Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate
`in Development for Human Epidermal Growth Factor R
`Positive Cancer
`eceptor 2
` 
`Patricia M. LoRusso, Denise Weiss, Ellie Guardino, et al.
`Clin Cancer Res  
`
`2011;17:6437-6447.
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`IMMUNOGEN 2179, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`-
`

`

`CCR FOCUS
`
`Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate
`in Development for Human Epidermal Growth Factor
`Receptor 2–Positive Cancer
`
`Patricia M. LoRusso1, Denise Weiss1, Ellie Guardino2, Sandhya Girish2, and Mark X. Sliwkowski2
`
`Abstract
`
`Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)–targeted antibody-
`drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1
`(derivative of maytansine), in phase III development for HER2-positive cancer. 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.
`Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1,
`with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were
`shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics
`analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II
`clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab
`have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast
`cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is
`evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating
`T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combina-
`tions of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive
`breast cancer) are also under investigation. Data from the phase III trials and other studies of
`T-DM1–containing agents are eagerly awaited. Clin Cancer Res; 17(20); 6437–47. Ó2011 AACR.
`
`Introduction
`
`Chemotherapies are limited by systemic toxicity and
`lack of tumor selectivity, and thus they have a narrow
`therapeutic index. Antibody-drug conjugates (ADCs) are
`a therapeutic class comprising a tumor antigen-specific
`targeting antibody linked to a cytotoxic drug. ADCs may
`improve the therapeutic index because they are designed to
`specifically deliver cytotoxic agents to tumor cells and limit
`collateral damage to normal cells. The concept of ADCs has
`existed for many years; however, it is only recently that
`advances in this technology have resulted in clinically useful
`therapeutic agents. A review of the key challenges in the
`development of these agents and ADCs currently in clinical
`development is included in this CCR Focus section (1). To
`date, the only ADC to have received approval from the U.S.
`Food and Drug Administration (FDA) is gemtuzumab
`ozogamicin (Mylotarg), which was approved for the treat-
`ment of relapsed CD33-positive acute myeloid leukemia in
`
`Authors' Affiliations: 1Karmanos Cancer Institute, Detroit, Michigan;
`2Genentech Inc., South San Francisco, California
`
`Corresponding Author: Patricia M. LoRusso, Karmanos Cancer Institute,
`4100 John R St., Detroit, MI 48201. Phone: 313-576-8716; Fax: 313-576-
`8719; E-mail: lorussop@karmanos.org
`
`doi: 10.1158/1078-0432.CCR-11-0762
`Ó2011 American Association for Cancer Research.
`
`older patients. However, it was recently withdrawn from use
`because postmarketing studies showed a lack of clinical
`benefit [reviewed in this CCR Focus section by Ricart (2)]. A
`number of other ADCs, however, are currently in clinical
`development
`for hematological malignancies. These
`include antibodies conjugated to microtubule polymeriza-
`tion inhibitors (3, 4), DNA intercalaters (2), and protein
`synthesis inhibitors (i.e., protein toxins; ref. 5). Antibody-
`radionuclide conjugates have also been approved for the
`treatment of hematologic malignancies (6). Trastuzumab
`emtansine (T-DM1), a human epidermal growth factor
`receptor (HER2)–targeted ADC composed of the microtu-
`bule polymerization inhibitor DM1 (derivative of maytan-
`sine) linked to trastuzumab, is in phase III development for
`HER2-positive breast cancer. As such, it is the only ADC in
`late-stage clinical development for a solid tumor.
`Breast cancer accounts for28% of all new cases of cancer
`in women (7), and 15% to 25% of these new cases contain
`gene amplifications or protein overexpression of HER2
`(8–10). HER2-positive disease is an aggressive form of
`breast cancer that typically is associated with a higher risk
`of distant recurrence with a shorter time to relapse, lower
`disease-free and overall survival rates, and greater therapeu-
`tic resistance compared with HER2-normal disease (8–14).
`Despite treatment advances, including the humanized anti-
`HER2 antibody trastuzumab and the dual epidermal
`growth factor
`receptor (EGFR)/HER2 tyrosine kinase
`
`www.aacrjournals.org
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`CCR FOCUS
`
`inhibitor lapatinib, HER2-positive breast cancer will even-
`tually progress in most patients, highlighting the need
`for novel, alternative therapies. In addition, currently avail-
`able HER2-targeted therapies are rarely given as mono-
`therapy but are generally given in combination with other
`agents (e.g., chemotherapy or hormonal therapy). Because
`toxicities associated with chemotherapy can be a significant
`source of comorbidity for patients with cancer, ADCs
`are a promising therapeutic approach for this patient
`population.
`Toxicity to normal cells can occur by both target-depen-
`dent and target-independent mechanisms. Perhaps the most
`important consideration for target-independent cytotoxicity
`in an ADC is the chemical nature of the linker moiety. ADCs
`containing maytansines were originally designed with lin-
`kers that contained disulfide bonds (15, 16). This strategy
`assumed that once the ADC engaged the cell surface recep-
`tor, the complex between the ADC and the receptor would
`be internalized and trafficked to an endocytic compartment
`that was sufficiently reducing to release the maytansine.
`Experimental data disproved this hypothesis when it was
`shown that the oxidizing potential of endosomes and lyso-
`somes limits the intracellular cleavage of disulfide-contain-
`ing ADCs (17). These and other observations regarding
`improved pharmacokinetics and tolerability guided the
`choice of incorporating a thioether linker containing a
`cyclohexane carboxylate spacer into the trastuzumab ADC
`(18). Additional studies indicated that once T-DM1 is inter-
`nalized, proteolytic digestion of the conjugate occurs, releas-
`e
`-4-(N-maleimidomethyl)
`ing the active metabolite lysine-N
`cyclohexane-1-carboxylate (MCC)-DM1. Because it is a
`e
`-MCC-DM1 does not readily cross the
`zwitterion, lysine-N
`plasma membrane of neighboring normal cells. This likely
`contributes to the overall safety profile of T-DM1 (19).
`The nonclinical activity of T-DM1 was initially assessed in
`experimental models that were refractory to trastuzumab or
`lapatinib (18, 20, 21), because trastuzumab and lapatinib
`are established for the treatment of HER2-postitive meta-
`static breast cancer (MBC). To date, meaningful antitumor
`activity has been observed in all of these models. To gain
`further insight into these findings, we conducted studies to
`assess the activity of trastuzumab relative to T-DM1. Mul-
`tiple lines of evidence, including the direct release of ade-
`nylate kinase, PARP cleavage, caspase 3/7 activation, and
`cell cycle analysis, indicate that T-DM1 induces a direct
`cytotoxic effect against cells that overexpress HER2 (18). The
`mechanisms of action for trastuzumab include inhibition of
`the HER3/phosphoinositide 3-kinases (PI3K)/AKT signal-
`ing pathway, inhibition of HER2 shedding, and Fcg recep-
`tor–mediated engagement of immune cells, which may
`result in antibody-dependent cellular cytotoxicity (22). Of
`importance, T-DM1 retains these same mechanisms of
`action of unconjugated trastuzumab (20).
`
`Clinical Efficacy of Single-Agent T-DM1
`
`T-DM1 was initially evaluated as a single agent in a dose
`escalation phase I trial in patients with HER2-positive MBC
`
`who previously received a trastuzumab-containing chemo-
`therapy regimen. T-DM1 was given at various doses on a
`weekly (23) or every 3 weeks schedule (ref. 24; Table 1). The
`maximum tolerated dose (MTD) was 3.6 mg/kg every 3
`weeks, based on the dose-limiting toxicity (DLT) of grade
`4 thrombocytopenia at 4.8 mg/kg every 3 weeks. In a
`group of 15 patients receiving 3.6 mg/kg every 3 weeks,
`the clinical benefit rate (CBR; objective response rate
`[ORR] plus stable disease at 6 months) was 73%
`(ref. 24; Table 1). Interim results for patients receiving
`weekly T-DM1 showed 9 partial responses (PR; 8 were
`confirmed) in 15 patients evaluable for response (ORR
`53%; ref. 23). On the basis of its clinical activity and
`dosing convenience, T-DM1 3.6 mg/kg every 3 weeks was
`selected for further clinical development.
`Two large multicenter, single-arm, phase II studies eval-
`uating single-agent T-DM1 3.6 mg/kg every 3 weeks in
`pretreated patients with locally assessed HER2-positive
`MBC following progression on previous chemotherapy and
`HER2-directed therapy have been completed (refs. 25,
`26; Table 1). In the first study, the ORR by independent
`review was 25.9% [95% confidence interval (CI), 18.4–
`34.4%] and 37.5% by investigator assessment, including 4
`complete responses (CR; see Table 1). The median progres-
`sion-free survival (PFS) was 4.6 months (95% CI, 3.9–8.6
`months; ref. 25). In the second study, patients had been
`previously treated with an anthracycline, a taxane, and
`capecitabine, as well as lapatinib and trastuzumab with a
`median of 8.5 agents (range: 5–19) in all settings and 7.0
`agents (range: 3–17) for metastatic disease (26). An interim
`report indicated that the ORR was 34.5% (all PRs; 95% CI,
`26.1–43.9%) and the CBR was 48.2% (95% CI, 38.8–
`57.9%) by independent review. The median PFS was 6.9
`months (95% CI, 4.2–8.4 months; Table 1).
`To examine the relationship between HER2-positive
`status and response to T-DM1 (Fig. 1) and identify asso-
`ciated biomarkers, LoRusso and colleagues (28) per-
`formed a retrospective analysis using archival
`tumor
`tissue from these 2 phase II studies. Confirmed HER2-
`positive status [immunohistochemistry (IHC) 3þ or fluo-
`rescence in situ hybridization (FISH)þ by central
`retesting] was associated with a higher ORR than
`HER2-normal status (TDM4258g: 33.8% in the 74 con-
`firmed HER2-positive patients vs. 4.8% in the 21 HER2-
`normal patients; TDM4374g: 40.8% in the 76 confirmed
`HER2-positive patients vs. 20.0% in the 15 HER2-normal
`patients). Analysis by quantitative reverse transcriptase
`polymerase chain reaction (qRT-PCR) showed that levels
`of HER2 mRNA expression equal to or above the median
`were also associated with a higher ORR than levels below
`the median [TDM4258g: 36.0% (n ¼ 25) vs. 28.0%
`(n ¼ 25); TDM4374g: 50.0% (n ¼ 26) vs. 33.3%
`(n ¼ 39); Table 2]. These results support the specificity of
`the effect of T-DM1 on HER2-positive MBC. They further
`suggest that tumor response to T-DM1 may be dependent
`on HER2 quantity, even among tumors that are already
`deemed HER2-positive by standard methods. It is important
`to note, however, that these data are from exploratory
`
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`

`Trastuzumab Emtansine: Unique ADC for HER2-Positive Cancer
`
`Table 1. Efficacy data from clinical trials of single-agent T-DM1 every 3 weeks in HER2-positive MBC
`
`Trial and
`reference
`
`Study design and
`T-DM1 dose
`
`Study population
`
`Patients, n ORR, % CR, % CBRc, % Median
`DOR
`(months)
`
`Median
`PFS
`(months)
`
`24
`
`25.0b
`
`0
`
`73
`
`NR
`
`NR
`
`112
`
`37.5 (25.9) 3.6 (0) NR
`
`9.4 (6.2–NE) 4.6 (4.6)
`
`110
`
`32.7 (34.5) 4.5 (0) 46.4 (48.2) NR (7.2)
`
`NR (6.9)
`
`47.8
`
`41.4
`
`4.5
`
`1.4
`
`55.2
`
`57.1
`
`NR
`
`NR
`
`NR
`
`NR
`
`TDM3569g
`(24)
`
`Phase I single arm;
`0.3–4.8 mg/kga
`
`TDM4258g
`(25)
`
`Phase II single arm;
`3.6 mg/kg
`
`TDM4374g
`(26)
`
`Phase II single arm;
`3.6 mg/kg
`
`TDM4450g
`(27)
`
`Phase II randomized;
`T-DM1 3.6 mg/kg
`vs. T þ Dd
`
`Previously treated
`with chemotherapy
`and progressed on T
`Previously treated
`with chemotherapy
`and progressed on
`HER2-targeted therapy
`Previously treated
`with anthracycline,
`a taxane, and
`capecitabine, plus
`lapatinib and T for MBC
`Recurrent, locally advanced
`breast cancer or MBC,
`with no prior chemotherapy
`for metastatic disease
`
`T-DM1,
`n ¼ 67
`T þ D,
`n ¼ 70
`Data shown are by investigator assessment, with independent review results in parentheses (where available).
`Abbreviations: CBR, clinical benefit rate; CR, complete response; D, docetaxel; DOR, duration of response; HER2, human epidermal
`growth factor receptor 2; MBC, metastatic breast cancer; NE, not estimable; NR, not reported; ORR, objective response rate; PFS,
`progression-free survival; T, trastuzumab; T-DM1, trastuzumab emtansine.
`aEfficacy outcomes reported are for patients treated at the MTD (3.6 mg/kg every 3 weeks; n ¼ 15).
`bConfirmed ORR among patients with measurable disease who were treated at the MTD (n ¼ 9) was 44%.
`cDefined as CR, PR, or stable disease  6 months.
`dTrastuzumab (8 mg/kg loading dose; 6 mg/kg every 3 weeks) þ docetaxel (75 or 100 mg/m2 every 3 weeks).
`
`analyses in a small number of patients; additional studies
`are necessary to adequately test these hypotheses.
`Patients with wild-type PI3K mutation status and normal
`PTEN expression appeared to achieve a better response in
`TDM4258g. This association, however, was not observed in
`patients in TDM4374g (see Table 2). Thus, although no
`consistent trend in T-DM1 activity was observed in patients
`with activating PI3K mutations and/or decreased PTEN
`expression, it should be noted that this analysis was limited
`because of the exclusive use of archival tissue from the
`patients’ initial diagnoses (28).
`A randomized, open-label phase II study (TDM4450g;
`ref. 29) is investigating single-agent T-DM1 compared with
`trastuzumab plus docetaxel in the first-line treatment of
`HER2-positive recurrent, locally advanced breast cancer or
`MBC (ref. 27; Table 1). Enrollment was completed in
`December 2009, and safety and ORR data as of April 2,
`2010, were included in an interim analysis. Thirteen
`patients in the T-DM1 arm (19.4%) and 18 patients in the
`trastuzumab-plus-docetaxel arm (25.7%) had previously
`received trastuzumab. The ORR by investigator assessment
`was 47.8% (n ¼ 32; 95% CI, 35.4–60.3%) for T-DM1 and
`41.4% (n ¼ 29; 95% CI, 30.2–53.8%) for trastuzumab plus
`docetaxel. There were 3 CRs (4.5%) and 1 CR (1.4%),
`
`respectively. Final analysis of the primary endpoint, PFS,
`is eagerly awaited.
`
`Clinical Safety of Single-Agent T-DM1
`
`The most common adverse events (AE) of all grades for
`T-DM1 seen to date include fatigue (range: 37.5–65.2%),
`anemia (10.4–29.2%), nausea (25.0–50.9%), and hypoka-
`lemia (4.2–24.1%). Among these, the incidence of grade
`3 or 4 AEs was <5%, with the exception of grade 3 or 4
`hypokalemia in one study (TDM4258g, 8.9%; refs. 24–
`27; Table 3). T-DM1 also had a favorable safety profile
`relative to standard-of-care treatment in the first-line
`setting (27), with fewer grade 3 or 4 AEs (37% with
`T-DM1 vs. 75% with trastuzumab plus docetaxel). In
`addition, many of the AEs associated with traditional
`chemotherapies (e.g., diarrhea, neutropenia, rash, neu-
`ropathy, and alopecia) were observed at much lower rates
`with T-DM1 treatment compared with trastuzumab plus
`docetaxel (see Table 3; ref. 27).
`frequently
`the most
`Thrombocytopenia was one of
`reported grade 3 or 4 laboratory abnormalities across the
`phase II studies of T-DM1 (range: 7.3–8.0%; refs. 25–27).
`These reductions in platelet count were generally reversible
`
`www.aacrjournals.org
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`

`

`CCR FOCUS
`
`Figure 1. Structure of T-DM1 and
`mechanisms of action. After T-DM1
`binds HER2, the HER2/T-DM1
`complex undergoes internalization,
`followed by lysosomal degradation.
`This process results in the
`intracellular release of DM1-
`containing catabolites that bind to
`tubulin and prevent microtubule
`polymerization as well as suppress
`microtubule dynamic instability.
`T-DM1 has also been shown to
`retain mechanisms of action of
`trastuzumab, including disruption
`of the HER3/PI3K/AKT signaling
`pathway and Fcg receptor–
`mediated engagement of immune
`effector cells, which leads to
`antibody-dependent cellular
`cytotoxicity.
`
`P
`
`P
`
`P
`
`(24, 30). Thrombocytopenia was observed as early as 1 day
`after T-DM1 treatment. In most patients, platelet counts
`reached a nadir by day 8 and recovered by day 18 (24, 30).
`This pattern persisted even after repeated dosing, and it
`appears to be distinguishable from immune-mediated
`
`thrombocytopenia (24, 30). Thrombocytopenia was not
`typically associated with clinically meaningful bleeding
`events. For example, in the first phase II study, 9 patients
`had grade 3 or 4 thrombocytopenia, but only 1 patient
`had a concurrent grade 3 bleeding event (i.e., epistaxis;
`
`Table 2. T-DM1 activity in efficacy-evaluable patients by HER2 qRT-PCR level, PI3K mutation status, and
`PTEN expression level (28)
`
`HER2 qRT-PCR level
`Mediana
`<Median
`PI3K mutationb
`Wild-type
`Mutant
`PTEN by IHCb
`Normal
`Decreased
`
`TDM4374g
`
`TDM4258g
`
`n
`
`26
`39
`
`48
`11
`
`38
`3
`
`ORR, % (95% CI)
`
`50.0 (29.9–70.1)
`33.3 (19.7–50.0)
`
`35.4 (22.2–50.0)
`36.4 (13.5–66.7)
`
`36.8 (22.6–53.5)
`33.3
`
`n
`
`25
`25
`
`42
`9
`
`30
`6
`
`ORR, % (95% CI)
`
`36.0 (18.5–56.9)
`28.0 (12.1–47.5)
`
`35.7 (21.6–51.9)
`22.2 (4.1–55.8)
`
`36.7 (20.5–56.0)
`16.7 (0.9–59.8)
`
`aMedian was based on TDM4258g data.
`bFISHþ and/or IHC3þ.
`
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`IPR2014-00676
`
`

`

`Trastuzumab Emtansine: Unique ADC for HER2-Positive Cancer
`
`Table 3. Most common AEs and AEs of special interest reported in clinical trials of single-agent T-DM1 in
`HER2-positive MBC
`
`Adverse event
`
`Incidence, n (%)
`
`TDM3569g
`(24), n ¼ 24a
`
`TDM4258g
`(25), N ¼ 112
`
`TDM4374g
`(26), N ¼ 110
`
`TDM4450g (27)
`
`Grade
`3/4
`
`All
`grades
`
`Grade
`3/4
`
`All
`grades
`
`Grade
`3/4
`
`All
`grades
`
`T-DM1 (n ¼ 67)
`
`Trastuzumab þ
`docetaxel (n¼ 68)
`
`Grade
`3/4
`
`All
`grades
`
`Thrombocytopenia
`Increased hepatic
`enzymesb
`Alopecia
`Neuropathy
`Diarrhea
`Neutropenia
`Rash
`Vomiting
`Fatigue
`Anemia
`Nausea
`Hypokalemia
`
`3 (12.5)
`0
`
`13 (54.2)
`10 (41.7)
`
`9 (8.0)
`NR
`
`NR
`NR
`
`8 (7.3)
`6 (5.5)
`
`36 (32.7)
`56 (50.9)
`
`5 (7.5)
`9 (13.4)
`
`15 (22.4)
`27 (40.3)
`
`n/a
`0
`NR
`0
`NR
`0
`0
`0
`0
`0
`
`NR
`2 (8.3)
`NR
`1 (4.2)
`NR
`3 (12.5)
`9 (37.5)
`7 (29.2)
`6 (25.0)
`1 (4.2)
`
`n/a
`NR
`0
`NR
`NR
`1 (0.9)
`5 (4.5)
`3 (2.7)
`1 (0.9)
`10 (8.9)
`
`NR
`NR
`29 (25.9)
`NR
`NR
`27 (24.1)
`73 (65.2)
`23 (20.5)
`57 (50.9)
`27 (24.1)
`
`n/a
`0
`0
`NR
`NR
`0
`5 (4.5)
`2 (1.8)
`1 (0.9)
`1 (0.9)
`
`NR
`20 (18.2)
`14 (12.7)
`NR
`NR
`18 (16.4)
`68 (61.8)
`22 (20.0)
`41 (37.3)
`23 (20.9)
`
`n/a
`NR
`NR
`NR
`NR
`NR
`3 (4.5)
`NR
`NR
`NR
`
`1 (1.5)
`4 (6.0)
`7 (10.4)
`5 (7.5)
`6 (9.0)
`NR
`31 (46.3)
`7 (10.4)
`32 (47.8)
`NR
`
`Abbreviations: n/a, not applicable; NR, not reported.
`aData are shown for patients treated with 0.3–4.8 mg/kg every 3 weeks.
`bIncludes alkaline phosphatase, aspartate transaminase, and alanine transaminase.
`
`Grade
`3/4
`
`1 (1.5)
`1 (1.5)
`
`n/a
`NR
`NR
`NR
`NR
`NR
`3 (4.4)
`NR
`NR
`NR
`
`All
`grades
`
`4 (5.9)
`9 (13.2)
`
`45 (66.2)
`12 (17.6)
`31 (45.6)
`39 (57.4)
`14 (20.6)
`NR
`29 (42.6)
`15 (22.1)
`27 (39.7)
`NR
`
`ref. 25). No patients discontinued treatment because of
`hemorrhagic events (25).
`Cardiotoxicity is an infrequent AE linked to HER2-direct-
`ed agents (31, 32). In the single-arm studies of single-agent
`T-DM1 reported to date, no dose-limiting cardiotoxicities
`[grade 3 left ventricular ejection fraction (LVEF) decline or
`symptomatic congestive heart failure] were observed (24–
`26). In the randomized comparative phase II study, T-DM1
`did not increase the risk of cardiotoxicity relative to trastu-
`zumab plus docetaxel. Absolute decreases in LVEF of 10%
`to 20% were observed in 7.8% (n ¼ 5) of patients in the
`T-DM1 arm and 16.4% (n ¼ 11) of patients in the trastu-
`zumab-plus-docetaxel
`arm (27). However,
`in all
`T-DM1 studies, a baseline LVEF of 50% was required for
`study entry.
`The potential of T-DM1 to prolong the QT interval was
`assessed in a dedicated multicenter, phase II study of
`patients with HER2-positive, recurrent, locally advanced
`breast cancer or MBC. Multiple analytes, including T-DM1
`and DM1-containing catabolites, were monitored in this
`study. An early report of this study indicated that T-DM1
`had a minimal effect on the QT interval that was below the
`threshold of safety concern (33).
`In addition, study
`TDM4874g (NCT01196052) is currently evaluating the
`cardiac safety of T-DM1 after the administration of doxo-
`rubicin plus cyclophosphamide (AC) or 5-fluorouracil
`
`(5-FU) plus epirubicin and cyclophosphamide (FEC) in
`patients with early-stage HER2-positive breast cancer (34).
`Increased serum concentrations of hepatic enzymes are
`laboratory abnormalities that have been associated with
`T-DM1 treatment. In phase I and phase II studies of
`single-agent T-DM1 in HER2-positive MBC, the overall
`incidence of grade 3 or 4 elevations of alkaline phospha-
`tase, aspartate transaminase, or alanine transaminase
`ranged between 0% and 13.4% (24, 26, 27). One patient
`died of hepatic dysfunction (in TDM4374g; ref. 26), but
`the relation of the death to the administration of T-DM1
`was unclear.
`
`Pharmacokinetic/Pharmacodynamic Profile of
`T-DM1
`
`The pharmacokinetics of T-DM1 has been assessed in
`nonclinical and clinical
`studies. Preliminary results
`showed that T-DM1 exhibits dose-proportional pharma-
`cokinetics in non–trastuzumab-binding species (i.e., mice
`and rats; refs. 35, 36) and a dose-dependent decrease in
`clearance associated with increasing dose in trastuzumab-
`binding species (i.e., cynomolgus monkeys and humans;
`refs. 36, 37). Results from a preclinical absorption, dis-
`tribution, metabolism, and excretion study of T-DM1 in
`rats suggest that T-DM1 nonspecifically distributes to
`
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`
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`

`

`CCR FOCUS
`
`Table 4. Serum T-DM1 pharmacokinetic parameters for patients treated with T-DM1 3.6 mg/kg every 3
`weeks in studies TDM3569g, TDM4258g, TDM4374g, and TDM4688g (37)
`
`Mean (SD)
`
`Analyte
`
`Serum T-DM1
`
`Cmax (mg/mL)
`
`83.1 (20.1)
`80.9 (20.7)
`79.5 (21.1)
`75.6 (21.9)
`
`AUCinf
`(day mg/mL)
`486 (124)
`457 (129)
`486 (141)
`431 (126)
`
`t1/2 (day)
`
`3.61 (0.67)
`3.53 (0.71)
`3.96 (0.96)
`4.02 (0.94)
`
`Study (number
`of patients)
`TDM3569g (n ¼ 15)a
`TDM4258g (n ¼ 101)
`TDM4374g (n ¼ 105)
`TDM4688g (n ¼ 51)
`Abbreviations: AUCinf, area under the curve to time infinity; t1/2, terminal half-life; Vss, volume of distribution at steady state; CL,
`clearance.
`aData are reported for patients treated at the MTD (3.6 mg/kg every 3 weeks; n ¼ 15).
`
`Vss (mL/kg)
`
`CL (mL/day/kg)
`
`29.6 (7.88)
`28.4 (12.9)
`31.2 (10.9)
`41.2 (24.5)
`
`7.87 (2.18)
`8.51 (2.69)
`8.04 (2.97)
`9.17 (3.03)
`
`tissues without accumulation. The major elimination
`routes of DM1-containing metabolites/catabolites are
`through the feces (80%) and urine (<10%; ref. 38).
`After dosing of T-[3H]DM1 in rats, T-DM1 was the pre-
`dominant species in plasma. More than 95% of radioac-
`tivity was protein-bound (in the acetonitrile-precipitable
`fraction), suggesting that the majority of DM1 remains
`conjugated as T-DM1. Low levels of DM1- and linker-
`containing catabolites (MCC-DM1 and Lys-MCC-DM1)
`were detected. Following T-DM1 administration in
`patients in TDM4688g, low levels of MCC-DM1, Lys-
`MCC-DM1, and DM1 were detected in plasma without
`accumulation (38).
`A consistent pharmacokinetics profile of T-DM1 has been
`observed across 4 clinical studies to date (TDM3569g,
`TDM4258g, TDM4374g,
`and TDM4688g;
`refs. 24,
`25, 37; Table 4). Plasma DM1 concentrations were low:
`the highest reported concentration of DM1 was 25 ng/mL,
`with no observed accumulation over treatment cycles
`despite repeat dosing. The average maximum concentration
`
`(Cmax) of DM1 ranged from 4.6  1.3 ng/mL to 5.42  1.6
`
`ng/mL (24, 25, 37).
`Gupta and colleagues (39) developed a population-phar-
`macokinetics model using pooled data (n ¼ 273) from the
`phase I and phase II single-agent trials to determine the effects
`of demographic and pathophysiologic covariates on the
`pharmacokinetics of T-DM1 and to identify clinical factors
`affecting T-DM1 exposure in individual patients. The inter-
`individual variability in T-DM1 clearance after adjusting for
`covariates was low (<21%), and although body weight,
`albumin, tumor burden, and aspartate aminotransferase
`levels were statistically significant covariates accounting for
`interindividual variability in T-DM1 exposure or clearance,
`the magnitude of their effect on T-DM1 exposure was min-
`imal (<25%) and expected to be clinically insignificant (Fig.
`2). T-DM1 exposure [Cmax and area under the curve (AUC)]
`was relatively consistent across the patient weight range (48–
`103 kg), following body weight–based T-DM1 dosing. The
`results of this population-pharmacokinetics analysis suggest
`that no dose adjustments for the evaluated covariates are
`necessary in patients with heavily pretreated MBC.
`
`The relationships between T-DM1 exposure and clinical
`response and safety were evaluated in an exploratory anal-
`ysis of 2 phase II studies (37). Although the analyses were
`limited to a narrow exposure range following 3.6 mg/kg
`every 3 weeks, variations in T-DM1 exposure did not cor-
`relate with response, and differences among patients in
`circulating levels of trastuzumab due to prior treatment
`with trastuzumab and the extracellular domain of HER2
`did not affect efficacy. Additionally, there was no obvious
`relationship between exposure to T-DM1 and the incidence
`of grade 3 thrombocytopenia or grade 3 increases in serum
`hepatic enzyme concentrations. Overall, 12 of 278 evalu-
`able patients (4.3%) across the 4 studies developed an
`antibody response to T-DM1 after being exposed to repeat-
`ed T-DM1 doses (Genentech, data on file). The clinical
`significance of antibody development against T-DM1 is
`unknown; however, there were no obvious changes in the
`pharmacokinetics, safety profiles, or efficacy outcomes of
`patients who developed an antibody response to T-DM1
`compared with data from patients who tested negative for
`antibodies to T-DM1.
`Preliminary assessments of pharmacokinetics-based drug
`interactions between T-DM1 and the HER2-targeted mono-
`clonal antibody pertuzumab in the TDM4373g study (40)
`or T-DM1 and paclitaxel in the TDM4652g study (41)
`showed that the combination had no effect on the phar-
`macokinetics of the individual agents and had a low risk for
`drug interactions.
`
`Phase III Studies of T-DM1
`
`Based on the efficacy and safety profile of T-DM1 in the
`phase I and phase II single-agent studies, 2 confirmatory,
`randomized, international, multicenter, phase III trials (EMI-
`LIA and MARIANNE) are recruiting patients. EMILIA
`(NCT00829166) is a randomized (1:1) study evaluating the
`safety and efficacy of T-DM1 compared with lapatinib plus
`capecitabine in patients with HER2-positive, locally advanced
`breast cancer or MBC following prior trastuzumab-based and
`taxane-containing chemotherapy (42, 43). The study will
`enroll 980 patients. The primary endpoints are PFS and
`
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`Downloaded from
`
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`on May 20, 2014. © 2011 American Association for Cancerclincancerres.aacrjournals.org
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`
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`
`

`

`Trastuzumab Emtansine: Unique ADC for HER2-Positive Cancer
`
`A
`
`50
`
`170
`
`Steady State AUC (μg⋅day/mL)
`290
`410
`
`AUC range
`
`230 μg⋅day/mL
`
`530
`
`650
`
`539 μg⋅day/mL
`
`Body weight
`
`48 kg (−19%)
`
`103 kg (+24.1%)
`
`Albumin
`
`SGOT
`
`31 g/L (−11.1%)
`
`46 g/L (+6.7%)
`
`73 IU/L (−9%)
`
`17 IU/L (+6.3%)
`
`Tumor burden
`
`20.6 cm (−5.3%)
`
`1.9 cm (+8.5%)
`
`Base = 362.1
`70-kg patient, albumin 40 g/L, SGOT 31 IU/L, tumor burden 8 cm
`
`B
`
`25
`
`45
`
`Steady State Cmax (μg/mL)
`65
`85
`
`105
`
`125
`
`Cmax range
`
`58.9 μg/mL
`
`Body weight
`
`48 kg (−16.1%)
`
`97.6 μg/mL
`
`103 kg (+19.7%)
`
`Albumin
`
`SGOT
`
`31 g/L (−0.9%)
`
`46 g/L (+0.6%)
`
`73 IU/L (−0.8%)
`
`17 IU/L (+0.6%)
`
`Tumor burden
`
`20.6 cm (−0.5%)
`
`1.9 cm (+0.8%)
`
`Base = 77.4
`70-kg patient, albumin 40 g/L, SGOT 31 IU/L, tumor burden 8 cm
`
`Figure 2. Sensitivity plots
`comparing the effect of covariates
`on the steady-state exposure of T-
`DM1. A, AUC and B, Cmax are
`shown for the 5th to 95th percentile
`range across the entire population.
`The solid vertical reference line is
`AUC or Cmax in the typical patient
`after a steady-state i.v. infusion at a
`dose of 3.6 mg/kg every 3 weeks.
`The label at each end of the bar
`represents the covariate, which
`produces that AUC or Cmax. The
`length of each bar describes the
`AUC or Cmax changes for
`individuals in the 5th to 95th
`percentile with specified
`covariates, showing the potential
`impact of that particular covariate
`on pharmacokinetics (39). SGOT,
`serum glutamic oxaloacetic
`transaminase. Adapted with
`permission from Gupta, et al. (64).
`
`overall survival; secondary endpoints include ORR, duration
`of response, patient-reported quality of life, and safety. MAR-
`IANNE (NCT01120184) is a randomized (1:1:1) 3-arm study
`comparing the efficacy and safety of single-agent T-DM1 plus
`placebo versus T-DM1 plus the HER2-targeted monoclonal
`antibody pertuzumab versus trastuzumab plus a taxane for
`the first-line treatment of HER2-positive, metastatic, or locally
`recurrent breast cancer (44, 45). The planned enrollment is
`1,092 patients. The primary endpoint is PFS. Secondary
`endpoints include safety, ORR, overall survival, duration of
`response, and quality of life.
`
`Ongoing Combination Studies of T-DM1
`
`Additional studies are evaluating novel T-DM1 combina-
`tions
`in HER2-positive breast
`cancer.
`TDM4373g
`(NCT00875979) is investigating the safety and efficacy of
`
`T-DM1 combined with pertuzumab in recurrent (n ¼ 46) or
`newly diagnosed (n ¼ 21) HER2-positive MBC (46). Inter-
`im results showed ORRs of 34.8% (n ¼ 16; 95% CI, 22.2–
`50.0%) in recurrent disease and 57.1% (n ¼ 12; 95% CI,
`34.0–78.2%) first-line; CBRs of 45.7% (n ¼ 21; 95% CI,
`30.9–60.2%) and 61.9% (n ¼ 13; 95% CI, 39.8–80.3%)
`were reported, respectively. Most AEs were grade 2 or lower,
`with reports of mild neuropathy and infrequent cardiotoxi-
`city. Only 1 patient was discontinued because of a decrease
`in LVEF. The efficacy and safety of T-DM1 plus pertuzumab
`is also being assessed in the second part of the phase II QTc
`study TDM4688g, following disease progression on single-
`agent T-DM1 (NCT00943670; ref. 47).
`TDM4652g is a phase Ib, multicenter, open-label, 3þ3
`design, dose-escalation study evaluating T-DM1 (both
`weekly and every 3 weeks) plus paclitaxel and pertuzuma