [40,41].
`
`Drug class/agent
`
`Target antigen
`
`Indication(s)
`
`Development stage
`
`Maytansine
`T-DM1
`MLN2704
`SAR3914
`BT-062
`IMGN901
`BIIB015
`IMGN388
`Auristatin
`CDX-011
`Brentuximab vedotin (SGN-35)
`SGN-75
`PSMA ADC
`MEDI-547
`MN immunoconjugate
`Calicheamicin
`Gemtuzumab ozogamicin
`
`Inotuzumab ozogamicin
`
`Duocarmycin
`MEDX-1203
`Anthracycline
`hLL1-DOX
`SGN-15
`
`HER2
`PSMA
`CD18
`CD138
`CD56
`Cripto
`av integrin
`
`GPMNB
`CD30
`CD70
`PSMA
`EphA2
`MN
`
`CD33
`
`CD22
`
`CD70
`
`CD74
`Leg
`
`Breast cancer
`Prostate cancer
`Non-Hodgkin’s lymphoma
`Multiple myeloma
`Multiple myeloma, solid tumors
`Solid tumors
`Solid tumors
`
`Breast cancer, melanoma
`Hodgkin’s lymphoma
`Non-Hodgkin’s lymphoma, renal cell cancer
`Prostate cancer
`Solid tumors
`Cancer
`
`Phase III
`Phase I/II
`Phase I
`Phase I
`Phase I
`Phase I
`Phase I
`
`Phase II
`Phase III
`Phase I
`Phase I
`Phase I
`Phase I
`
`Acute myeloid leukaemia
`
`Non-Hodgkin’s lymphoma
`Acute lymphoblastic leukemia
`
`Approved but
`withdrawn from market
`Phase III
`Phase I
`
`Non-Hodgkin’s lymphoma, renal cell cancer
`
`Phase I
`
`Multiple myeloma
`Prostate cancer, ovarian cancer
`
`Phase I/II
`Phase II
`
`in Phase III development in which the antibody moiety has
`antitumor properties. In traditional ADCs,
`the antibody
`moiety merely serves a targeting function.
`T-DM1 is unlike many other ADCs that use a reducible
`disulfide linker to combine the antibody and cytotoxic.
`DM1 is conjugated to trastuzumab via a unique non-
`reducible thioether linker (N-maleimidomethyl cyclohexane-
`1-carboxylate, known as MCC after conjugation) [44,46,48-49].
`The lack of molecular dissociation and minimal systemic
`exposure with the MCC linker in T-DM1 offers improved
`efficacy and pharmacokinetics and reduced toxicity compared
`with alternative ADCs with reducible linkers [44]. Indeed
`clinical studies have shown that DM1 plasma levels are consis-
`tently low. For example, in the Phase II open-label, single-
`arm multicenter trial TDM4258g, maximum DM1 levels
`averaged 5.35 ± 2.03 ng/ml in Cycle 1, and the highest
`reportable concentration of DM1 was < 17 ng/ml [50]. Side
`effects that would be expected with a maytansine derivative,
`such as a substantial incidence of grade 3 or 4 peripheral neu-
`ropathy, have not been observed in Phase II T-DM1 single-
`agent trials [50,51]. These data provide additional supporting
`evidence that there is indeed low systemic exposure to DM1.
`
`3.1 Chemistry
`Figure 1 shows the chemical structure of T-DM1, including
`the antibody, linker and cytotoxic agent [48]. Owing to its
`unique and complex structure, a prolonged manufacturing
`
`process is needed. Developing trastuzumab as a recombinant
`antibody takes approximately 6 months. The conversion of
`maytansinol (a structural analog of maytansine) to DM1 is
`completed over 9 months. Finally, during a 14-week process,
`the antibody is chemically linked to MCC though lysine res-
`idues, and the free sulfhydryl on DM1 is reacted with the
`linker-antibody intermediate [49]. The T-DM1 end product
`has an average DM1-to-antibody ratio of 3.5:1 [48].
`
`3.2 Pharmacodynamics
`The binding of T-DM1 to HER2 results in internalization of
`the receptor--ADC complex and subsequent lysosomal degrada-
`tion of T-DM1 [52]. Cytotoxic DM1 molecules are released
`into the cytoplasm, causing microtubule destabilization and
`tumor cell death [44]. Application of 3H-labeled T-DM1 to
`BT474 EEI breast tumor cells revealed that lysine-MCC-
`DM1 was the predominant metabolite, acting as the tubulin-
`binding agent, and preventing mitosis. Since the metabolite
`does not cross the membranes of (normal) cells adjacent to
`the tumor, a ‘bystander’ killing effect is avoided [44].
`However, T-DM1 provides more than just targeted deliv-
`ery of a cytotoxin, since the antibody moiety is also biologi-
`cally active. In vitro studies showed that conjugation of
`trastuzumab to DM1 does not affect binding to HER2, since
`T-DM1 binds to the HER2 receptor on the surface of breast
`cancer cells with an affinity similar to that of trastuzumab [46].
`Once bound, T-DM1 retained the hypothesized mechanisms
`
`Expert Opin. Biol. Ther. (2011) 11(6)
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`
`Trastuzumab emtansine
`
`NH
`
`O
`
`O N
`
`S
`
`O
`
`O
`
`N
`
`Me
`
`O
`
`O
`
`O
`
`O
`
`Cl
`
`Me
`
`N
`
`MeO
`
`O
`
`O
`
`NH
`
`OH
`OMe
`
`DM1
`(derivative of maytansine)
`
`MCC
`
`Trastuzumab
`
`Figure 1. Schematic of T-DM1 including the N-maleimidomethyl cyclohexane-1-carboxylate (MCC) linker.
`Reprinted with permission. Ó 2008 American Society of Clinical Oncology. All rights reserved [48].
`
`including inhibition of PI3K/
`of action of trastuzumab,
`inhibition of HER2 shedding and Fcg
`AKT signaling,
`receptor-mediated engagement of immune cells, leading to
`antibody-dependent cellular toxicity [44,46].
`
`3.3 Metabolism and pharmacokinetics
`Following dosing of
`radiolabeled T-DM1 in Sprague-
`Dawley rats [53], radioactivity was observed mainly in the
`plasma, with comparatively lower levels detected in perfused
`organs (liver > kidneys > lungs > heart). By day 14 post-
`dosing,
`there was no persistence or
`accumulation of
`T-DM1 in the kidney or thymus. The majority of the radio-
`active dose of T-DM1 was eliminated in the feces (~ 80%); a
`small amount was detected in the urine (< 10%).
`Clinical factors affecting the pharmacokinetics of novel
`ADCs are complex, given their distinct constituents of large
`and small molecules [48]. Phase I and II studies [48,50], as well
`as a population pharmacokinetics model based on data from
`274 patients [54], showed that T-DM1 has predictable phar-
`macokinetics. At the MTD of 3.6 mg/kg in the Phase I trial,
`T-DM1 clearance was 12.9 ± 3.4 ml/d/kg, compared with
`3.3 ± 2.7 ml/d/kg for total trastuzumab [48]. In a Phase II trial
`of T-DM1 3.6 mg/kg every three weeks, Cmax and AUC
`were higher for total trastuzumab than for T-DM1, and total
`trastuzumab had a longer terminal half-life than T-DM1 [50].
`Systemic exposure to DM1 was consistently low (generally
`< 10 ng/ml) and transient, and there was no evidence of
`DM1 accumulation with repeated T-DM1 doses (consistent
`with a half life of » 4 days) [48,50,54]. Although there was
`some interindividual variance in pharmacokinetic parameters
`such as clearance, AUC, and Cmax (based on body weight,
`albumin, tumor burden, and aspartate transaminase levels),
`the magnitude of its effect on T-DM1 exposure was minimal
`
`(< 26% variance compared with typical parameter values) [54].
`The pharmacokinetics of T-DM1 are compatible with
`the clinical
`3-weekly dosing [54], which is the focus of
`development program.
`The question remains as to whether T-DM1 administered
`at the MTD provides equivalent trastuzumab exposure to
`unconjugated trastuzumab. Given the differences in structure
`and pharmacokinetic behavior between T-DM1 and trastuzu-
`mab, direct exposure comparisons are difficult to evaluate.
`The most informative study would be to compare the phar-
`macokinetics of T-DM1 and unconjugated trastuzumab
`when each agent is administered every 3 weeks.
`Recent analyses of patients enrolled in ongoing Phase I/II tri-
`als suggest that the pharmacokinetics of T-DM1 are unaltered
`in combination with paclitaxel or pertuzumab [55,56].
`
`3.4 Clinical efficacy
`3.4.1 Preclinical
`in vitro studies, T-DM1 had greater anti-
`In preclinical
`tumor potency than unconjugated trastuzumab in the
`HER2-positive trastuzumab-sensitive breast cancer cell lines
`BT474
`and SK-BR-3,
`inducing dose-dependent
`cell
`death [44,57]. The potency of T-DM1 also was five times
`greater than that of DM1 in SK-BR-3 cells. In HER2-normal
`(MCF7) or HER2-negative (MDA-MB-468) lines, T-DM1
`had a low antiproliferative effect, unlike DM1, which retained
`similar cytotoxicity to that observed in HER2-positive
`cells [44]. Therefore, T-DM1 maintains selectivity for HER2-
`overexpressing cells. In the HER2-positive,
`trastuzumab-
`responsive mouse model KPL4, T-DM1 led to complete
`tumor regression, in contrast to unconjugated trastuzumab,
`which caused transient
`regression then regrowth after
`treatment cessation [44].
`
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`The antitumor potency of T-DM1 has also been shown in
`HER2-positive cell lines resistant to trastuzumab (including
`BT474 EEI, HCC1954 and KPL4) [44]. In two mouse models
`of HER2-positive breast cancer bearing trastuzumab-resistant
`[44,58], T-DM1 components
`Fo5 breast
`tumor xenografts
`administered singly or unconjugated but in combination were
`ineffective, whereas T-DM1 provided a rapid and durable
`reduction in tumor volume. This has been attributed to
`T-DM1 directing DM1 to HER2-positive cells, rather than
`trastuzumab augmenting DM1 activity after its release in the
`tumor [49]. The antitumor efficacy of T-DM1 also has been
`shown in lapatinib-resistant breast cancer cells (SK-BR-3 and
`BT474) [44,57] and in vivo tumor xenograft models [46].
`T-DM1 also may potentiate the antitumor effects of other
`agents. In in vitro studies, T-DM1 potentiated the antiproli-
`ferative effects of the chemotherapeutic agents doxorubi-
`[59] and in in vivo
`[46], and docetaxel
`cin [46], paclitaxel
`models, T-DM1 enhanced the potency of docetaxel [59,60].
`Synergistic efficacy also has been reported with T-DM1 com-
`bined with the monoclonal antibody pertuzumab, or the
`PI3K inhibitor GDC-0941, compared with the single-agent
`treatment alone [61,62]. A recent study combining T-DM1
`with GDC-0941 and a dual PI3K/mammalian target of
`rapamycin (mTOR) inhibitor (GDC-0980) demonstrated
`increased inhibition of tumor cell proliferation in HER2-
`positive cell
`lines and xenograft models when compared
`with single agent T-DM1 [63]. These results provide the ratio-
`nale for clinical testing of T-DM1 combined with various
`agents in patients with HER2-positive breast cancer.
`Table 2 summarizes efficacy results from clinical trials of
`T-DM1 in patients with HER2-positive advanced breast
`cancer or MBC [48,50,51,64-66].
`
`3.4.2 Phase I
`single-agent T-DM1 in patients
`The clinical efficacy of
`with HER2-positive MBC was evaluated initially in a Phase I
`study of weekly (1.2 mg/kg -- 2.9 mg/kg intravenously) [67]
`and 3-weekly therapy (0.3 mg/kg to 4.8 mg/kg intravenously)
`(TDM3569g) [48]. A total of 24 patients receiving a median
`of four prior chemotherapeutic agents for MBC, and progress-
`ing on prior trastuzumab, were enrolled in the 3-weekly cohort.
`At the MTD of 3.6 mg/kg every 3 weeks (n = 15), the clinical
`benefit rate (objective response rate [ORR] plus stable disease
`for at least 6 months) was 73%,
`including five objective
`responses. In patients with measurable disease at the MTD
`(n = 9), the confirmed response rate was 44%. A second arm
`of
`the
`trial
`(n =
`27)
`investigated weekly
`dosing
`(1.2 -- 2.9 mg/kg), and found 9 partial responses (8 confirmed)
`in 15 patients evaluable for response [67]. The 3-weekly T-DM1
`dose of 3.6 mg/kg was selected for further Phase II evaluation
`for its convenience, since weekly dosing of T-DM1 did not
`appear to offer any advantages in terms of pharmacokinetics,
`safety or anti-tumor activity.
`Phase I/Ib open-label, single-arm, dose-escalation trials are
`assessing T-DM1 for HER2-positive advanced breast cancer
`
`Burris
`
`or MBC in combination with other agents -- paclitaxel with
`or without pertuzumab (TDM4652g), docetaxel (BO22572),
`[41,64].
`or
`the PI3K inhibitor GDC-0941 (GDC4627g)
`Interim results from the dose-limiting toxicity observation
`period of TDM4652g (n = 14) defined the MTD as T-DM1
`2.0 mg/kg every 3 weeks in combination with paclitaxel
`(80 mg/m2). At this dose, two confirmed objective responses
`and four partial responses were observed [64]. Adding pertuzu-
`mab to this regimen will be explored further in Part 2 of the
`trial. B022572 and GDC-0941 continue to recruit patients
`(anticipated enrolment 38 patients and 25 patients), with trial
`completion expected in September 2012 and October 2011,
`respectively.
`
`3.4.3 Phase II
`Two Phase II studies have assessed the efficacy and safety of
`single agent T-DM1 (3.6 mg/kg every 3 weeks) in heavily pre-
`treated patients with HER2-positive MBC, following disease
`progression on prior treatment with HER2-directed therapy
`and chemotherapy.
`trial
`single-arm multicenter
`A Phase
`II open-label,
`(TDM4258g) enrolled 112 patients, who had received a
`median of eight antitumor agents for breast cancer (including
`five for MBC) and prior trastuzumab (median exposure
`17.6 months) [50]. Of these patients 60% also had received
`lapatinib (median exposure 6.0 months). For all 112 treated
`patients, the ORR by independent assessment was 25.9%
`(95% CI: 18.4 -- 34.4%). The median duration of response
`by independent assessment was not reached due to insufficient
`events (lower limit of 95% CI: 6.2 months). Investigator
`assessment
`reported a 9.4-month median duration of
`response. The ORR in patients who had received lapatinib
`(n = 67) was 24.2% (95% CI: 14.5 -- 36.0%). Median PFS
`in the efficacy-evaluable population was 4.6 months (95%
`CI: 3.9 -- 8.6). Retrospective
`exploratory analysis of
`HER2 positivity using central laboratory testing (defined by
`an immunohistochemistry [IHC] score of 3 or more, and/
`or HER2/CEP17 ratio of 2.0 or more by fluorescence
`in situ hybridization [FISH]), showed that the ORR was
`higher in patients with HER2-positive tumors (n = 74,
`33.8%) compared with those who were HER2-normal
`(n = 21, 4.8%).
`A second Phase II study of identical design (TDM4374g)
`evaluated T-DM1 in 110 patients with HER2-positive
`MBC who had previous exposure to an anthracycline, a tax-
`ane and capecitabine and had two HER2-directed therapies
`in the metastatic setting, with progression on the last
`regimen received [51]. The median number of prior therapies
`received was 8.5 (7.0 for MBC), and the median duration
`of prior trastuzumab and lapatinib therapy was 19.7 and
`6.8 months, respectively. The ORR by independent assess-
`ment was 34.5% (95% CI: 26.1 -- 43.9%), and the median
`duration of
`response was 7.2 months
`(lower
`limit of
`95% CI: 4.6 months, upper limit not reached). Median PFS
`was 6.9 months (95% CI: 4.2 -- 8.4%) (Figure 2) [51].
`
`Expert Opin. Biol. Ther. (2011) 11(6)
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`
`Trastuzumab emtansine
`
`NR
`
`NR
`
`NR
`
`(months)
`PFS,
`
`NR
`
`NR
`
`NR
`
`15confirmed(33.3)
`Relapsed:19(42.2),
`2confirmed(9.1)
`9(40.9),
`First-line:
`
`45relapsed)
`67(22First-line,
`
`(28.6)
`
`z
`4
`
`(42.9)
`
`z
`6
`
`14(Part1ofstudy)
`
`theMTD(73.3)
`11/15at
`
`6/24*(25.0)
`
`6/24*(25.0)
`
`of3.6mg/kg)
`24(15attheMTD
`
`CBR,n(%)
`
`PRs,n(%)
`
`ORR,n(%)
`
`Patients,n
`
`Table2.SummaryofclinicalefficacydatafromT-DM1clinicaltrials[48,50,51,64-66].
`
`PFS:Progression-freesurvival;PR:Partialresponse.
`CBR:Clinicalbenefitrate(objectivecompleteresponse,partialresponseorstabledisease‡6months);HER2:HumanEGFR2;MBC:Metastaticbreastcancer;NR:Notreported;ORR:Objectiveresponserate;
`§Byindependentreviewfacility.
`FourPRswereunconfirmed.
`*Fiveconfirmed.
`
`z
`
`NR
`NR
`
`40(57.1)
`37(55.2)
`
`28(40.0)
`29(43.3)
`
`29(41.4)
`32(47.8)
`
`6.9
`
`53(48.2)§
`
`38(34.5)§
`
`38(34.5)§
`
`4.9§
`
`44(39.3)§
`
`29(25.9)§
`
`29(25.9)§
`
`70
`67
`
`110
`
`112
`
`or100mg/m2every3weeks
`3weeks+docetaxel75mg/m2
`dosethen6mg/kgevery
`ortrastuzumab8mg/kgloading
`T-DM13.6mg/kgevery3weeks
`therapiesinthemetastaticsetting
`capecitabineandtwoHER2-directed
`toananthracycline,ataxane,
`MBCfollowingpriorexposure
`3weeksforHER2-positive
`T-DM13.6mg/kgevery
`therapy
`andprogressiononHER2-targeted
`MBCfollowingpriorchemotherapy
`3weeksforHER2-positive
`T-DM13.6mg/kgevery
`
`therapy
`chemotherapyandHER2-directed
`first-lineorfollowingprior
`3weeks,forHER2-positiveMBC
`loadingdosethen420mgevery
`3weeks+pertuzumab840mg
`T-DM13.6mg/kgevery
`
`priortrastuzumabinanyline
`forHER2-positiveMBCfollowing
`3weeks+paclitaxel80mg/m2
`T-DM12.0mg/kgevery
`
`andprogressionontrastuzumab
`followingpriorchemotherapy
`treatedHER2-positiveMBC
`every3weeksforpreviously
`T-DM10.3to4.8mg/kg
`
`andsetting
`Treatmentregimen(s)
`
`TDM4450g/BO21976[66]
`
`TDM4374g[51]
`
`TDM4258g[50]
`PhaseII
`
`TDM4373g/BO22495[65]
`PhaseIb/II
`
`TDM4652g[64]
`PhaseIb
`
`TDM3569g[48]
`PhaseI
`
`Trialandref.
`
`812
`
`Expert Opin. Biol. Ther. (2011) 11(6)
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`Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by JHU John Hopkins University on 05/22/14
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`For personal use only.
`
`IMMUNOGEN 2060, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Burris
`
`T-DM1 (n = 110)
`Median PFS: 6.9 months
`95% CI: 4.2 to 8.4 months
`Range: 0.0 + to 19.2 + months
`Number progressed: 63 (57.3%)
`Number censored: 47 (42.7%)
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`0
`
`2
`
`4
`
`6
`
`8
`10
`12
`Time on study (Months)
`
`14
`
`16
`
`18
`
`20
`
`Progression-free survival rate
`
`Number at risk
`T-DM1
`109
`
`83
`
`59
`
`41
`
`33
`
`22
`
`19
`
`14
`
`8
`
`3
`
`0
`
`Figure 2. Kaplan-Meier plot of progression-free survival (PFS) (by independent review facility assessment) for patients
`receiving single agent T-DM1 in Phase II trials in patients with human EGFR2 (HER2)-positive metastatic breast cancer (MBC)
`who previously received two HER2-directed therapies for MBC (TDM4374g).
`Reproduced with permission from Krop ESMO 2010 [51].
`T-DM1: Trastuzumab emtansine.
`
`Supporting the results of TDM4258g, HER2-positive status
`by central retesting was associated with a higher ORR to
`T-DM1 (n = 76, 40.8%) compared with HER2-normal status
`(n = 15, 20.0%).
`A Phase Ib/II study investigating T-DM1 (3.6 mg/kg every
`3 weeks) combined with pertuzumab (every 3 weeks, 840 mg
`in cycle 1, 420 mg in subsequent cycles) for HER2-positive
`MBC recently reported interim results (data cut-off March
`30, 2010) (TDM4373g) [65]. Patients received this regimen
`in a relapsed setting (following progression on prior HER2-
`targeted therapy for MBC, n = 45) or first line for MBC
`(n = 22). The median number of prior systemic agents
`for all patients was seven, and a median of five cycles of
`T-DM1 and pertuzumab were received. Tumor responses
`were observed in 19 patients in the relapsed group (42%;
`15 confirmed, 33%) and in nine patients receiving the
`combination first line (41%; 2 confirmed, 9%).
`Also in the first-line setting, a Phase II randomized, open-
`label, two-arm, multicenter study is assessing the efficacy
`and safety of single agent T-DM1 (3.6 mg/kg every 3 weeks)
`compared with trastuzumab (initial dose 8 mg/kg then
`6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 or
`100 mg/m2 every 3 weks) in patients with recurrent, locally
`advanced breast cancer or MBC (TDM4450g) [66]. Enrol-
`ment completed in December 2009, and preliminary tumor
`response results have been reported for all
`randomized
`patients (n = 137; data cut-off April 2, 2010). In the
`T-DM1 arm (n = 67), the ORR was 47.8% (95% CI:
`35.4 -- 60.3%), and there were three complete responses. In
`the trastuzumab plus docetaxel arm (n = 70), the ORR was
`41.4% (95% CI: 30.2 -- 53.8%), with one complete response.
`Final PFS data are expected in 2011.
`
`3.4.4 Phase III
`Two Phase III trials of T-DM1 currently are recruiting patients
`(Figures 3A and 3B) [41]. EMILIA (BO21977/TDM4370g;
`is an
`http://clinicaltrials.gov/ct2/show/NCT00829166 [68])
`open-label, randomized, parallel-assignment, two-arm, multi-
`center, registrational
`trial of patients with HER2-positive
`locally advanced breast cancer or MBC who have received prior
`taxane and trastuzumab-based therapy (planned enrollment,
`n = 980 across more than 200 sites). The aim of EMILIA is
`to evaluate the efficacy and safety of T-DM1 versus capecita-
`bine plus lapatinib. The primary endpoints are OS, PFS and
`safety. Study completion is expected in August 2013.
`MARIANNE (BO22589/TDM4788g; http://clinicaltrials.
`three-
`gov/ct2/show/NCT01120184 [69]) is a randomized,
`arm, multicenter trial examining the combination of T-DM1
`and pertuzumab first line in patients with HER2-positive
`progressive or recurrent,
`locally advanced breast cancer or
`untreated MBC. The comparator regimens are trastuzumab
`plus docetaxel or paclitaxel, and T-DM1 plus placebo. The pri-
`mary endpoints are PFS and safety. Anticipated enrollment is
`1092 patients across 263 sites, and trial completion is expected
`in July 2017.
`
`3.5 Safety and tolerability
`Phase I and II results have shown that single agent T-DM1 is
`well
`tolerated at
`the MTD of
`3.6 mg/kg
`every
`3 weeks [48,50,51,66]. In a randomized Phase II study of the
`first-line treatment of patients with HER2-positive breast can-
`cer, single agent T-DM1 was associated with a much lower
`incidence of grade 3/4 adverse events (AEs) compared with
`the standard of care, trastuzumab + docetaxel (38 versus
`75%) [66]. The most common AEs associated with T-DM1
`
`Expert Opin. Biol. Ther. (2011) 11(6)
`
`813
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`Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by JHU John Hopkins University on 05/22/14
`
`For personal use only.
`
`IMMUNOGEN 2060, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`
`Trastuzumab emtansine
`
`A.
`
`B.
`
`Previously-treated HER2-positive
`locally-advanced BC or MBC
`(n = 980)
`
`Treatment continues until PD or
`unacceptable toxicity
`
`T-DM1 (3.6 mg/kg) Q3W
`
`Lapatinib (1250 mg/day) Days 1 – 21
`+ capecitabine (2000 mg/m2/day)
`Days 1 – 14 Q3W
`
`(cid:129) Primary end points: PFS assessed by IRF, OS
`(cid:129) Secondary end points: ORR, duration of response, QoL
`
`HER2-positive
`progressive or recurrent
`locally-advanced or untreated MBC
`(n = 1092)
`
`Treatment continues until PD or
`unacceptable toxicity
`
`T-DM1 (3.6 mg/kg) +
`pertuzumab (840 mg loading
`dose, then 420 mg) Q3W
`
`T-DM1 (3.6 mg/kg) +
`placebo (840 mg loading
`dose, then 420 mg) Q3W
`
`Trastuzumab 8 mg/kg loading dose,
`then 6 mg/kg Q3W
`+ docetaxel 75 mg/m2 Q3W
`or
`Trastuzumab 4 mg/kg loading dose,
`then 2 mg/kg QW
`+ paclitaxel 80 mg/m2 QW
`
`(cid:129) Primary end points: PFS assessed by IRF
`(cid:129) Secondary end points: OS, ORR, CBR, duration of response, QoL
`
`Figure 3. Study designs of ongoing Phase III T-DM1 trials: (A) EMILIA (TDM4370g), (B) MARIANNE (TDM4788g) [41].
`BC: Breast cancer; CBR: Clinical benefit rate; HER2: Human EGFR2; IRF: Independent review facility; MBC: Metastatic breast cancer; ORR: Objective response rate;
`OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; Q3w: Every 3 weeks; QoL: Quality of life; T-DM1: Trastuzumab emtansine.
`
`across trials in heavily pretreated patients with HER2-positive
`MBC are shown in Table 3 [50,51]. The majority of AEs were
`grade 1 or 2, and grade > 2 events were generally infrequent
`and manageable. Thrombocytopenia was rarely associated
`temporally with severe hemorrhage, and platelet transfusions
`were rare [50]. Thrombocytopenia has no clear aetiology in rela-
`tion to T-DM1 and is inconsistent with the mild platelet effects
`observed in preclinical studies [48]. However, as this AE is usu-
`ally rapidly reversible and non-cumulative, it has been postu-
`lated that tubulin-dependent mechanisms such as proplatelet
`release from mature megakaryocytes may be responsible, rather
`than the antimitotic effects on megakaryocyte precursors seen
`with traditional chemotherapies [48].
`All-grade reversible elevations in hepatic enzymes (aspartate
`aminotransferase
`[AST]/alanine
`aminotranferease
`[ALT])
`were observed with T-DM1 in 41.7% of patients receiving
`[48] and 26.4% of heavily
`T-DM1 in the Phase I trial
`
`pretreated patients in the Phase II study TDM4374g [51].
`Similar elevations have been seen in other clinical studies of
`ADCs [70]. The cause is unclear but it may be attributed to
`transient and low levels of circulating DM1 following
`T-DM1 administration [48].
`Alopecia is often associated with microtubule inhibitors
`but notable by its infrequency with T-DM1 therapy. No alo-
`pecia at grade > 1 severity was observed in the Phase I trial [48],
`and only one patient (1.5%) experienced this AE in the
`T-DM1 arm of the first-line Phase II comparator study
`(TDM4450g), compared with 45 patients (66.2%) in the
`trastuzumab plus docetaxel arm [66]. This suggests that the
`specificity of DM1 delivery with T-DM1 minimizes
`systemic exposure.
`An infequent but potentially serious AE of unconjugated
`trastuzumab is cardiotoxicity, manifesting as
`sub-clinical
`and clinical congestive heart
`failure and decreased left
`
`814
`
`Expert Opin. Biol. Th