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Drug Annotation
Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast CancerClick to copy article linkArticle link copied!
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ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States
*J.M.L.: e-mail, [email protected]; phone, 781-895-0600.
*R.V.J.C.: e-mail, [email protected]; phone, 781-895-0600.
Abstract
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Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
This publication is licensed for personal use by The American Chemical Society.
Copyright © 2014 American Chemical Society
Introduction
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The HER2/neu proto-oncogene (also called c-erbB-2), shares extensive sequence homology with the epidermal growth factor receptor gene and other members of the epidermal growth factor receptor family. The gene was first identified in 1981 and was subsequently found to encode a 185 kDa transmembrane glycoprotein with tyrosine kinase activity. Amplification of the gene occurs in about 20–25% of human breast cancers and is associated with aggressive tumor growth and poor clinical outcome. (1) A panel of murine monoclonal antibodies against the extracellular domain of HER2 was derived from immunization of mice with a cell line that had been transfected with the erbB-2 gene. From more than 100 antibodies that were obtained, 4D5 was chosen as the lead. This antibody was shown to specifically bind to HER2 and induced cytostatic growth inhibition of a number of HER2 overexpressing cell lines in vitro. This antibody also inhibited growth of HER2-expressing human breast tumor xenografts in athymic mice. In addition, treatment of tumor-bearing mice with a combination of 4D5 and the chemotherapeutic drug cis-platin resulted in synergistic anti-tumor activity. (2) Since the 4D5 antibody was of murine origin and had the potential to be immunogenic in humans, a series of humanized versions were produced by grafting the complementarity determining regions, involved in antigen binding, from the murine antibody into the human antibody framework. A humanized monoclonal antibody of the IgG1 isotype, trastuzumab, was selected as the lead based on its high binding affinity to the extracellular domain of HER2 and on the retention in the humanized antibody of the ability to inhibit growth of HER2-overexpressing cell lines and xenografts.
There are multiple mechanisms through which trastuzumab is believed to effect cell kill. These include inhibition of constitutive HER2 signaling and disruption of HER2/HER3 interactions in HER2-overexpressing cells resulting in inhibition of cellular proliferation, together with activation of immune effector systems via binding of tumor cell-bound trastuzumab to the FcγRIII receptor on immune effector cells, leading to antibody-dependent cell mediated cytotoxicity (ADCC). (3, 4) Trastuzumab was also shown to enhance the cytotoxic effect of paclitaxel, in a dose-dependent manner, toward HER2 overexpressing breast cancer cells in vitro and also increase the antitumor activity of paclitaxel in breast carcinoma xenografts in vivo. On the basis of these preclinical data, trastuzumab, was advanced into clinical evaluation and ultimately received marketing approval by the U.S. Food and Drug Administration (FDA) in 1998 for use as a single agent for the treatment of patients with metastatic breast cancer (MBC) whose tumors overexpress the HER2 protein and who had received one or more prior chemotherapy regimens. When added to chemotherapy, trastuzumab (Herceptin) was shown to improve time to disease progression and overall survival in patients with HER2-positive MBC compared to chemotherapy alone. (5) Thus, trastuzumab was also approved in combination with paclitaxel in a first-line setting for the treatment of patients with MBC whose tumors overexpress the HER2 protein and who had not received prior chemotherapy.
Although trastuzumab has had a major impact in the treatment of patients with HER2-positive MBC, a subset of patients do not respond to treatment, and most patients who are initially responsive to treatment ultimately experience disease progression. (6) The finding that tumors in these patients continued to express HER2 set off a wave of further research to develop additional approaches to target HER2. These included the development of small molecule kinase inhibitors of HER2, such as lapatinib, and antibodies such as pertuzumab that bind to different sites on HER2 than trastuzumab. Pertuzumab acts by binding to the extracellular dimerization domain II of HER2, thus inhibiting the binding of HER2 to other HER family members, especially HER3, preventing HER2–HER3 dimerization which is a robust activator of the PI3 kinase signaling pathway. (7) Despite these noteworthy advances in HER2-targeted therapy, breast cancer in these patients will eventually progress, underscoring the need for alternative therapies. These new HER2-targeted agents are generally given together with chemotherapeutic agents, thus retaining the toxic effects of chemotherapy in the therapeutic regimen.
The concept of antibody–drug conjugates (ADCs) evolved as a means either to improve the tumor selectivity of cytotoxic drugs or to confer higher potency to monoclonal antibodies that display preferential binding to tumor cells but lack sufficient cytotoxicity. The FDA approvals of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, have provided proof of concept to this approach and have generated tremendous excitement. There are over 30 ADCs currently in clinical evaluation, and almost every major pharmaceutical company has embraced this technology. (8) The majority of ADCs in clinical evaluation utilize the highly potent tubulin-interacting agents, maytansinoids or auristatins. A few ADCs in the clinic have incorporated other potent effector molecules, such as the topoisomerase 1 inhibitor SN-38, and the DNA interacting agents, calicheamicin and pyrrolobenzodiazepines.
Targeted delivery of a cytotoxic agent to HER2-positive tumors in the form of an ADC, using trastuzumab as the targeting antibody, affords the potential of improved therapeutic activity with lower systemic toxicity. This annotation will review the rationale and preclinical data that drove the linker design and cytotoxic agent selection leading to the development of ado-trastuzumab emtansine (T-DM1). (9) Clinical data that led to the approval of T-DM1 by the U.S. FDA, for the treatment of patients with HER2-positive metastatic breast who have received prior treatment with trastuzumab and a taxane, will be briefly discussed.
Design of T-DM1
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(a) Selection of the Cytotoxic Agent
Since taxanes were already used with trastuzumab in the clinic, an obvious ADC design would have consisted of linking taxanes directly to trastuzumab. However, at the time of the selection of the appropriate cytotoxic agent for use in an ADC with trastuzumab, clinical results with ADCs prepared utilizing conventional anticancer drugs such as methotrexate, doxorubicin, and vinblastine had failed to demonstrate therapeutic benefit. A careful retrospective analysis of the preclinical data that were used to support clinical development of these early ADCs revealed several shortcomings. (A) Poor in vitro potency is one shortcoming. Conjugation often led to decreased potency compared to the parent free drug. For example, an ADC with des-acetylvinblastine was reported to be 8-fold less potent than the unconjugated desacetylvinblastine drug. Similarly, a doxorubicin conjugate with the BR96 antibody was about 8-fold less potent than doxorubicin. Unlike the unconjugated dug that can freely diffuse into cells, delivery of the cytotoxic molecule by an antibody is limited by the relatively moderate number of antigen molecules on the cell surface to which the antibody can bind (typically ∼105 receptors/cell). In addition, internalization of cell-surface bound antigen–antibody complex, or intracellular processing to release the active drug moiety, may be inefficient. (B) Modest in vivo activity is another shortcoming. Although these early ADCs were shown to be more active than the corresponding unconjugated drugs in tumor xenograft models, long-term tumor regressions in such xenograft models were only achieved when large doses of ADC were used. For example, the doxorubicin conjugate BR96-Dox was used at a dose of 1 g/kg in vivo, while the clinically achievable dose was only ∼19 mg/kg. (C) Localization in human tumors is also a shortcoming. Dosimetry studies with radiolabeled antibodies in cancer patients have revealed that uptake by the tumor was quite low, ranging from 0.003% to 0.01% injected dose/g tumor. (10) On the basis of these findings, a cytotoxic compound with considerably higher potency (IC50 ≈ 10–11 M) than the drugs used in the early ADCs was set as a key requirement. In addition to high potency, an important requirement that is often overlooked is that cytotoxic molecules for use in ADCs have to be stable and adequately soluble in the aqueous milieu of the antibody. (8, 11)
Maytansine (1), a benzoansamacrolide natural product originally derived from the bark of the African shrub Maytenus ovatus, fits these requirements. (12) Maytansine was found to be a potent inhibitor of tubulin polymerization. Although maytansine bound to the same site on tubulin as the Vinca alkaloids, with similar in vitro inhibition constants, it was considerably more potent as a cell-killing agent. In a direct comparison of in vitro cytotoxicity toward the Burkitt’s lymphoma cell line Namalwa, maytansine was several orders of magnitude more potent than clinically used anticancer drugs such as vinblastine, methotrexate, mitomycin C, and daunorubicin (Figure 1). Further testing of the cytotoxicity of maytansine on a panel of solid tumor cell lines typically showed IC50 values between 30 and 100 pM, with the two tested breast cancer cell lines being among the most sensitive (IC50 values of 30 and 44 pM for SK-Br-3 and MCF-7, respectively). (13) Since breast cancer in humans is known to be sensitive to tubulin agents, with paclitaxel and docetaxel often used in first-line treatment regimens, and given that maytansine is a tubulin agent with high potency toward breast tumor cell lines, it was deemed to be ideally suited for use in an ADC of trastuzumab. Maytansine had been extensively evaluated in phase I and II clinical trials in humans and was discontinued because of an insufficient therapeutic index. (14) However, the wealth of safety data from these trials provided some level of comfort in the selection of maytansine as an effector molecule for ADCs. In addition, maytansine had excellent stability and acceptable solubility in aqueous solutions for use in ADCs.
Figure 1
Figure 1. Comparison of the in vitro potency of cytotoxic drugs toward the Burkitt lymphoma cell line Namalwa: maytansine (blue circle), vinblastine (red triangle), daunorubicin (green diamond), methotrexate (brown square), mitomycin C (purple triangle).
(b) Design and Synthesis of Maytansinoids for Linkage to Antibodies
Although maytansine met all the biochemical and biological criteria for use as an effector molecule in ADCs, it lacked a suitable functional group that could facilitate conjugation to an antibody. Introduction of a thiol functionality into maytansine would provide the opportunity to exploit the two most efficient coupling chemistries available at, or near, neutral pH in the dilute aqueous solution necessitated by the antibody, namely, (a) thiol–disulfide exchange and (b) thioether formation with a reactive Michael acceptor, such as a maleimide. In order to introduce a thiol substituent, without affecting potency, a careful analysis of the SAR studies of maytansine was conducted to determine the best site for such incorporation. The aminoacyl side chain at C3 appeared to be ideal, as it was reported to be quite tolerant to different acyl chain lengths and was synthetically amenable to alterations. (15) Thus, synthetic methods were developed for the incorporation of new ester side chains bearing a terminal thiol group to enable linkage to antibodies (see Scheme 1). Aminoacyl side chains at the C3 position of the maytansinoid molecule are typically installed by first hydrolyzing the C3 ester of maytansine to provide maytansinol and then re-esterification with different side chains to produce maytansinoids of interest. The first challenge was to find a source of maytansine, a plant product in short supply. Fortunately, the ansamitocins, which are a mixture of C3 esters (∼80% isobutanoyl and smaller amounts of n-propanoyl, isopropanoyl, and n-butanoyl) of maytansinol, could be obtained readily by fermentation of the microorganism Actinosynnema pretiosum. Since the maytansinoid molecule was known to be susceptible to β-elimination of the ester under mild alkaline conditions, controlled reduction with LiAl(OMe)3H at −40 °C was employed to convert ansamitocins into maytansinol. Esterification with a carboxylic acid that contained a disulfide in the presence of a coupling agent N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and a Lewis acid (zinc chloride) provided maytansinoid disulfides. A panel of disulfide-containing maytansinoids were prepared to examine the effect of length of the acyl side chain on potency. (16) In addition, one or two methyl groups were introduced on the carbon atom geminal to the disulfide to evaluate the effect of steric hindrance on potency. (13) The in vitro cytotoxicity data of a representative set of these new maytansinoids on human cancer cell lines are shown in Table 1. All these maytansine analogues had similar or higher potency than maytansine, indicating that the disulfide substituent did not adversely affect potency. Reduction of the disulfide bond with dithiothreitol gave the desired thiol-bearing maytansinoids for linkage to antibodies.
Scheme 1
Scheme 1. Synthesis of Thiol-Containing Maytansinoidsa
Scheme aReaction conditions: (a) LiAlH(OMe)3/THF, −40 °C, (b) EDC/ZnCl2/CH2Cl2, rt, (c) dithiothreitol, rt.
Table 1. In Vitro Potency of Maytansinoids toward KB (Human Epidermal Carcinoma) and SK-Br-3 (Human Breast Tumor) Cell Lines, Using a Clonogenic Assay and a 72 h Exposure to the Drugs
| IC50, nM | ||
|---|---|---|
| maytansinoid | KB cells | SK-Br-3 cells |
| 1 (maytansine) | 0.034 | 0.030 |
| 4a (DM0-SMe) | 0.190 | 0.180 |
| 4b (DM1-SMe) | 0.029 | 0.014 |
| 4c (DM2′-SMe) | 0.009 | 0.038 |
| 4d (DM3-SMe) | 0.011 | 0.004 |
| 4e (DM4-SMe) | 0.001 | 0.003 |
(c) Selection of the Linker
The availability of a reactive moiety in the form a sulfhydryl group on the maytansinoid molecule afforded the opportunity to link it to trastuzumab via a disulfide linker or a thioether linker. The disulfide bond strength of the conjugate could be modulated by using a maytansinoid with a sterically hindered thiol and reacting it with an antibody that had been modified with a linker bearing a sterically hindered disulfide bond. (17) The bifunctional cross-linking agent, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) was used to introduce maleimido group on the antibody to enable linkage of the maytansinoid via a nonreducible thioether bond. Linker structures used in these conjugations are shown (Figure 2).
Figure 2
Figure 2. Structures of cross-linkers used in conjugate preparation.
(d) Conjugation Methods
Lysine residues on the antibody were selected as the conjugation sites, since a portion of their surface-accessible amino groups can be modified without disturbing the structural integrity and native function of the antibody, along with preserving its favorable pharmacokinetic properties. Briefly, treatment of the antibody with the disulfide-containing linkers resulted in aminolysis of the N-hydroxysuccinimide esters of the linker by lysine residues on the antibody, leading to amide formation and the incorporation of reactive disulfide groups (Scheme 2a). Disulfide exchange between the modified antibody and the thiol-containing maytansinoids resulted in the incorporation of an average of 3.5 maytansinoid molecules linked per antibody molecule. In order to test the role of linker, a trastuzumab conjugate bearing a nonreducible thioether link was prepared by reaction of the antibody with SMCC to introduce maleimido groups. Reaction with the thiol-containing maytansinoid DM1 proceeded smoothly to give a trastuzumab conjugate with an average of 3.5 DM1 molecules linked via thioether bonds (Scheme 2b). Mass spectrometric analysis of T-DM1 shows molecular masses corresponding to a distribution of different number of maytansinoid molecules linked per antibody. The maytansinoid to antibody ratio for T-DM1 was selected based on the desire to (a) minimize the amount of unconjugated antibody, which would diminish the cytotoxic potency of the conjugate, and (b) avoid species with higher maytansinoid load, which might pose manufacturing challenges because of lower solubility. Thus, an average maytansinoid load of ∼3.5 was found to be optimal, as the conjugate maintained good biochemical characteristics with a minimal amount of unconjugated antibody. (18, 19)
Scheme 2
Scheme 2. Representative Conjugation Processes for Trastuzumab-Maytansinoid Conjugates
Preclinical Evaluation Leading to the Selection of Maytansinoid and Linker Component of T-DM1
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(a) In Vitro Studies
The five trastuzumab–maytansinoid conjugates (four with a disulfide linker and one with a thioether linker) shown in Figure 3 were evaluated for their in vitro potency toward the HER2-amplified cell lines BT-474 and SK-BR-3. (20) The nature of the linker did not affect potency, as all five conjugates displayed similar high cytotoxicity, with IC50 values ranging from 0.085 to 0.148 μg/mL toward BT-474 cells and from 0.007 to 0.018 μg/mL (4.7 × 10–11 to 1.2 × 10–10 M) toward SK-BR-3 cells, after 3 days of exposure to the ADCs. In contrast, unconjugated trastuzumab displayed only a modest cytotoxic effect (IC50 > 10 μg/mL), indicating that conversion of trastuzumab into an ADC greatly enhanced its cell killing power. Breast tumor cell lines that had little (MCF-7) or no (MDA-MB-468) HER2 expression were much less susceptible to killing by any of the trastuzumab maytansinoid conjugates, with IC50 values of >10 μg/mL for MCF-7 cells and about 3–5 μg/mL for MDA-MB-468 cells, demonstrating good antigen specificity of the cytotoxic effect, regardless of linker choice.
Figure 3
Figure 3. Structural representation of trastuzumab-maytansinoid conjugates with a disulfide linker (8a–d) or a thioether linker (8e). Adapted by permission from the American Association for Cancer Research (
(b) In Vivo Pharmacokinetic Studies
Since the in vitro potency assay did not distinguish between the ADCs bearing different linkers, all were submitted for in vivo evaluation. A pharmacokinetic study was conducted in CD1 mice to determine the serum concentration of the ADCs at various time points and thus gauge the relative stabilities of the linkers in vivo. In contrast to the in vitro cytotoxicity data, there were clear differences between the conjugates, with a clear correlation between the rate of reduction of the disulfide bond of the ADC as measured in vitro, and the in vivo half-life and exposure. As expected, the trastuzumab ADC with the least hindered disulfide (T-SPDP-DM1) showed the fastest clearance, with no detectable conjugate after 3 days in circulation. (20) For the remaining ADCs, the clearance rate was also determined by the degree of steric hindrance of the disulfide bond. Thus, the ADC with one methyl group on each side of the disulfide bond (T-SSNPP-DM1) gave a higher serum concentration than the ADC with a methyl group just on one side of the disulfide bond. The clearance rate of the ADC with a high degree of steric hindrance (T-SSNPP-DM4) bearing three methyl groups adjacent to the disulfide bond mirrored that of the conjugate bearing the nonreducible thioether link (T-MCC-DM1). Overall, the stability ranking of the trastuzumab–maytansinoid conjugates determined in vivo matched well with the disulfide cleavage rate of a set of non-trastuzumab–maytansinoid ADCs, upon treatment with the reducing agent dithiothreitol. (17)
(c) In Vivo Antitumor Activity
The in vivo efficacy of the trastuzumab ADCs with different linkers was evaluated in the trastuzumab-resistant MMTV-HER2 Fo5 mammary tumor model, a syngeneic tumor-transplant model where murine tumors cells express the human erbB-2 gene. Although the tumors express high levels of human HER2 (3+ expression by immunohistochemistry), they do not respond to trastuzumab alone, making it a suitable model to assess the value of arming the antibody with a maytansinoid. Four of the five linker-maytansinoid ADC formats evaluated in the pharmacokinetic study were tested (the ADC with the most labile linker (SPDP) was not included in the study). From this in vivo efficacy study, it was concluded that higher linker stability correlated with increased antitumor activity, since the nonreducible conjugate with the SMCC linker displayed a statistically significant improvement in activity over the ADC with the disulfide linker, SPP, at the single tested dose (Figure 04). (20) Subsequently, however, a more thorough comparison, at three different doses, of trastuzumab conjugated to DM1 via an SMCC linker or an SPP linker failed to show a measurable difference in antitumor activity in a BT474-EEI tumor model. (21)
Figure 4
Figure 4. Comparison of the in vivo efficacy of trastuzumab–maytansinoid conjugates with a disulfide linker (8b (green triangle), 8c (purple cross), 8d (red boxed cross)) or a thioether linker (8e (blue square)) at a single iv dose of 10 mg/kg conjugate and a vehicle control (×). Adapted by permission from the American Association for Cancer Research (
Metabolism Studies
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(a) In Vitro Studies
In order to study the intracellular fate of T-DM1 and the role of linker on the amount and nature of catabolites formed, trastuzumab conjugates with the noncleavable SMCC linker (T-DM1) and a disulfide linker (T-SPP-DM1) were prepared using [3H]DM1, with the radiolabel incorporated at the C20 methoxy group of DM1. The HER2-overexpressing cell line BT474-EEI was exposed to the radiolabeled conjugates, and the cells were harvested at various time points, followed by extraction of protein-free maytansinoid catabolites using acetone. The extracts were subjected to HPLC analysis. Exposure to T-DM1 resulted in the formation of a sole metabolite that was identified as lysine-Nε-MCC-DM1, presumably arising from lysosomal degradation of the antibody component leaving the lysine residue of the antibody attached to DM1 via the linker. The peak size increased significantly from the first time point (3 h) to the last one (24 h). Representative chromatograms at the 6 and 24 h time points are shown (Figure 05A). Treatment of cells with the disulfide-linked conjugate, T-SPP-DM1, gave the expected lysine- Nε-SPP-DM1 catabolite resulting from lysosomal degradation of the antibody. However, in this case, subsequent cleavage of the disulfide bond gave rise to the maytansinoid thiol, DM1, which was isolated as a stabilized N-ethylmaleimide (NEM) adduct. At the 6 h time point, the peak area for lysine-SPP-DM1 is somewhat greater than that of DM1, but at the 24 h time point further reduction has taken place to give DM1 as the major peak (Figure 05B). The rate and extent of processing of T-SPP-DM1 by BT474-EEI cells in vitro were compared to those of T-DM1. The protein-free maytansinoid catabolites produced at various time points after exposure to the conjugates were quantified. Processing of both conjugates was found to be equally efficient and approached ∼70% at 24 h (Figure 05C). (21)
Figure 5
Figure 5. (A) In vitro catabolism by BT474-EEI cells of the trastuzumab-MCC-DM1 conjugate 8e (thioether linker): top panel, 6 h time point; bottom panel, 24 h time point. (B) In vitro catabolism by BT474-EEI cells of the trastuzumab-SPP-DM1 conjugate 8b (disulfide linker): top panel, 6 h time point; bottom panel, 24 h time point. (C) Comparison of the rate and extent of in vitro processing of trastuzumab-SPP-DM1 conjugate 8b (disulfide linker: blue squares) and trastuzumab-MCC-DM1 conjugate 8e (thioether linker, red squares) by BT474-EEI cells.
(b) In Vivo Studies
In order to determine how the results from the in vitro metabolism studies related to the in vivo situation, tumor xenografts were established in mice with the same cell line used for the in vitro studies (BT474-EEI). Mice bearing these tumor xenografts were treated with either radiolabeled T-DM1 or T-SPP-DM1 prepared with [3H]DM1. Tumors were excised at various time points and analyzed for both total radioactivity (antibody-bound plus small molecular weight catabolites) and protein-free maytansinoid catabolites by HPLC analysis. Although the T-SPP-DM1 conjugate displayed a faster plasma clearance than T-DM1, the amount of maytansinoid catabolites in the tumor xenograft at the various time points was quite similar, with maximum accumulation occurring between 2 and 4 days (Figure 6A). It was thus unsurprising that the antitumor activity of the two compounds was also similar in this study. The nature of the catabolites mirrored the pattern observed with the same cell line in vitro, with T-DM1 giving just one catabolite (lysine-Nε-MCC-DM1) and with T-SPP-DM1 yielding the same two catabolites observed in vitro (lysine- Nε-SPP-DM1 and DM1, stabilized as N-ethylmaleimide adduct). The catabolite profiles for the 2-day time-point are shown (Figure 6B), with T-SPP-DM1 giving predominantly DM1 (isolated as an N-ethylmaleimide adduct) after reduction of the SPP linker within tumor cells and T-DM1 showing a single peak of its sole catabolite. (21)
Figure 6
Figure 6. (A) Time dependent formation of catabolite: comparison of in vivo catabolism of trastuzumab–maytansinoid conjugates in BT474-EEI tumor xenografts in mice: trastuzumab-SPP-DM1 conjugate 8b (disulfide linker, blue square) and trastuzumab-MCC-DM1 conjugate 8e (thioether linker, red square). (B) In vivo catabolism of trastuzumab–maytansinoid conjugates in BT474-EEI tumor xenografts in mice at 2-day time-point: top panel, 8b, disulfide linker (SPP); bottom panel, 8e, thioether linker (SMCC).
In Vivo Tolerability Studies
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In order to select the final linker format for the maytansinoid conjugated trastuzumab for ADC development, the tolerability of the two conjugates (SMCC linker versus SPP linker) was evaluated in Sprague–Dawley rats. In this single dose acute toxicity study, the ADC with the nonreducible SMCC linker was found to be at least about 2-fold better tolerated than the conjugate with the disulfide (SPP) linker. Thus, treatment at a dose of 22 mg/kg with the SPP conjugate resulted in significant (∼10%) body weight loss, while the SMCC conjugate could be dosed at 50 mg/kg without any weight loss. On the basis of these preliminary acute toxicity results, the SMCC linker afforded at least about a 2-fold greater therapeutic index in mice to a trastuzumab-DM1 conjugate compared with that provided by the disulfide linker, and so SMCC was the linker of choice for T-DM1, the development candidate ADC. (20)
Biological Activity of T-DM1
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(a) In Vitro Cytotoxicity
Testing of the in vitro cytotoxicity of T-DM1 (8e) in comparison to unconjugated trastuzumab was expanded to a panel of cell lines with different levels of expression of HER2 and varying sensitivity to trastuzumab. (20) This panel also included HER2-positive cell lines from tumor types other than breast, such as the lung carcinoma cell line Calu-3, the ovarian cancer cell line SK-OV-3, and the gastric carcinoma cell line MKN7. In all cases, T-DM1 was considerably more potent than free trastuzumab (Table 2) toward the cancer cell lines. In contrast, the normal human mammary epithelial cells (HMEC) and normal human epidermal keratinocytes (NHEK) were much less sensitive to trastuzumab and T-DM1. (20) Since the small molecule kinase inhibitor lapatinib is used in the treatment of trastuzumab refractory breast cancer, it was important to test the potency of T-DM1 for HER2-amplified cells that were resistant to lapatinib. As a first test, SK-Br-3 cells, which are highly sensitive to T-DM1 and lapatinib, were exposed to increasing concentrations of lapitinib over a 9-month period. The resulting lapitinib-resistant clone was ∼200-fold less sensitive to lapatinib but remained as sensitive to T-DM1 as the parent clone. Another mechanism of resistance to lapatinib involves activation of the PI3 kinase pathway, either through the acquisition of a PIKCA mutation or loss of PTEN. The MCF7-neo/HER2 cell line cell line, which has an activated PI3 kinase pathway, was found to be resistant to lapatinb (IC50 ≈ 20 μM) and to trastuzumab (IC50 > 66 nM) but was quite sensitive to T-DM1 (IC50 ≈ 0.16 nM). These results demonstrate that T-DM1 is a highly potent agent even against cells that are resistant to the approved therapy options (trastuzumab and lapatinib) for HER2-positive breast cancer. (22, 23)
Table 2. Comparison of the in Vitro Potency of Trastuzumab and Trastuzumab-MCC-DM1 Conjugate toward Human Tumor and Normal Cell Lines after a 3-Day Exposure to the Antibody or Conjugate
| IC50, μg/mL | |||
|---|---|---|---|
| cell line | origin | trastuzumab-MCC-DM1 | trastuzumab |
| SK-Br-3 | human breast tumor | 0.011 | >10 |
| BT-474-EEI | human breast tumor | 0.004 | >10 |
| HCC1954 | human breast tumor | 0.015 | >10 |
| KPL-4 | human breast tumor | 0.011 | >10 |
| Calu-3 | human lung carcinoma | 0.062 | >10 |
| MKN-7 | human gastric carcinoma | 0.266 | >10 |
| SK-OV-3 | human ovarian cancer | 0.009 | >10 |
| HMEC | human mammary epithelial cells | 4.0 | >10 |
| NHEK | normal human epidermal keratinocytes | 10.0 | >10 |
Maytansinoids are reported to be substrates for the MDR1/PgP transporter leading to poorer killing of multidrug resistant (MDR) cells. MDR1/PgP is believed to confer resistance to maytansinoids via two mechanisms: (a) mediating efflux of the drug that diffuses into the plasma membrane from the extracellular space, thereby preventing the compound from reaching the cytoplasm and (b) effluxing any drug that does enter the cytoplasm back to the outside of the cell. (24) ADCs, such as T-DM1, deliver the maytansinoids into cells via antigen-mediated endocytosis, thus bypassing the first MDR1 mechanism. Upon intracellular processing, T-DM1 is processed into a charged cytotoxic metabolite, lysine-Nε-MCC-DM1, which is less susceptible to MDR1/PgP-mediated efflux. Only high levels of MDR1/PgP expression appear to confer resistance to DM1 and T-DM1, and the free maytansinoid and ADC were not substrates for BCRP/ABCG2. Breast cancer lines expressing a range of levels of MRP3/ABCC3 were not resistant to DM1 or T-DM1. (25)
(b) In Vivo Evaluation
The in vivo antitumor activity of T-DM1 was more thoroughly evaluated in multiple HER2-positive models in mice. For example, in a breast tumor xenograft model established with KPL-4 cells, a single iv administration of T-DM1 at 15 mg/kg gave complete tumor regression lasting for the duration of the experiment (125 days), while treatment with four weekly doses of trastuzumab at 15 mg/kg only achieved a modest delay in tumor growth (Figure 7A). (20) In another example using the BT474-EEI breast tumor xenograft model, T-DM1 displayed dose-dependent antitumor activity, with tumor growth delay at the lower doses (0.3–3 mg/kg, q3w × 3), tumor regression at the 10 mg/kg dose, and complete regression at the 15 mg/kg dose (Figure 7B). (20) Unconjugated trastuzumab showed little activity in this model. Similar results were obtained in the MMTV-HER2 Fo5 trastuzumab-resistant transgenic transplant model. Treatment with a control, nonbinding conjugate gave no tumor growth inhibition, demonstrating the antigen specificity of the activity of T-DM1. (20, 26)
Figure 7
Figure 7. (A) Comparison of the in vivo antitumor activity of trastuzumab (red circle, 15 mg/kg × 4) and T-DM1 (blue square, 15 mg/kg, single dose), vehicle control (×), in the KPL-4 model. (Excerpted from Lewis-Phillips et al. (20)). (B) Dose-dependent antitumor activity of T-DM1 in the BT474-EEI model (dosing q3w × 3). Doses of T-DM1, are the following: 0.3 mg/kg (purple-outline triangle), 1 mg/kg (green triangle), 3 mg/kg (blue-outline triangle), 10 mg/kg (red triangle), 15 mg/kg (blue square), vehicle control (×); unconjugated trastuzumab (red circle, 15 mg/kg). Parts A and B are adapted by permission from the American Association for Cancer Research (
Following up on the in vitro study described above, wherein T-DM1 was found to be active against lapatinib-resistant cell lines, an in vivo study was conducted to compare the activity of T-DM1 and lapatinib. Mice bearing established Fo5 tumors were found to insensitive to lapatinib, and regressions could not be attained even after daily treatment for 3 weeks. Treatment with T-DM1, however, was quite effective, resulting in complete regression in 3/10 animals and partial regression in 6/10 mice. (22)
A pharmacokinetic study was conducted in rats to compare the levels of T-DM1 and total trastuzumab. Serum concentration of total antibody was determine using a specific ELISA for trastuzumab, while intact T-DM1 conjugate was assayed by ELISA using an antibody against DM1. Circulating serum concentrations of T-DM1 measured for 1 week were similar to the measurement of total serum trastuzumab concentrations, demonstrating that there was negligible release of maytansinoid from the conjugate over 7 days in circulation in rats. (20) The anti-DM1 antibody used in the ELISA was found to bind appropriately with antibodies with different maytansinoid load, including one maytansinoid per antibody. Plasma samples spiked with T-DM1 were also analyzed by capillary LC–MS, using anti-DM1 antibody as the capture probe, and the results matched those obtained through ELISA measurements. (27)
(c) Functional Activity
Since trastuzumab is by itself an active antibody with biological function, it was important to show that conjugation to DM1 did not affect its functional properties. In a head to head comparison, T-DM1 was shown to retain the binding affinity of trastuzumab to the HER2 antigen. Thus, in a competition binding assay, T-DM1 competed as well as trastuzumab with the binding of radioiodinated trastuzumab to the antigen (HER2 extracellular domain) coated on a plate. Some of the functional activity of trastuzumab is attributed to its ability to cause ADCC. Both T-DM1 and trastuzumab were shown to mediate ADCC equally well in vitro. In control experiments, a nonbinding antibody–DM1 conjugate and a trastuzumab mutant that been engineered to abolish binding to FcγR on immune cells did not mediate ADCC. The cytotoxic effect of trastuzumab has been attributed, in part, to its ability to inhibit the phosphorylation of the HER family member HER3 resulting in inhibition of the PI3 kinase pathway. T-DM1 and trastuzumab were found to show similar levels of inhibition of AKT phosphorylation, demonstrating that conjugation to DM1 did not affect trastuzumab’s ability to inhibit AKT phosphorylation. (22)
Preclinical Toxicology and Toxicokinetics of T-DM1
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Single- and repeat-dose safety toxicology studies were performed with T-DM1 in both rats and cynomolgus monkeys. (28) Trastuzumab recognized HER2 in cynomolgus monkeys but does not bind to the rat antigen. Thus, rats allowed assessment of antigen-independent toxicity of T-DM1, while cynomolgus monkeys allowed evaluation of the potential for any antigen-mediated effects in addition to antigen-independent toxicity. The toxicity of the free maytansinoid, DM1, was assessed in rats only. (28) T-DM1 was well-tolerated at single intravenous doses up to 46 mg/kg (protein dose, equivalent to ∼4400 μg DM1/m2) in rats and 30 mg/kg (∼6000 μg DM1/m2) in monkeys. Rats given 60 mg/kg T-DM1 (∼6800–7800 μg DM1/m2) showed clinical signs of morbidity and/or mortality. DM1 was only tolerated up to 0.2 mg/kg (∼1600 μg DM1/m2) in rats, suggesting that 2–3 times higher doses of maytansinoid are tolerated in rats given T-DM1 versus free DM1. As noted above, the major low molecular weight maytansinoid metabolite of T-DM1 is the lysine adduct, lysine-Nε-MCC-DM1. (21) The hydrophilic nature of the charged amino and carboxyl groups of the lysine greatly reduces the cytotoxicity of the adduct relative to DM1 and other noncharged maytansinoids and likely alters its distribution in vivo relative to noncharged maytansinoids, with a favorable effect on the tolerable dose. (13, 21) Thus, the hydrophilic metabolite lysine-Nε-MCC-DM1 is >200-fold less potent (IC50 ≈ 7.5–17 nM) when applied to cancer cells in vitro, compared to noncharged maytansinoids such as maytansine (IC50 ≈ 0.03–0.09 nM). (29)
The principal acute toxicities in rats were comparable between T-DM1 and DM1 and were associated with dose-dependent effects in bone marrow/hematologic systems, lymphoid organs, and liver. Both agents induced minimal to moderate reductions in lymphocyte counts and reticulocyte counts and minimal to mild reductions in platelets, as well as an increase in absolute neutrophil counts. (28) These clinical laboratory observations were consistent with histologic findings of bone marrow and lymphoid organ toxicities, although such findings were more severe for DM1 than for T-DM1 at their respective maximum tolerated doses (MTD), 1600 and 4400 μg DM1/m2, respectively. Elevations of serum transaminase levels were in the range of 2- to 4-fold at the MTD of both T-DM1 and DM1, consistent with histologic findings of liver toxicity. (28) At the tolerated doses, all findings were partially or completely reversed during the recovery period. Histopathology revealed an increase in mitotic figures in a variety of tissues in rats dosed with T-DM1, notably in adrenals, liver, kidney, eye (corneal epithelium), and skin (epidermis), findings consistent with the expected pharmacologic action of maytansinoids in disrupting microtubule dynamicity resulting in cell cycle arrest. (28) Mitotic figures were found only in liver and kidney in rats dosed with free DM1.
While the toxicity profiles of T-DM1 and DM1 were similar, the differences in severity in some findings (e.g., reduction in reticulocytes was more severe for DM1 versus T-DM1; different distribution of mitotic figures) are likely related to differences of pharmacokinetics, distribution, and metabolism between T-DM1 and DM1. Separate ELISA methods were used to measure T-DM1 and total trastuzumab in serum of rats dosed with T-DM1. The terminal t1/2 of T-DM1 in rats was about 3–5 days, with a slow clearance (CL) of 13–15 mL day–1 kg–1 and a volume of distribution approximating the plasma volume, characteristics of an antibody-based biologic agent. (28) On the other hand, in rats dosed with DM1, pharmacokinetics showed a large volume of distribution (>5000 mL/kg) and rapid CL (20–55 mL min–1 kg–1), as expected for the small molecule “payload”. The clearance of total trastuzumab (all conjugated species and any unconjugated antibody) in rats dosed with T-DM1 was about 2-fold slower than that of T-DM1, a finding that could be accounted for by one (or both) of two mechanisms: a certain rate of deconjugation in vivo to form species with a lower DM1-to-antibody ratio (DAR) or a somewhat faster clearance of species with higher-than-average DAR versus species with lower-than-average DAR. Free serum DM1 concentrations in rats treated with T-DM1 were low, approximately 50-fold lower than that of conjugated DM1 at any time-point. (28) Even this low level of free DM1 may be an overestimate of in vivo plasma concentrations, given that sample preparation utilized treatment with a reducing agent, which may result in ex vivo cleavage of any oxidized derivatives of the thioether. (30)
T-DM1 was well tolerated in cynomolgus monkeys upon repeat dosing at 3-week intervals with 4 doses of up to 30 mg/kg (∼6000 μg DM1/m2) or with 8 doses at 10 mg/kg (∼2000 μg DM1/m2). Most adverse findings were similar to those described for rats, with liver and bone marrow/hematologic systems being the primary target organs for toxicity. A minimal to mild decrease in platelets was noted on day 3 after each dose, as was a reversible 2- to 4-fold increase in serum hepatic transaminase levels. Microscopic findings showed an increase in the number of cells in mitotic arrest in a variety of tissues in addition to liver findings. However, despite the fact that epithelial cells of many tissues express HER2, the incidence of cellular mitotic arrest in the rat studies was noted to be more widespread than in monkey, indicating that antigen-independent mechanisms predominate in the uptake and intracellular catabolism of T-DM1 and that antigen-dependent binding and uptake by normal tissue may not be a major safety concern. (28) That antigen-mediated uptake does occur in cynomolgus monkeys was clearly demonstrated by the nonlinear pharmacokinetics, with the CL in animals treated at 3 mg/kg being 50% faster than those in the higher dose groups. At doses of ≥10 mg/kg, the t1/2 of T-DM1 in cynomolgus monkeys was approximately 3–5 days (as in rat), with CL in the range of 9.4–11.5 mL day–1 kg–1. There was no accumulation of T-DM1 upon repeat dosing at 3-week intervals. As in the rat, free DM1 concentrations were always at least 50-fold lower than conjugated DM1 at any time-point. Also as observed in rats, the CL of the intact T-DM1 conjugate was faster than that of total trastuzumab. In 4 of 36 monkeys (11%) given repeated doses of T-DM1, antiproduct antibodies were detected, although there were no apparent effects on the toxicokinetic profiles in these animals.
Dose-dependent axonal degeneration was observed in the repeat-dose cynomolgus monkey studies, although these histopathologic findings were without any clinical observations of neurologic deficit. (28) These finding were not reversible within the 6-week recovery period. Neuropathy is a common toxicity finding with microtubule-acting agents such as taxanes and the Vinca alkaloids, especially with the longer exposures of repeat-dose schedules of administration. There were no cardiovascular safety signals in the monkey studies. (28) The overall conclusions of the toxicity evaluation of T-DM1 were that the mechanism of toxicity is consistent with the pharmacology of DM1 as a microtubule-acting compound and that the observed toxicities were primarily through antigen-independent mechanisms of T-DM1 catabolism. The starting dose level of T-DM1 for the first-in-human phase I clinical trial was 0.3 mg/kg based on 1/12 of the highest nonseverely toxic dose in cynomolgus monkeys. (28, 31)
Clinical Evaluation of T-DM1
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(a) Phase I Studies
The safety, tolerability, and pharmacokinetics of T-DM1 was evaluated in a phase I dose-escalation trial in patients with HER2-positive metastatic breast cancer (HER2-positive MBC) who had previously received a trastuzumab-containing regimen. Twenty-four patients were given T-DM1 at doses ranging from 0.3 to 4.8 mg/kg as an intravenous infusion once every 21 days. (31) At the 4.8 mg/kg dose, two of three subjects had dose-limiting thrombocytopenia (grade 4). A total of 15 patients were treated at the maximum tolerated dose (MTD) of 3.6 mg/kg, where nearly all patients exhibited thrombocytopenia, generally grade 1 or 2 and rapidly reversible, with a nadir by about day 8 and recovery typically by day 15 of each cycle. Other commonly reported adverse events (AEs) included elevated hepatic transaminases (41.5% of patients), fatigue (37.5%), anemia (29.2%), and nausea (25.0%), generally grade 1 or 2, and reversible. There were no reports of greater than grade 1 nausea, vomiting, alopecia, or neuropathy or any cardiac observations that required dose modification.
Pharmacokinetics were nonlinear in the dose range 0.3–4.8 mg/kg, consistent with the anticipated antigen-mediated clearance at these doses. (31, 32) The t1/2 of T-DM1 at the 3.6 mg/kg dose (n = 15) was about 3.5 days. (31) Six of the 24 patients had an objective partial response (five confirmed). All the responding patients had previously received at least one tubulin-acting agent among their prior chemotherapy treatments. In the 15 patients treated at the MTD, the confirmed response rate in patients with measurable disease (n = 9) was 44%, while the clinical benefit rate (CBR), including patients with stable disease of ≥6 months, was 73%, a substantial level of clinical activity in a heavily pretreated patient population.
Once MTD had been established, a second arm of the study was opened to evaluate weekly administration. Twenty-eight patients received weekly T-DM1, from 1.2 to 2.9 mg/kg (5 dose levels). Two of three patients dosed at 2.9 mg/kg experienced dose-limiting toxicities (DLTs) preventing dosing on day 8, one case of grade 3 thrombocytopenia, and one case of grade 3 hepatic transaminase (AST) levels. (33) The MTD for T-DM1 administered weekly was established at 2.4 mg/kg, for a cumulative dose of 7.2 mg/kg over 3 weeks which was double that given as a single dose q3 weeks. The most common drug-related grade ≥3 adverse events seen in >10% of patients were increased AST (11%) and thrombocytopenia (11%). There was only a low incidence of any gastrointestinal toxicity, very few reports of infusion reactions, and no significant cardiac abnormalities in the study. Thirteen patients experienced eye disorders, two of which were grade 3. (33) In general, the tolerability of T-DM1 on the weekly schedule was similar to that of the q3 week schedule, with patients receiving a somewhat longer median duration of treatment (18.9 weeks versus 16.7 weeks). The DLT, reversible thrombocytopenia, was the same for both regimens, together with reversible minimal to moderate increases in hepatic transaminases consistently observed on both schedules. The incidence of adverse events associated with administration of maytansine, severe diarrhea, vomiting, and sensory neuropathy were low and of low grade when reported, consistent with minimal systemic exposure to free maytansinoid and demonstrating the benefit of the concept of an antibody–drug conjugate. (14)
Confirmed partial responses were reported in 46% (13 of 28) of patients enrolled in the weekly dosing arm of the phase I study, and the six-month CBR was 57% (16 of 28 patients). (33) Both the weekly and the q3 week schedules demonstrate that T-DM1 has substantial clinical activity in patients with previously treated HER2-positive MBC. The q3 week schedule was chosen for the subsequent phase II clinical evaluation of T-DM1.
(b) Phase II Clinical Trials of T-DM1 as a Single Agent
A single arm phase II study (TDM4258g) was conducted in 112 patients with HER2-positive MBC utilizing the 3.6 mg/kg q3 week dosing schedule. (34) Patients had received a median of eight prior anticancer agents including trastuzumab (100%), a taxane (84%), an anthracycline (71%), capecitabine (66%), and lapatanib (60%). In this heavily pretreated patient population, 29 patients (25.9%) had objective partial responses by independent assessment. The median progression-free survival (PFS) was 4.6 months, while the medial duration of response was 9.4 months (investigator assessment). The overall response rate (ORR) was higher (33.8%) in patients whose HER2-overexpression status on archival primary tumor specimens was confirmed by a central laboratory (74 confirmed positive of 95 patients reassessed). The ORR in the 21 patients reassessed as HER2-normal was only 4.8%. T-DM1 was well-tolerated in this study, with safety findings similar to those observed in the phase I study. The median dose intensity (dose delivered/expected dose) was 99.7%, and dose modifications or discontinuations due to AEs were infrequent. (34) Twenty-one patients (18.8%) completed at least 1 year on treatment, suggesting that long-term administration was tolerated.
A subsequent confirmatory single arm phase II study was conducted in 110 patients with HER2-positive MBC who had previously received a taxane, an anthracycline, capecitabine, as well as two HER2-targeted agents, trastuzumab and lapatinib, for a median of seven prior anticancer agents for their metastatic disease. (35) The ORR was 34.5% (38 of 110 patients). The median PFS was 6.9 months, and the median duration of response was 7.2 months. With inclusion of patients in stable disease for at least 6 months, the overall CBR was 48.2%. The HER2-positive (HER2-overexpression) status was confirmed upon reassessment by a central laboratory in 84% of patients, and in this subgroup of 80 patients, the ORR was 41% with a median PFS of 7.3 months. There were no new safety signals in this confirmatory phase II study, most adverse events being grade 1 or 2. Reversible thrombocytopenia was observed in 38.2% of patients (only 9.1% of grade ≥3); as with the prior studies, platelet transfusions were infrequent, hemorrhagic adverse events were generally mild, and no patient discontinued T-DM1 due to a bleeding event. (35) This trial also confirmed the observation of generally mild transaminase elevations indicative of hepatic toxicities that appeared in temporal relationship with T-DM1 dosing (AST increases were seen in 26.4% of patients), although a few patients (8.2%) experienced a grade ≥3 adverse event. (35)
Given the encouraging efficacy signals and tolerable safety profile of T-DM1 in these single arm, single agent studies, a phase II randomized study was performed to directly compare T-DM1 as a single agent with an active regimen for first-line treatment of HER2-positive MBC, trastuzumab plus docetaxel. (36) After a median follow-up of about 14 months, there was a significant improvement in PFS in patients treated with T-DM1 (14.2 months) compared with those treated with the standard-of-care (9.2 months). The overall response rates were similar, 64.2% in those patients treated with T-DM1 (n = 67), including seven complete responses (CRs), versus 58% in those patients treated with trastuzumab/docetaxel (n = 70) including three CRs. (36) Regarding safety in the first-line setting, the T-DM1 arm had about half the number of grade ≥3 adverse events than the trastuzumab/docetaxel arm (46.4% versus 90.9%, respectively). Only 7.2% of AEs led to discontinuation of treatment in patients treated with T-DM1, compared with 40.9% for patients treated with standard-of-care. There were no cases of clinically significant cardiac events, a concern due to the known association of trastuzumab with cardiac toxicity, although three patients on each arm had decreased left ventricular ejection fraction. (36, 37) Not only was the incidence of grade ≥3 AEs lower in the T-DM1 arm in comparison to the trastuzumab/docetaxel arm, but their nature was also different. The most common grade ≥3 AEs in the latter arm were neutropenia (62.1%), leukopenia (24.2%), and febrile neutropenia (13.6%), together with a high incidence of alopecia (66.7%), while grade ≥3 AEs in patients treated with T-DM1 were increases in hepatic transaminases (AST 8.7%; ALT 10.1%), thrombocytopenia (7.2%), and neutropenia (5.8%) with only a low incidence of alopecia (4.3%). This randomized study demonstrates the potential for an antibody–drug conjugate to deliver improved clinical benefit and decreased toxicity risk in these patients that should be validated in phase III trials.
(c) Phase III Clinical Trials of T-DM1
The phase I and phase II studies led to a pivotal phase III trial (“EMILIA”) in which 991 patients with advanced HER2-positive MBC whose disease had progressed following treatment with trastuzumab and a taxane were randomized to receive either T-DM1 (single agent at 3.6 mg/kg, q3 weeks) or lapatinib plus capecitabine. (38) Preliminary results were first reported at the 2012 Annual Meeting of the American Society of Clinical Oncology. The median ORR, PFS, and overall survival all significantly favored the T-DM1 arm of the study, as summarized in Table 03. The number of AEs of grade ≥3 was less in the T-DM1 arm (40.8%) than in the lapatinib/capecitabine arm (57.0%). As anticipated from the phase I and phase II experience, the incidence of thrombocytopenia, and of increased serum hepatic transaminase levels, were higher in patients treated with T-DM1, while the incidence of diarrhea, nausea, vomiting, and hand–foot syndrome were higher in patients treated with lapatinib/capecitabine (Table 03). The rates of cardiac adverse events were low, about 1.6–1.7% in both arms.
Table 3. Efficacy and Safety Results Reported for the Phase III Clinical Trial, “EMILIA”, Which Randomized HER2-Positive Breast Cancer Patients Who Had Previously Received Trastuzumab and a Taxane for Treatment of Their Metastatic Disease To Receive Either T-DM1 (single agent) or Lapatinib + Capecitabine (38)
| Efficacy | T-DM1 | lapatinib + capecitabine |
|---|---|---|
| no. of patients evaluable | n = 397 | n = 389 |
| objective response rate | 43.6% | 30.8% |
| complete response | 1% (n = 4) | 0.5% (n = 2) |
| partial response | 42.6% (n = 169) | 30.3% (n = 118) |
| median duration of response | 12.6 months | 6.5 months |
| estimated 1-year survival | 85.2% | 78.4% |
| estimated 2-year survival | 64.7% | 51.8% |
| median progression-free survival | 9.6 months | 6.4 months |
| median overall survival | 30.9 months | 25.1 months |
| Safety | T-DM1 | lapatinib + capecitabine | ||
|---|---|---|---|---|
| no. of subjects evaluable | n = 490 | n = 488 | ||
| adverse events (≥15% of patients) | any grade | grade ≥3 | any grade | grade ≥3 |
| any adverse event | 95.9% | 40.8% | 97.7% | 57.0% |
| diarrhea | 23.3% | 1.6% | 79.7% | 20.7% |
| hand–foot syndrome | 1.2% | 0 | 58.0% | 16.4% |
| vomiting | 19.0% | 0.8% | 29.3% | 4.5% |
| fatigue | 35.1% | 2.4% | 27.9% | 3.5% |
| nausea | 39.2% | 0.8% | 44.7% | 2.5% |
| mucosal inflammation | 6.7% | 0.2% | 19.1% | 2.3% |
| thrombocytopenia | 28.0% | 12.9% | 2.5% | 0.2% |
| elevated serum ALT | 16.9% | 2.9% | 8.8% | 1.4% |
| elevated serum AST | 22.4% | 4.3% | 9.4% | 0.8% |
The “EMILIA” trial established the safety and effectiveness of T-DM1, and it was approved as a new therapy for patients with HER2-positive late stage (metastatic) breast cancer, previously treated with trastuzumab and taxane chemotherapy, by the U.S. FDA on February 22, 2013. T-DM1 (ado-trastuzumab emtansine, Kadcyla) is the first antibody–drug conjugate to receive full approval from FDA on the basis of a randomized study for any indication.
First results of another phase III trial (“TH3RESA”), in which 602 patients with advanced HER2-positive MBC previously treated with at least two HER2-directed therapies were randomized 2:1 to receive either T-DM1 or physician’s choice of treatment, were reported at the European Cancer Congress in September 2013. (39) The median PFS increased from 3.3 months in the reference arm to 6.2 months in patients receiving T-DM1. The ORR was 31.3% in the T-DM1 arm compared with only 8.6% in these very heavily pretreated patients receiving physician’s choice of treatment. Overall survival showed a trend in favor of T-DM1 (although it did not reach statistical significance at the reported interim analysis), and as with “EMILIA”, there were fewer grade ≥3 AEs in the T-DM1 arm.
A phase III trial comparing single agent T-DM1 to trastuzumab plus docetaxel in first-line treatment of HER2-positive MBC is ongoing. This trial, called “MARIANNE”, builds upon the experience of the earlier phase II trial in patients previously untreated for metastatic disease and also includes a comparison of single agent T-DM1 to T-DM1 plus pertuzumab, another HER2-targeting antibody that binds to a distinct site on the HER2 extracellular domain. (36) Pertuzumab is approved for use in combination with trastuzumab and docetaxel to treat patients with HER2-positive breast cancer. (40) Including a T-DM1 plus pertuzumab arm in the MARIANNE trial was based on preclinical studies suggesting increased activity of the combination and an earlier phase Ib trial of the safety and preliminary efficacy of the combination in HER2-positive MBC patients. (41, 42) The results of the “MARIANNE” trial are expected in 2014 and are eagerly awaited.
Brain metastases are common in patients with HER2-positive MBC and are associated with poor prognosis. (43) Up to now, patients with symptomatic brain metastases were excluded from enrollment in clinical trials of T-DM1. (31, 34, 38) However, a preliminary report documents a finding that brain metastases of a HER2-postive breast cancer patient can respond to systemic therapy with single-agent T-DM1, suggesting that the blood–brain barrier is impaired in the vicinity of the tumor and can allow passage of antibodies into the metastatic tumor tissue. (43) Further investigation of the potential of T-DM1 for treating HER2-positive MBC patients with brain metastases is warranted.
Besides development of T-DM1 in MBC, there is an ongoing phase II/III clinical trial to evaluate T-DM1 versus taxane therapy in patients with previously treated, advanced HER2-positive gastric cancer (www.clinicaltrials.gov). Preclinical studies have demonstrated that T-DM1 is active in HER2-positive gastric cancer models. (23)
Clinical Pharmacokinetics and Metabolism of T-DM1
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The pharmacokinetic properties of T-DM1 were assessed utilizing two analytical methodologies, those typically used for large proteinaceous molecules (e.g., antibodies), as well as those used for quantifying small molecules. The analytes included total trastuzumab concentrations (unconjugated antibody as well as conjugated antibody irrespective of the number of linked DM1 molecules) and DM1-conjugated trastuzumab concentrations (T-DM1), both measured by specific ELISA methods, as well as free DM1 and DM1 catabolites which were measured using LC–MS/MS methodology. (44)
T-DM1 showed linear pharmacokinetics across doses ranging from 2.4 to 4.8 mg/kg. Lower doses (<1.2 mg/kg) administered to patients in the phase I trial showed evidence of nonlinearity, consistent with a contribution of concentration-dependent target-mediated clearance to the overall clearance. (44) In an analysis of 272 patients dosed at 3.6 mg/kg across four clinical studies, the Cmax for T-DM1 was 75.6–80.9 μg/mL, the t1/2 was about 4.0 days, and the CL was 7.0–13 mL day–1 kg–1. (44) There was no significant accumulation of T-DM1 on the q3 week schedule. The total trastuzumab measurements showed a longer t1/2 (about 9–11 days) and a slower CL (about 4–5 mL day–1 kg–1) than T-DM1, which can be explained by a slow rate of deconjugation. (44, 45) Furthermore, given that T-DM1 is a mixture of molecules from one to eight linked DM1 molecules per antibody, a slightly faster clearance of T-DM1 species bearing higher amounts of linked DM1 (e.g., species with ≥5 DM1/antibody) versus species with lower amounts of linked DM1 (e.g., ≤3 DM1/antibody) could also contribute to the observed slow decrease in the average ratio of DM1/antibody in circulation over time. (45, 46) Population pharmacokinetic analysis suggests that T-DM1 exposure was relatively constant among patients, although body weight did have the greatest impact on the interindividual variability in some of the pharmacokinetic parameters. (47) Markers of liver function of renal function had no clinically meaningful effect on the pharmacokinetics of T-DM1.
Plasma DM1 concentrations were consistently low, with an average level of about 5 ng/mL in patients dosed with T-DM1 at 3.6 mg/kg, levels of free DM1 that correspond to only about 0.3% of the total conjugated DM1 in circulation, demonstrating the good stability of the linker chemistry in vivo. (44, 47) Exploratory analysis of maytansinoid catabolites from T-DM1 showed low concentrations of the linker–DM1 adduct (MCC-DM1) and lysine–linker–DM1 (lysine-Nε-MCC-DM1) in plasma (<1.9–122 ng/mL and <1.08–6.38 ng/mL, respectively). The MCC-DM1 levels were highest immediately after dosing, while the lysine-Nε-MCC-DM1 levels peaked at later time-points as might be expected for a catabolite generated via intracellular proteolytic degradation of T-DM1 within lysosomes of cells. (21, 48) The maytansinoid metabolites detected in clinical samples were as expected from metabolic studies in rats of T-DM1 made with tritium-labeled DM1. The fecal/biliary route appears to be the major pathway of elimination of the DM1-containing catabolites. (29, 48)
The incidence of a human anti-T-DM1 antibody response has been low (<5%) in patients exposed to repeated doses of T-DM1. Where they were observed in clinical trials (in 13 of 286 patients), there were no obvious changes in pharmacokinetics, safety profiles, or efficacy outcomes. (44)
Safety and Tolerability Profile of T-DM1
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Nearly all patients receiving T-DM1 at 3.6 mg/kg, q3 weeks, experience transient declines in platelets, often beginning 1 day after each dose and reaching a nadir on about day 8 with recovery by about day 15. (31, 34, 35, 38, 47, 49) Most such AEs were grade 1 or 2, while grade ≥3 events were infrequent, seen in about 10% of patients across most studies, and were generally rapidly reversible and noncumulative. (31, 34, 35, 47) Reports of any clinically significant bleeding events were uncommon, and only rarely were there any reports of the need for platelet transfusions. Nonclinical studies suggest that T-DM1 can be taken up by megakaryocytes via nontarget mediated uptake mechanisms (perhaps pinocytosis), whereupon intracellular generation of the active catabolite, lysine-Nε-MCC-DM1, can result in disruption of microtubules and proplatelet production, pointing to a possible mechanism for thrombocytopenia in patients. (49) It is interesting to note that while thrombocytopenia defined the DLT of T-DM1 in human, the severity of thrombocytopenia in the non-human primate toxicology studies was minimal at much higher doses and did not define MTD in the preclinical safety studies (see Preclinical Toxicology and Toxicokinetics of T-DM1, above).
Similar to thrombocytopenia, reversible elevations in serum levels of hepatic transaminases were seen in many patients upon dosing with T-DM1, the majority of such events being grade 1 or 2 with grade 3 or 4 AEs seen in less than 10% of patients and one grade 5 event reported to date in a patient with underlying fatty liver disease. (35, 38) Other potential toxicities common to microtubule-disrupting agents were notable by their infrequency: alopecia was almost never seen, while neutropenia, leukopenia, and nervous system toxicities were not reported at clinically significant grades or frequencies. (31, 34, 36) While a serious adverse event of trastuzumab treatment is cardiotoxicity seen in <5% of patients, (50) the clinical studies thus far suggest that the risk of cardiotoxicity of T-DM1 is low, (31, 32, 34, 38) although most evidence reported to date is for patients who previously received trastuzumab, so susceptible patients may have been excluded from most of the reported clinical studies. (34, 38)
Conclusion
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T-DM1, ado-trastuzumab emtansine, is the first antibody–drug conjugate (ADC) to receive full approval from FDA (February 22, 2013). It was approved as a new therapy for patients with HER2-positive late stage (metastatic) breast cancer, previously treated with trastuzumab and taxane chemotherapy. It fulfils the long-sought objective of ADC development, that of better tolerated, more active anticancer agents, and its early promise encourages the development of other agents based on similar ADC platform technologies for a wide array of cancers.
Acknowledgment
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We thank Dr. Gail Lewis Phillips from Genentech, a member of the Roche group, for kindly providing us some figures for inclusion in this paper.
| T-DM1 | ado-trastuzumab emtansine |
| DM1 | N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)maytansine |
| SPDP | N-succinimidyl 3-(2-pyridyldithio)propionate |
| SPP | N-succinimidyl 4-(2-pyridyldithio)pentanoate |
| SSNPP | N-sulfosuccinimidyl 4-(5-nitro-2-pyridyldithio)pentanoate |
| SMCC | N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate |
| MCC | 4-(N-maleimidomethyl)cyclohexane-1-carboxylate |
| EDC | N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride |
| rt | room temperature |
| HER2 | human epidermal growth factor receptor 2 |
| ADC | antibody–drug conjugate |
| ADCC | antibody-dependent cell-mediated cytotoxicity |
| ELISA | enzyme-linked immunosorbent assay |
| FDA | Food and Drug Administration |
| MBC | metastatic breast cancer |
| SAR | structure–activity relationship |
| MDR | multidrug resistance |
| DAR | DM1-to-antibody ratio |
| MTD | maximum tolerated dose |
| DLT | dose-limiting toxicity |
| AE | adverse event |
| CBR | clinical benefit rate |
| ORR | overall response rate |
| CR | complete response |
| PFS | progression-free survival |
| AST | aspartate aminotransferase |
| ALT | alanine aminotransferase |
References
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This article references 50 other publications.
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- 2Pegram, M. D.; Konecny, G. E.; O’Callaghan, C.; Beryt, M.; Pietras, R.; Slamon, D. J. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer J. Natl. Cancer Inst. 2004, 96, 739– 749Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkt1Sqsbo%253D&md5=1fb831bd3fbb62277de025c4a99f383dRational Combinations of Trastuzumab With Chemotherapeutic Drugs Used in the Treatment of Breast CancerPegram, Mark D.; Konecny, Gottfried E.; O'Callaghan, Carminda; Beryt, Malgorzata; Pietras, Richard; Slamon, Dennis J.Journal of the National Cancer Institute (2004), 96 (10), 739-749CODEN: JNCIEQ; ISSN:0027-8874. (Oxford University Press)Trastuzumab, a humanized anti-HER2 antibody, increases the clin. benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress HER2. We characterized interactions between trastuzumab and chemotherapeutic agents commonly used in the treatment of breast cancer. Multiple drug effect/combination index isobologram anal. was used to study the efficacy of chemotherapeutic drug plus trastuzumab combinations tested against four HER2-overexpressing breast cancer cell lines (SK-BR-3, BT-474, MDA-MB-361, and MDA-MB-453). Combination index values were derived from parameters of the median effect plots, and statistical tests were used to det. whether the mean combination index values at multiple effect levels were statistically significantly different from a combination index value of 1.0. Values less than 1.0 indicate synergistic interactions, values greater than 1.0 indicate antagonistic interactions, and values equal to 1.0 indicate additive interactions. At a wide range of clin. achievable drug concns., synergistic interactions were obsd. in all four breast cancer cell lines for trastuzumab plus carboplatin (mean combination index values ranged from 0.32 [P<.001] to 0.53 [P<.001]), 4-hydroxycyclophosphamide (mean combination index values ranged from 0.38 [P<.001] to 0.73 [P = .010]), docetaxel (mean combination index values ranged from 0.30 [P<.001] to 0.62 [P<.001]), and vinorelbine (mean combination index values ranged from 0.24 [P<.001] to 0.78 [P<.034]). Additive interactions were obsd. in all four cell lines with trastuzumab plus doxorubicin, epirubicin, and paclitaxel. Interactions between trastuzumab and gemcitabine were synergistic at low concns. of gemcitabine and antagonistic at high concns. A synergistic interaction was obsd. with a three-drug combination of docetaxel plus carboplatin plus trastuzumab in SK-BR-3 cells (mean combination index value = 0.09; P<.001). Consistent synergistic interactions of trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine across a wide range of clin. relevant concns. in HER2-overexpressing breast cancer cells indicate that these are rational combinations to test in human clin. trials.
- 3Shepard, H. M.; Lewis, G. D.; Sarup, J. C.; Fendly, B. M.; Maneval, D.; Mordenti, J.; Figari, I.; Kotts, C. E.; Palladino, M. A., Jr.; Ullrich, A. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic J. Clin. Immunol. 1991, 11, 117– 127Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmsFent7w%253D&md5=8c323a0c6d081fc00a2b3328a8711f75Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinicShepard, H. Michael; Lewis, Gail D.; Sarup, Jay C.; Fendly, Brian M.; Maneval, Daniel; Mordenti, Joyce; Figari, Irene; Kotts, Claire E.; Palladino, Michael A., Jr.; et al.Journal of Clinical Immunology (1991), 11 (3), 117-27CODEN: JCIMDO; ISSN:0271-9142.A review, with 35 refs., on: the HER2 protoncogene and human cancer; derivation of muMAb 4D5; in vivo preclin. efficacy; and mechanism of action.
- 4Spector, N. L.; Blackwell, K. L. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer J. Clin. Oncol. 2009, 27, 5838– 5847Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVWitro%253D&md5=d54f228c3b69c973238fb1279ee8572dUnderstanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancerSpector, Neil L.; Blackwell, Kimberly L.Journal of Clinical Oncology (2009), 27 (34), 5838-5847CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)A review. Purpose: Targeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) -pos. breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clin. benefit also is discussed. Methods: An extensive literature review of trastuzumab and proposed mechanisms of action was performed. Results: At least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclin. setting. These include activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, redn. of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clin. benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated. The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway. Targeting both HER2, with various approaches, and other pathways may enhance the clin. benefit obsd. with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1). Conclusion: Trastuzumab is the foundation of care for patients with HER2-pos. BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clin. benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.
- 5Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; Baselga, J.; Norton, L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N. Engl. J. Med. 2001, 344, 783– 792Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXisVGktrc%253D&md5=81112f11ffc66fc3a898b61e104322b6Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2Slamon, Dennis J.; Leyland-Jones, Brian; Shak, Steven; Fuchs, Hank; Paton, Virginia; Bajamonde, Alex; Fleming, Thomas; Eiermann, Wolfgang; Wolter, Janet; Pegram, Mark; Baselga, Jose; Norton, LarryNew England Journal of Medicine (2001), 344 (11), 783-792CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 % of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive std. chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addn. of trastuzumab to chemotherapy was assocd. with a longer time to disease progression (median, 7.4 vs. 4.6 mo; P<0.001), a higher rate of objective response (50 % vs. 32 %, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 mo; P<0.001), a lower rate of death at 1 yr (22 % vs. 33 %, P=0.008), longer survival (median survival, 25.1 vs. 20.3 mo; P=0.046), and a 20 % redn. in the risk of death. The most important adverse event was cardiac dysfunction, which occurred in 27 % of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 % of the group given an anthracycline and cyclophosphamide alone; 13 % of the group given paclitaxel and trastuzumab; and 1 % of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with std. medical management. Trastuzumab increases the clin. benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.
- 6Nahta, R.; Esteva, F. J. HER-2-targeted therapy: lessons learned and future directions Clin. Cancer Res. 2003, 9, 5078– 5084Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovVOgtb4%253D&md5=0c48944fbc257ee35c8197d04b31595fHER-2-Targeted Therapy: Lessons Learned and Future DirectionsNahta, Rita; Esteva, Francisco J.Clinical Cancer Research (2003), 9 (14), 5078-5084CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. HER-2 is overexpressed in 20-25% of invasive breast cancers and is assocd. with an aggressive tumor phenotype and reduced survival rates. The HER-2 status of a tumor is the crit. determinant of response to the HER-2-targeted antibody trastuzumab. Thus, accurate assessment of HER-2 expression levels is essential for identifying breast cancer patients who will benefit from HER-2-targeted therapy. Trastuzumab combined with chemotherapy increases response rates, time to progression, and survival. However, the majority of cancers that initially respond to trastuzumab begin to progress again within 1 yr. This minireview describes HER-2 targeting strategies currently in use or in stages of development for the treatment of breast cancer.
- 7Metzger-Filho, O.; Winer, E. P.; Krop, I. Pertuzumab: optimizing HER2 blockade Clin. Cancer Res. 2013, 19, 5552– 5556Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ahurzK&md5=a72443fe22216b25ad4b438bd604f44ePertuzumab: Optimizing HER2 BlockadeMetzger-Filho, Otto; Winer, Eric P.; Krop, IanClinical Cancer Research (2013), 19 (20), 5552-5556CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. Pertuzumab has been approved by the U.S. Food and Drug Administration for use in combination with trastuzumab and docetaxel for the first-line treatment of patients with advanced HER2-pos. (HER2+) breast cancer. Pertuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2 and inhibits heterodimerization of HER2 with other HER family members, including EGF receptor (EGFR), HER3, and HER4. The HER2-HER3 heterodimer is a robust activator of phosphoinositide 3-kinase (PI3K) pathway signaling and functions as the most transforming and mitogenic of the receptor complexes formed by the HER family of proteins; thus, blockade of HER2-HER3 likely represents the most relevant action of pertuzumab. In the seminal phase III study, patients with HER2+ metastatic breast cancer were randomized to receive trastuzumab and docetaxel, with or without pertuzumab: Addn. of pertuzumab significantly prolonged progression-free survival with an increase of 6.1 mo (12.4 vs. 18.5 mo, resp.). In a subsequent anal. with 30 mo of median follow-up, pertuzumab conferred a 34% redn. in the risk of mortality. Here, we review the mechanism of action of pertuzumab, the rationale for combining it with trastuzumab/pertuzumab, clin. data, and future directions for this work. Clin Cancer Res; 19(20); 5552-6. ©2013 AACR.
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- 13Widdison, W. C.; Wilhelm, S. D.; Cavanagh, E. E.; Whiteman, K. R.; Leece, B. A.; Kovtun, Y.; Goldmacher, V. S.; Xie, H.; Steeves, R. M.; Lutz, R. J.; Zhao, R.; Wang, L.; Blattler, W. A.; Chari, R. V. Semisynthetic maytansine analogues for the targeted treatment of cancer J. Med. Chem. 2006, 49, 4392– 4408Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFent7o%253D&md5=a06c19d2d5166b0ca806babf9624c48bSemisynthetic Maytansine Analogs for the Targeted Treatment of CancerWiddison, Wayne C.; Wilhelm, Sharon D.; Cavanagh, Emily E.; Whiteman, Kathleen R.; Leece, Barbara A.; Kovtun, Yelena; Goldmacher, Victor S.; Xie, Hongsheng; Steeves, Rita M.; Lutz, Robert J.; Zhao, Robert; Wang, Lintao; Blaettler, Walter A.; Chari, Ravi V. J.Journal of Medicinal Chemistry (2006), 49 (14), 4392-4408CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clin. trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
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- 16Chari, R. V.; Martell, B. A.; Gross, J. L.; Cook, S. B.; Shah, S. A.; Blattler, W. A.; McKenzie, S. J.; Goldmacher, V. S. Immunoconjugates containing novel maytansinoids: promising anticancer drugs Cancer Res. 1992, 52, 127– 131Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xht1Snu7s%253D&md5=33e7613da2a71800fc13e0b2bc6e21f1Immunoconjugates containing novel maytansinoids: promising anticancer drugsChari, Ravi V. J.; Martell, Bridget A.; Gross, Jonathan L.; Cook, Sherrilyn B.; Shah, Sudhir A.; Blattler, Walter A.; McKenzie, Sara J.; Goldmacher, Victor S.Cancer Research (1992), 52 (1), 127-31CODEN: CNREA8; ISSN:0008-5472.The potential of immunoconjugates of cytotoxic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concns. of these drugs to the target cells. In an effort to overcome this problem the authors have synthesized maytansinoids that have 100- to 1000-fold higher cytotoxic potency than clin. used anticancer drugs. These maytansinoids are linked to antibodies via disulfide bonds, which ensures the release of fully active drug inside the cells. The conjugates show high antigen-specific cytotoxicity for cultured human cancer cells (50% inhibiting concn., 10 to 40 pM), low systemic toxicity in mice, and good pharmacokinetic behavior.
- 17Kellogg, B. A.; Garrett, L.; Kovtun, Y.; Lai, K. C.; Leece, B.; Miller, M.; Payne, G.; Steeves, R.; Whiteman, K. R.; Widdison, W.; Xie, H.; Singh, R.; Chari, R. V.; Lambert, J. M.; Lutz, R. J. Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage Bioconjugate Chem. 2011, 22, 717– 727Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsFKnsro%253D&md5=ef2969ceaaea23e81da2edf06f62ea7eDisulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkageKellogg, Brenda A.; Garrett, Lisa; Kovtun, Yelena; Lai, Katharine C.; Leece, Barbara; Miller, Michael; Payne, Gillian; Steeves, Rita; Whiteman, Kathleen R.; Widdison, Wayne; Xie, Hongsheng; Singh, Rajeeva; Chari, Ravi V. J.; Lambert, John M.; Lutz, Robert J.Bioconjugate Chemistry (2011), 22 (4), 717-727CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to redn. of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to redn. by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two Me groups on the maytansinoid side of the disulfide bond and no Me groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addn. to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity obsd. for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one addnl. factor contributing to the activity of these conjugates in vivo.
- 18Wakankar, A.; Chen, Y.; Gokarn, Y.; Jacobson, F. S. Analytical methods for physicochemical characterization of antibody drug conjugates mAbs 2011, 3, 161– 172Google ScholarThere is no corresponding record for this reference.
- 19Wakankar, A. A.; Feeney, M. B.; Rivera, J.; Chen, Y.; Kim, M.; Sharma, V. K.; Wang, Y. J. Physicochemical stability of the antibody–drug conjugate trastuzumab-DM1: changes due to modification and conjugation processes Bioconjugate Chem. 2010, 21, 1588– 1595Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVyltbk%253D&md5=6c67fb904a35f97adfeb62ec69b7d4bePhysicochemical Stability of the Antibody-Drug Conjugate Trastuzumab-DM1: Changes due to Modification and Conjugation ProcessesWakankar, Aditya A.; Feeney, Maria B.; Rivera, Javier; Chen, Yan; Kim, Michael; Sharma, Vikas K.; Wang, Y. JohnBioconjugate Chemistry (2010), 21 (9), 1588-1595CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)In the manuf. of the antibody-drug conjugate Trastuzumab-DM1 (T-DM1), the lysine residues on the antibody trastuzumab (Tmab) are modified to form the intermediate Tmab-MCC (T-MCC) and then conjugated with the drug DM1. Our goal is to understand the effects of modification and conjugation steps on the physicochem. stability of the antibody. The structural stability of Tmab relative to its modified and conjugated forms was assessed, employing thermally induced stress conditions to formulations contg. Tmab, T-MCC, and T-DM1. DSC, SEC, CE-SDS, and LC-MS were used to study the stability of Tmab, T-MCC, and T-DM1 to thermal stress. The DSC thermograms show a decrease in melting temp. for the CH2 transition, in the order Tmab > T-MCC > T-DM1. As per SEC anal., a significant increase in level of aggregation was detected in T-MCC (∼32%) and T-DM1 (∼5%) after 14 days at 40°. Tmab did not show significant aggregate formation. CE-SDS and LC-MS data demonstrate that the aggregation in the case of T-MCC is largely covalent and involves mechanisms other than formation of intermol. disulfide crosslinks. The aggregation obsd. for T-MCC was significantly inhibited upon addn. of amino acids with nucleophilic side chains contg. thiol (Cys) and hydroxyl moieties (Ser, Tyr). The covalent aggregation obsd. for T-MCC and the ability of nucleophilic amino acids, particularly Cys, to inhibit it indicate that the maleimide moiety in the MCC linker may react to form intermol. covalent crosslinks between T-MCC mols., possibly through a Michael addn. mechanism. In addn., DSC results demonstrate that the conjugation of the drug moiety DM1 to Tmab results in destabilization of the CH2 domain of the antibody.
- 20Lewis Phillips, G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Blattler, W. A.; Lambert, J. M.; Chari, R. V.; Lutz, R. J.; Wong, W. L.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate Cancer Res. 2008, 68, 9280– 9290Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlOmt7rK&md5=e86e8687d5f8884f8e28514299dcbbf1Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug ConjugateLewis Phillips, Gail D.; Li, Guangmin; Dugger, Debra L.; Crocker, Lisa M.; Parsons, Kathryn L.; Mai, Elaine; Blaettler, Walter A.; Lambert, John M.; Chari, Ravi V. J.; Lutz, Robert J.; Wong, Wai Lee T.; Jacobson, Frederic S.; Koeppen, Hartmut; Schwall, Ralph H.; Kenkare-Mitra, Sara R.; Spencer, Susan D.; Sliwkowski, Mark X.Cancer Research (2008), 68 (22), 9280-9290CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-pos. breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We detd. in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymg. agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was detd. in mouse breast cancer models, and toxicity was assessed in rats as measured by body wt. loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concns. of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was obsd. on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addn., trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clin. development.
- 21Erickson, H. K.; Lewis Phillips, G. D.; Leipold, D. D.; Provenzano, C. A.; Mai, E.; Johnson, H. A.; Gunter, B.; Audette, C. A.; Gupta, M.; Pinkas, J.; Tibbitts, J. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates Mol. Cancer Ther. 2012, 11, 1133– 1142Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xms1yrtLs%253D&md5=e7485e8164a5bf3210f6c68f174df112The Effect of Different Linkers on Target Cell Catabolism and Pharmacokinetics/Pharmacodynamics of Trastuzumab Maytansinoid ConjugatesErickson, Hans K.; Lewis Phillips, Gail D.; Leipold, Douglas D.; Provenzano, Carmela A.; Mai, Elaine; Johnson, Holly A.; Gunter, Bert; Audette, Charlene A.; Gupta, Manish; Pinkas, Jan; Tibbitts, JayMolecular Cancer Therapeutics (2012), 11 (5), 1133-1142CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-pos. metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions. The efficacy findings are unique, as other disulfide-linked antibody-drug conjugates (ADC) have shown greater efficacy than thioether-linked designs. To explore this further, the in vitro and in vivo activity, PK, and target cell activation of T-DM1 and the disulfide-linked T-SPP-DM1 were examd. Both ADCs showed high in vitro potency, with T-DM1 displaying greater potency in two of four breast cancer cell lines. In vitro target cell processing of T-DM1 and T-SPP-DM1 produced lysine-N.vepsiln.-MCC-DM1, and lysine-N.vepsiln.-SPP-DM1 and DM1, resp.; in vivo studies confirmed these results. The in vitro processing rates for the two conjugate to their resp. catabolites were similar. In vivo, the potencies of the conjugates were similar, and T-SPP-DM1 had a faster plasma clearance than T-DM1. Slower T-DM1 clearance translated to higher overall tumor concns. (conjugate plus catabolites), but unexpectedly, similar levels of tumor catabolite. These results indicate that, although the ADC linker can have clear impact on the PK and the chem. nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor. Mol Cancer Ther; 11(5); 1133-42.
- 22Junttila, T. T.; Li, G.; Parsons, K.; Phillips, G. L.; Sliwkowski, M. X. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer Breast Cancer Res. Treat. 2011, 128, 347– 356Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnslehsbo%253D&md5=f3b04d9b9bb099007f338c619dd65f00Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancerJunttila, Teemu T.; Li, Guangmin; Parsons, Kathryn; Phillips, Gail Lewis; Sliwkowski, Mark X.Breast Cancer Research and Treatment (2011), 128 (2), 347-356CODEN: BCTRD6; ISSN:0167-6806. (Springer)Trastuzumab (Herceptin) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clin. benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine deriv.). Currently T-DM1 is being tested in multiple clin. trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcγ receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.
- 23Barok, M.; Tanner, M.; Koninki, K.; Isola, J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer Cancer Lett. 2011, 306, 171– 179Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsV2nt7k%253D&md5=b3c549e901da81d69ccdf85af4808310Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancerBarok, Mark; Tanner, Minna; Koeninki, Katri; Isola, JormaCancer Letters (New York, NY, United States) (2011), 306 (2), 171-179CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)Background: A novel antibody-drug conjugate (trastuzumab-DM1, T-DM1) is currently in clin. trials for patients with trastuzumab resistant HER2-pos. breast cancer. Since no clin. data is available from gastric cancer, we studied T-DM1 on HER2-pos. human gastric cancer cells and xenograft tumors. Methods: Effects of T-DM1 were studied in four HER2-pos. gastric cancer cell lines (N-87, OE-19, SNU-216 and MKN-7) in vitro. Xenograft tumors from N-87 and OE-19 were studied to det. the effect of T-DM1 in vivo. Results: T-DM1 was found more effective than trastuzumab in N-87 and OE-19, and moderately effective in MKN-7 cells. On SNU-216 cells both trastuzumab and T-DM1 showed limited efficacy. In xenograft tumor expts., complete pathol. response was obsd. in all OE-19 xenografted mice and in half of the N-87 xenografted mice. The results were equally good irresp. of the tumor burden at therapy initiation, or preceding trastuzumab treatment. T-DM1 treatment showed direct effects (apoptotic cell death and aberrant mitosis) as well as it mediated antibody-dependent cellular cytotoxcity (ADCC). Conclusions: T-DM1 showed a promising anti-tumor effect in HER2-pos. gastric cancer cell lines in vitro and in vivo, even in tumors which had developed resistance to trastuzumab. T-DM1 therapy may warrant clin. trials for HER2-pos. gastric cancer patients.
- 24Kovtun, Y. V.; Audette, C. A.; Mayo, M. F.; Jones, G. E.; Doherty, H.; Maloney, E. K.; Erickson, H. K.; Sun, X.; Wilhelm, S.; Ab, O.; Lai, K. C.; Widdison, W. C.; Kellogg, B.; Johnson, H.; Pinkas, J.; Lutz, R. J.; Singh, R.; Goldmacher, V. S.; Chari, R. V. Antibody–maytansinoid conjugates designed to bypass multidrug resistance Cancer Res. 2010, 70, 2528– 2537Google ScholarThere is no corresponding record for this reference.
- 25Guo, J.; Li, G.; Lewis Phillips, G. D. Role of multidrug resistance transporters in the biological response to trastuzumab–cytotoxic drug conjugates Cancer Res. 2010, 70 (Suppl. 1) Abstract 618Google ScholarThere is no corresponding record for this reference.
- 26Jumbe, N. L.; Xin, Y.; Leipold, D. D.; Crocker, L.; Dugger, D.; Mai, E.; Sliwkowski, M. X.; Fielder, P. J.; Tibbitts, J. Modeling the efficacy of trastuzumab–DM1, an antibody drug conjugate, in mice J. Pharmacokinet. Pharmacodyn. 2010, 37, 221– 242Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnslyktLw%253D&md5=28bac6e680530a3aeba7b44607669c8cModeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in miceJumbe, Nelson L.; Xin, Yan; Leipold, Douglas D.; Crocker, Lisa; Dugger, Debra; Mai, Elaine; Sliwkowski, Mark X.; Fielder, Paul J.; Tibbitts, JayJournal of Pharmacokinetics and Pharmacodynamics (2010), 37 (3), 221-242CODEN: JPPOAH; ISSN:1567-567X. (Springer)Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer. One challenge in oncol. drug development is detg. the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using exptl. data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-pos. breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concn. required for tumor stasis.
- 27Kaur, S.; Xu, K.; Saad, O. M.; Dere, R. C.; Carrasco-Triguero, M. Bioanalytical assay strategies for the development of antibody–drug conjugate biotherapeutics Bioanalysis 2013, 5, 201– 226Google ScholarThere is no corresponding record for this reference.
- 28Poon, K. A.; Flagella, K.; Beyer, J.; Tibbitts, J.; Kaur, S.; Saad, O.; Yi, J. H.; Girish, S.; Dybdal, N.; Reynolds, T. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability Toxicol. Appl. Pharmacol. 2013, 273, 298– 313Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslGlsbbO&md5=f2ae6f6fc865d8ad027752e1301be3ccPreclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerabilityPoon, Kirsten Achilles; Flagella, Kelly; Beyer, Joseph; Tibbitts, Jay; Kaur, Surinder; Saad, Ola; Yi, Joo-Hee; Girish, Sandhya; Dybdal, Noel; Reynolds, TheresaToxicology and Applied Pharmacology (2013), 273 (2), 298-313CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclin. studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, resp., in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (~ 4400 μg DM1/m2) and 30 mg/kg (~ 6000 μg DM1/m2) in rats and monkeys, resp. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m2). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addn., T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematol. (primarily platelet), lymphoid organ, and neuronal toxicities, and increased nos. of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date.
- 29Sun, X.; Widdison, W.; Mayo, M.; Wilhelm, S.; Leece, B.; Chari, R.; Singh, R.; Erickson, H. Design of antibody–maytansinoid conjugates allows for efficient detoxification via liver metabolism Bioconjugate Chem. 2011, 22, 728– 735Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFyitL4%253D&md5=042dafa46e287f5a8a76af8714c124ceDesign of Antibody-Maytansinoid Conjugates Allows for Efficient Detoxification via Liver MetabolismSun, Xiuxia; Widdison, Wayne; Mayo, Michele; Wilhelm, Sharon; Leece, Barbara; Chari, Ravi; Singh, Rajeeva; Erickson, HansBioconjugate Chemistry (2011), 22 (4), 728-735CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Antibody-maytansinoid conjugates (AMCs) are targeted chemotherapeutic agents consisting of a potent microtubule-depolymg. maytansinoid (DM1 or DM4) attached to lysine residues of a monoclonal antibody (mAb) using an uncleavable thioether linker or a stable disulfide linker. Most of the administered dose of an antibody-based therapeutic is slowly catabolized by the liver and other tissues of the reticuloendothelial system. Maytansinoids released from an AMC during this catabolic process could potentially be a source of toxicity. To investigate this, we isolated and identified liver metabolites in mice for three different [3H]AMCs with structures similar to those currently undergoing evaluation in the clinic. We then synthesized each metabolite to confirm the identification and assessed their cytotoxic potencies when added extracellularly. We found that the uncleavable mAb-SMCC-[3H]DM1 conjugate was degraded to a single major maytansinoid metabolite, lysine-SMCC-[3H]DM1, that was nearly 50-fold less cytotoxic than maytansine. The two disulfide-linked conjugates, mAb-SPP-[3H]DM1 and mAb-SPDB-[3H]DM4, were also catabolized to the analogous lysine-linked maytansinoid metabolites. However, subsequent redn., S-methylation, and NADPH-dependent oxidn. steps in the liver yielded the corresponding S-Me sulfoxide and S-Me sulfone derivs. The cytotoxic potencies of the oxidized maytansinoids toward several human carcinoma cell lines were 5- to 50-fold less potent than maytansine. Our results suggest that liver plays an important role in the detoxification of both cleavable and uncleavable AMCs.
- 30Fishkin, N.; Maloney, E. K.; Chari, R. V.; Singh, R. A novel pathway for maytansinoid release from thioether linked antibody–drug conjugates (ADCs) under oxidative conditions Chem. Commun. 2011, 47, 10752– 10754Google ScholarThere is no corresponding record for this reference.
- 31Krop, I. E.; Beeram, M.; Modi, S.; Jones, S. F.; Holden, S. N.; Yu, W.; Girish, S.; Tibbitts, J.; Yi, J. H.; Sliwkowski, M. X.; Jacobson, F.; Lutzker, S. G.; Burris, H. A. Phase I study of trastuzumab–DM1, an HER2 antibody–drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer J. Clin. Oncol. 2010, 28, 2698– 2704Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslykt7c%253D&md5=98ba29a289f4ac0ea38c37a9b6bd0c5dPhase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancerKrop, Ian E.; Beeram, Muralidhar; Modi, Shanu; Jones, Suzanne F.; Holden, Scott N.; Yu, Wei; Girish, Sandhy; Tibbitts, Jay; Yi, Joo-Hee; Sliwkowski, Mark X.; Jacobson, Fred; Lutzker, Stuart G.; Burris, Howard A.Journal of Clinical Oncology (2010), 28 (16), 2698-2704CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-pos. cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-pos. breast cancer. Patients and Methods: Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by std. solid-tumor phase I methods. Results: Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-wk schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the max.-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade ≤ 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clin. benefit rate (objective response plus stable disease at 6 mo) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. Conclusion: At the MTD of 3.6 mg/kg every 3 wk, T-DM1 was assocd. with mild, reversible toxicity and substantial clin. activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-pos. breast cancer are under way.
- 32Baselga, J. Phase I and II clinical trials of trastuzumab Ann. Oncol. 2001, 12 (Suppl. 1) S49– S55Google ScholarThere is no corresponding record for this reference.
- 33Beeram, M.; Krop, I. E.; Burris, H. A.; Girish, S. R.; Yu, W.; Lu, M. W.; Holden, S. N.; Modi, S. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer Cancer 2012, 118, 5733– 5740Google ScholarThere is no corresponding record for this reference.
- 34Burris, H. A., 3rd; Rugo, H. S.; Vukelja, S. J.; Vogel, C. L.; Borson, R. A.; Limentani, S.; Tan-Chiu, E.; Krop, I. E.; Michaelson, R. A.; Girish, S.; Amler, L.; Zheng, M.; Chu, Y. W.; Klencke, B.; O’Shaughnessy, J. A. Phase II study of the antibody drug conjugate trastuzumab–DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy J. Clin. Oncol. 2011, 29, 398– 405Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFWmsrc%253D&md5=94f0c939a12a7875590fc02f3f056d65Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapyBurris, Howard A., III; Rugo, Hope S.; Vukelja, Svetislava J.; Vogel, Charles L.; Borson, Rachel A.; Limentani, Steven; Tan-Chiu, Elizabeth; Krop, Ian E.; Michaelson, Richard A.; Girish, Sandhya; Amler, Lukas; Zheng, Maoxia; Chu, Yu-Waye; Klencke, Barbara; O'Shaughnessy, Joyce A.Journal of Clinical Oncology (2011), 29 (4), 398-405CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biol. activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2) -overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the max.-tolerated dose of 3.6 mg/kg every 3 wk, with evidence of efficacy, in patients with HER2-pos. metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of i.v. T-DM1 (3.6 mg/kg every 3 wk) in patients with HER2-pos. MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. With a follow-up of ≥ 12 mo among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 mo), and median progression-free survival time was 4.6 mo (95% CI, 3.9 to 8.6 mo). The response rates were higher among patients with confirmed HER2-pos. tumors (immunohistochem. 3+ or fluorescent in situ hybridization pos.) by retrospective central testing (n = 74). Higher response rates were also obsd. in patients whose tumors expressed ≥ median HER2 levels by quant. reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-pos. MBC and is well tolerated at the recommended phase II dose.
- 35Krop, I. E.; LoRusso, P.; Miller, K. D.; Modi, S.; Yardley, D.; Rodriguez, G.; Guardino, E.; Lu, M.; Zheng, M.; Girish, S.; Amler, L.; Winer, E. P.; Rugo, H. S. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine J. Clin. Oncol. 2012, 30, 3234– 3241Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKrsL%252FJ&md5=e3c54c63b8a2c6a585818e35c0e4aab9A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabineKrop, Ian E.; LoRusso, Patricia; Miller, Kathy D.; Modi, Shanu; Yardley, Denise; Rodriguez, Gladys; Guardino, Ellie; Lu, Michael; Zheng, Maoxia; Girish, Sandhya; Amler, Lukas; Winer, Eric P.; Rugo, Hope S.; Krop, Ian E.; Winer, Eric P.Journal of Clinical Oncology (2012), 30 (26), 3234-3241CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose. To det. whether the antibody-drug conjugate trastuzumab emtansine (T-DM1), which combines human epidermal growth factor receptor 2 (HER2) -targeted delivery of the potent antimicrotubule agent DM1 with the antitumor activity of trastuzumab, is effective in patients with HER2-pos. metastatic breast cancer (MBC) who have previously received all std. HER2-directed therapies. Patients and Methods. In this single-arm phase II study, T-DM1 3.6 mg/kg was administered i.v. every 3 wk to patients with HER2-pos. MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. The primary objectives were overall response rate (ORR) by independent review and safety. Results. Among 110 pretreated patients (median, seven prior agents for MBC; median follow-up, 17.4 mo), the ORR was 34.5% (95% CI, 26.1% to 43.9%), clin. benefit rate was 48.2% (95% CI, 38.8% to 57.9%), median progression-free survival (PFS) was 6.9 mo (95% CI, 4.2 to 8.4 mo), and median duration of response was 7.2 mo (95% CI, 4.6 mo to not estimable). In patients with confirmed HER2-pos. tumors (n = 80 by retrospective central testing), the response rate was 41.3% (95% CI, 30.4% to 52.8%), and median PFS was 7.3 mo (95% CI, 4.6 to 12.3 mo). Most adverse events were grades 1 to 2; the most frequent grade ≥ 3 events were thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%). Conclusion. T-DM1 is well tolerated and has single-agent activity in patients with HER2-pos. MBC who have previously received both approved HER2-directed therapies and multiple chemotherapy agents. T-DM1 may be an effective new treatment for this patient population.
- 36Hurvitz, S. A.; Dirix, L.; Kocsis, J.; Bianchi, G. V.; Lu, J.; Vinholes, J.; Guardino, E.; Song, C.; Tong, B.; Ng, V.; Chu, Y. W.; Perez, E. A. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer J. Clin. Oncol. 2013, 31, 1157– 1163Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVyhtbs%253D&md5=95cd6eb05ce016e971b2af745d1b587fPhase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancerHurvitz, Sara A.; Dirix, Luc; Kocsis, Judit; Bianchi, Giulia V.; Lu, Janice; Vinholes, Jeferson; Guardino, Ellie; Song, Chunyan; Tong, Barbara; Ng, Vivian; Chu, Yu-Waye; Perez, Edith A.Journal of Clinical Oncology (2013), 31 (9), 1157-1163CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clin. activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting. Patients and Methods: Patients (N = 137) with HER2-pos. MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clin. benefit rate, and quality of life. Results: Median PFS was 9.2 mo with HT and 14.2 mo with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approx. 14 mo in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile vs. HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approx. 23 mo in both arms. Conclusion: In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-pos. MBC provided a significant improvement in PFS, with a favorable safety profile, vs. HT.
- 37Suter, T. M.; Procter, M.; van Veldhuisen, D. J.; Muscholl, M.; Bergh, J.; Carlomagno, C.; Perren, T.; Passalacqua, R.; Bighin, C.; Klijn, J. G.; Ageev, F. T.; Hitre, E.; Groetz, J.; Iwata, H.; Knap, M.; Gnant, M.; Muehlbauer, S.; Spence, A.; Gelber, R. D.; Piccart-Gebhart, M. J. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial J. Clin. Oncol. 2007, 25, 3859– 3865Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFanu7zE&md5=9aa4ecb50b0566677b2552e7c645b2f2Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trialSuter, Thomas M.; Procter, Marion; van Veldhuisen, Dirk J.; Muscholl, Michael; Bergh, Jonas; Carlomagno, Chiara; Perren, Timothy; Passalacqua, Rodolfo; Bighin, Claudia; Klijn, Jan G. M.; Ageev, Fail T.; Hitre, Erika; Greetz, Juergen; Iwata, Hiroji; Knap, Malgorzata; Gnant, Michael; Muehlbauer, Susanne; Spence, Alison; Gelber, Richard D.; Piccart-Gebhart, Martine J.Journal of Clinical Oncology (2007), 25 (25), 3859-3865CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: The purpose of this anal. was to investigate trastuzumab-assocd. cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Patients and Methods: The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 wk with observation in patients with HER-2-pos. breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF ≥ 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. Results: Data were available for 1,693 patients randomly assigned to 1 yr trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 mo. Patients with trastuzumab-assocd. cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index. Conclusion: Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.
- 38Verma, S.; Miles, D.; Gianni, L.; Krop, I. E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D. Y.; Dieras, V.; Guardino, E.; Fang, L.; Lu, M. W.; Olsen, S.; Blackwell, K. Trastuzumab emtansine for HER2-positive advanced breast cancer N. Engl. J. Med. 2012, 367, 1783– 1791Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1ekt73M&md5=3be5bac27a81b530442dc8a6b4a1f82eTrastuzumab emtansine for HER2-positive advanced breast cancerVerma, Sunil; Miles, David; Gianni, Luca; Krop, Ian E.; Welslau, Manfred; Baselga, Jose; Pegram, Mark; Oh, Do-Youn; Dieras, Veronique; Guardino, Ellie; Fang, Liang; Lu, Michael W.; Olsen, Steven; Blackwell, KimNew England Journal of Medicine (2012), 367 (19), 1783-1791CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor 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. METHODS: We randomly assigned patients with HER2-pos. advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 mo with T-DM1 vs. 6.4 mo with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim anal. crossed the stopping boundary for efficacy (30.9 mo vs. 25.1 mo; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all addnl. secondary end points favored T-DM1. Rates of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-pos. advanced breast cancer previously treated with trastuzumab and a taxane.
- 39Krop, I. E.; Kim, S. B.; Gonzalez-Martin, A.; LoRusso, P. M.; Ferrero, J. M.; Smitt, M.; Yu, R.; Leung, A.; Wildiers, H. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomized open-label phase 3 trial Lancet Oncol. 2014, 15, 689– 699Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntl2gs7o%253D&md5=975dd9e786d96360b163c2583aefc4b8Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trialKrop, Ian E.; Kim, Sung-Bae; Gonzalez-Martin, Antonio; LoRusso, Patricia M.; Ferrero, Jean-Marc; Smitt, Melanie; Yu, Ron; Leung, Abraham C. F.; Wildiers, HansLancet Oncology (2014), 15 (7), 689-699CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients.This randomised, open-label, phase 3 trial took place in medical centers in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncol. Group performance status 0-2) with progressive HER2-pos. advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg i.v. every 21 days) or physician's choice using a permuted block randomization scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), no. of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS anal. and the first interim overall survival anal. This study is registered with ClinicalTrials.gov, no. NCT01419197.From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 mo (IQR 5·0-10·1 mo) in the trastuzumab emtansine group and 6·5 mo (IQR 4·1-9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 mo [95% CI 5·59-6·87] vs 3·3 mo [2·89-4·14]; stratified hazard ratio [HR] 0·528 [0·422-0·661]; p<0·0001). Interim overall survival anal. showed a trend favoring trastuzumab emtansine (stratified HR 0·552 [95% CI 0·369-0·826]; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events [32%] in 403 patients vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [<1%] vs eight [4%]), and febrile neutropenia (one [<1%] vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Trastuzumab emtansine should be considered as a new std. for patients with HER2-pos. advanced breast cancer who have previously received trastuzumab and lapatinib.Genentech.
- 40Baselga, J.; Cortes, J.; Kim, S. B.; Im, S. A.; Hegg, R.; Im, Y. H.; Roman, L.; Pedrini, J. L.; Pienkowski, T.; Knott, A.; Clark, E.; Benyunes, M. C.; Ross, G.; Swain, S. M. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N. Engl. J. Med. 2012, 366, 109– 119Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFSlt7Y%253D&md5=8f8a05c82e4722049923dd069f1863b4Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancerBaselga, Jose; Cortes, Javier; Kim, Sung-Bae; Im, Seock-Ah; Hegg, Roberto; Im, Young-Hyuck; Roman, Laslo; Pedrini, Jose Luiz; Pienkowski, Tadeusz; Knott, Adam; Clark, Emma; Benyunes, Mark C.; Ross, Graham; Swain, Sandra M.New England Journal of Medicine (2012), 366 (2), 109-119CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)BACKGROUND The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-pos. metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-pos. breast cancer. METHODS We randomly assigned 808 patients with HER2-pos. metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS The median progression-free survival was 12.4 mo in the control group, as com pared with 18.5 mo in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P < 0.001). The interim anal. of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-pos. metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.
- 41Phillips, G. D.; Fields, C. T.; Li, G.; Dowbenko, D.; Schaefer, G.; Miller, K.; Andre, F.; Burris, H. A., 3rd; Albain, K. S.; Harbeck, N.; Dieras, V.; Crivellari, D.; Fang, L.; Guardino, E.; Olsen, S. R.; Crocker, L. M.; Sliwkowski, M. X. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy Clin. Cancer Res. 2014, 20, 456– 468Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFKrs7c%253D&md5=71f2be1c5fccaee1d613d09c0eaf48b5Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination TherapyPhillips, Gail D. Lewis; Fields, Carter T.; Li, Guangmin; Dowbenko, Donald; Schaefer, Gabriele; Miller, Kathy; Andre, Fabrice; Burris, Howard A.; Albain, Kathy S.; Harbeck, Nadia; Dieras, Veronique; Crivellari, Diana; Fang, Liang; Guardino, Ellie; Olsen, Steven R.; Crocker, Lisa M.; Sliwkowski, Mark X.Clinical Cancer Research (2014), 20 (2), 456-468CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-pos. cancers. We investigated combining the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta). Exptl. Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-pos. locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed std. pertuzumab dose in a 3+3 phase Ib/II study design. Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addn. of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the max. tolerated dose (MTD; 3.6 mg/kg every 3 wk) with std. dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clin. activity. Conclusions: Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456-68. ©2013 AACR.
- 42Lu, D.; Burris, H. A., 3rd; Wang, B.; Dees, E. C.; Cortes, J.; Joshi, A.; Gupta, M.; Yi, J. H.; Chu, Y. W.; Shih, T.; Fang, L.; Girish, S. Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer Curr. Drug Metab. 2012, 13, 911– 922Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1OlurrO&md5=ee2756eb89baee7a08a95ff9d43eb736Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancerLu, Dan; Burris, Howard A., III; Wang, Bei; Dees, E. Claire; Cortes, Javier; Joshi, Amita; Gupta, Manish; Yi, Joo-Hee; Chu, Yu-Waye; Shih, Ted; Fang, Liang; Girish, SandhyaCurrent Drug Metabolism (2012), 13 (7), 911-922CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (deriv. of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-pos., locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estd. by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-pos. MBC. T-DM1 clearance and vol. of distribution in the central compartment, as estd. by population PK anal., were also comparable between this study and historical single-agent studies in patients with HER2-pos. MBC. Summary statistics of pertuzumab trough and maximal exposure (concns. at predose and 15-30 min after the end of infusion at cycle 1 and at steady state) were similar with those obsd. in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
- 43Bartsch, R.; Berghoff, A. S.; Preusser, M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1 J. Neuro-Oncol. 2014, 116, 205– 206Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252Fht1SlsA%253D%253D&md5=cb5391468373267301aadd8c16fc8e06Breast cancer brain metastases responding to primary systemic therapy with T-DM1Bartsch Rupert; Berghoff Anna S; Preusser MatthiasJournal of neuro-oncology (2014), 116 (1), 205-6 ISSN:.There is no expanded citation for this reference.
- 44Girish, S.; Gupta, M.; Wang, B.; Lu, D.; Krop, I. E.; Vogel, C. L.; Burris, H. A., III; LoRusso, P. M.; Yi, J. H.; Saad, O.; Tong, B.; Chu, Y. W.; Holden, S.; Joshi, A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer Cancer Chemother. Pharmacol. 2012, 69, 1229– 1240Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmt1Kru70%253D&md5=f4b2a4ef4aaa79a96adbb1810a0c44d9Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancerGirish, Sandhya; Gupta, Manish; Wang, Bei; Lu, Dan; Krop, Ian E.; Vogel, Charles L.; Burris, Howard A., III; LoRusso, Patricia M.; Yi, Joo-Hee; Saad, Ola; Tong, Barbara; Chu, Yu-Waye; Holden, Scott; Joshi, AmitaCancer Chemotherapy and Pharmacology (2012), 69 (5), 1229-1240CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymn. inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 wk (q3w) were assessed in aggregate. Methods: Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liq. chromatog. tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calcd. using std. noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concns.). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays. Results: PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were obsd. between T-DM1 exposure and efficacy, thrombocytopenia, or increased concns. of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w. Conclusions The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clin. responses or key adverse events.
- 45Lu, D.; Joshi, A.; Wang, B.; Olsen, S.; Yi, J. H.; Krop, I. E.; Burris, H. A.; Girish, S. An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer Clin. Pharmacokinet. 2013, 52, 657– 672Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVSnu7jI&md5=b5b591684a66774da1b9161926217f32An Integrated Multiple-Analyte Pharmacokinetic Model to Characterize Trastuzumab Emtansine (T-DM1) Clearance Pathways and to Evaluate Reduced Pharmacokinetic Sampling in Patients with HER2-Positive Metastatic Breast CancerLu, Dan; Joshi, Amita; Wang, Bei; Olsen, Steve; Yi, Joo-Hee; Krop, Ian E.; Burris, Howard A.; Girish, SandhyaClinical Pharmacokinetics (2013), 52 (8), 657-672CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)Background and Objective: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. It comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to the HER2-targeted humanized monoclonal antibody trastuzumab via a stable linker. To characterize the pharmacokinetics of T-DM1 in patients with metastatic breast cancer, concns. of multiple analytes were quantified, including serum concns. of T-DM1 conjugate and total trastuzumab (the sum of conjugated and unconjugated trastuzumab), as well as plasma concns. of DM1. The clearance of T-DM1 conjugate is approx. 2 to 3 times faster than its parent antibody, trastuzumab. However, the clearance pathways accounting for this faster clearance rate are unclear. An integrated population pharmacokinetic model that simultaneously fits the pharmacokinetics of T-DM1 conjugate and total trastuzumab can help to elucidate the clearance pathways of T-DM1. The model can also be used to predict total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data, thereby reducing the frequency of pharmacokinetic sampling. Methods: T-DM1 conjugate and total trastuzumab serum concn. data, including baseline trastuzumab concns. prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes. Results: The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degrdn. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estd. to be ∼0.4 L/day. Proteolytic degrdn. clearances for T-DM1 and trastuzumab were similar (∼0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one addnl. steady state cycle. Conclusions: This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degrdn. and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance vs. that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.
- 46Chudasama, V. L.; Schaedeli Stark, F.; Harrold, J. M.; Tibbitts, J.; Girish, S. R.; Gupta, M.; Frey, N.; Mager, D. E. Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer Clin. Pharmacol. Ther. 2012, 92, 520– 527Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtl2iurfP&md5=1d04057bdead10453770c704e5ed28f4Semi-mechanistic Population Pharmacokinetic Model of Multivalent Trastuzumab Emtansine in Patients with Metastatic Breast CancerChudasama, V. L.; Schaedeli Stark, F.; Harrold, J. M.; Tibbitts, J.; Girish, S. R.; Gupta, M.; Frey, N.; Mager, D. E.Clinical Pharmacology & Therapeutics (New York, NY, United States) (2012), 92 (4), 520-527CODEN: CLPTAT; ISSN:0009-9236. (Nature Publishing Group)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple mols. of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-pos. metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclin. modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concn. profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclin. studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems. Clin. Pharmacol. & Therapeutics (2012); 92 4, 520-527. doi:10.1038/clpt.2012.153.
- 47Bender, B. C.; Schaedeli-Stark, F.; Koch, R.; Joshi, A.; Chu, Y. W.; Rugo, H.; Krop, I. E.; Girish, S.; Friberg, L. E.; Gupta, M. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer Cancer Chemother. Pharmacol. 2012, 70, 591– 601Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVentbjN&md5=52d01f2d24af314edf8c54d87304af23A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancerBender, Brendan C.; Schaedeli-Stark, Franziska; Koch, Reinhold; Joshi, Amita; Chu, Yu-Waye; Rugo, Hope; Krop, Ian E.; Girish, Sandhya; Friberg, Lena E.; Gupta, ManishCancer Chemotherapy and Pharmacology (2012), 70 (4), 591-601CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-pos. cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. Methods: A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concn.-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEM 7 software was used for model development. Data from a sep. phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. Results: The model described the platelet data well and predicted the incidence of grade ≥3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 wk (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. Conclusions: This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the ∼8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or redns. for TCP.
- 48Shen, B. Q.; Bumbaca, D.; Saad, O.; Yue, Q.; Pastuskovas, C. V.; Khojasteh, S. C.; Tibbitts, J.; Kaur, S.; Wang, B.; Chu, Y. W.; LoRusso, P. M.; Girish, S. Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism Curr. Drug Metab. 2012, 13, 901– 910Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1OlurrN&md5=faf70e5692e4d6a5a7789a0510705837Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolismShen, Ben-Quan; Bumbaca, Daniela; Saad, Ola; Yue, Qin; Pastuskovas, Cinthia V.; Khojasteh, S. Cyrus; Tibbitts, Jay; Kaur, Surinder; Wang, Bei; Chu, Yu-Waye; LoRusso, Patricia M.; Girish, SandhyaCurrent Drug Metabolism (2012), 13 (7), 901-910CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clin. development for the treatment of human epidermal growth factor receptor 2 (HER2)-pos. cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metab., and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concns. were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1-carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-pos. metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 wk) in a phase 2 clin. study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-contg. catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.
- 49Thon, J. N.; Devine, M. T.; Begonja, A. J.; Tibbitts, J.; Italiano, J. E., Jr. High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)-mediated inhibition of platelet production Blood 2012, 120, 1975– 1984Google ScholarThere is no corresponding record for this reference.
- 50Sendur, M. A.; Aksoy, S.; Altundag, K. Cardiotoxicity of novel HER2-targeted therapies Curr. Med. Res. Opin. 2013, 29, 1015– 1024Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFeqsL%252FN&md5=a5a593ec4ce6bbbb95584eb1e1d38d05Cardiotoxicity of novel HER2-targeted therapiesSendur, Mehmet A. N.; Aksoy, Sercan; Altundag, KadriCurrent Medical Research and Opinion (2013), 29 (8), 1015-1024CODEN: CMROCX; ISSN:0300-7995. (Informa Healthcare)A review. Background: Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the std. treatment for both early and metastatic HER2-pos. breast cancer. In addn. to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-pos. early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely assocd. with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Scope: Novel HER2-targeted therapies showed favorable results in HER2 pos. metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstrs. were searched until Jan. 2013 using the following search keywords; trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib mols. are evaluated in the study. Findings: In a comprehensive anal., 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was obsd. only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addn. of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was obsd. with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T-DM1 group experienced redn. of left ventricular ejection fraction (LVEF) and grade III LVEF redn. developed only in one patient (0.2%) in the T-DM1 group compared to the lapatinib plus capecitabine group. In phase I-II trials with neratinib no cardiotoxicity was reported whereas cardiotoxicity was seen between 0-5.3% with afatinib treatment. Conclusion: Although cardiac toxicity has been reported as an adverse event for novel HER2-targeted therapies, cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastuzumab did not significantly increase the cardiac adverse events.
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Abstract
Figure 1
Figure 1. Comparison of the in vitro potency of cytotoxic drugs toward the Burkitt lymphoma cell line Namalwa: maytansine (blue circle), vinblastine (red triangle), daunorubicin (green diamond), methotrexate (brown square), mitomycin C (purple triangle).
Scheme 1
Scheme 1. Synthesis of Thiol-Containing MaytansinoidsaScheme aReaction conditions: (a) LiAlH(OMe)3/THF, −40 °C, (b) EDC/ZnCl2/CH2Cl2, rt, (c) dithiothreitol, rt.
Figure 2
Figure 2. Structures of cross-linkers used in conjugate preparation.
Scheme 2
Scheme 2. Representative Conjugation Processes for Trastuzumab-Maytansinoid ConjugatesFigure 3
Figure 3. Structural representation of trastuzumab-maytansinoid conjugates with a disulfide linker (8a–d) or a thioether linker (8e). Adapted by permission from the American Association for Cancer Research (
Lewis Phillips. G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Lambert, J. M.; Chari, R. V.; Lutz, R. J.; Wong, W. L.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008, 68, 9280–9290). (20)Figure 4
Figure 4. Comparison of the in vivo efficacy of trastuzumab–maytansinoid conjugates with a disulfide linker (8b (green triangle), 8c (purple cross), 8d (red boxed cross)) or a thioether linker (8e (blue square)) at a single iv dose of 10 mg/kg conjugate and a vehicle control (×). Adapted by permission from the American Association for Cancer Research (
Lewis Phillips. G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Lambert, J. M.; Chari, R. V.; Lutz, R. J.; Wong, W. L.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008, 68, 9280–9290). (20)Figure 5
Figure 5. (A) In vitro catabolism by BT474-EEI cells of the trastuzumab-MCC-DM1 conjugate 8e (thioether linker): top panel, 6 h time point; bottom panel, 24 h time point. (B) In vitro catabolism by BT474-EEI cells of the trastuzumab-SPP-DM1 conjugate 8b (disulfide linker): top panel, 6 h time point; bottom panel, 24 h time point. (C) Comparison of the rate and extent of in vitro processing of trastuzumab-SPP-DM1 conjugate 8b (disulfide linker: blue squares) and trastuzumab-MCC-DM1 conjugate 8e (thioether linker, red squares) by BT474-EEI cells.
Figure 6
Figure 6. (A) Time dependent formation of catabolite: comparison of in vivo catabolism of trastuzumab–maytansinoid conjugates in BT474-EEI tumor xenografts in mice: trastuzumab-SPP-DM1 conjugate 8b (disulfide linker, blue square) and trastuzumab-MCC-DM1 conjugate 8e (thioether linker, red square). (B) In vivo catabolism of trastuzumab–maytansinoid conjugates in BT474-EEI tumor xenografts in mice at 2-day time-point: top panel, 8b, disulfide linker (SPP); bottom panel, 8e, thioether linker (SMCC).
Figure 7
Figure 7. (A) Comparison of the in vivo antitumor activity of trastuzumab (red circle, 15 mg/kg × 4) and T-DM1 (blue square, 15 mg/kg, single dose), vehicle control (×), in the KPL-4 model. (Excerpted from Lewis-Phillips et al. (20)). (B) Dose-dependent antitumor activity of T-DM1 in the BT474-EEI model (dosing q3w × 3). Doses of T-DM1, are the following: 0.3 mg/kg (purple-outline triangle), 1 mg/kg (green triangle), 3 mg/kg (blue-outline triangle), 10 mg/kg (red triangle), 15 mg/kg (blue square), vehicle control (×); unconjugated trastuzumab (red circle, 15 mg/kg). Parts A and B are adapted by permission from the American Association for Cancer Research (
Lewis Phillips. G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Lambert, J. M.; Chari, R. V.; Lutz, R. J.; Wong, W. L.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008, 68, 9280–9290). (20)References
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- 1Colomer, R.; Shamon, L. A.; Tsai, M. S.; Lupu, R. Herceptin: from the bench to the clinic Cancer Invest. 2001, 19, 49– 56There is no corresponding record for this reference.
- 2Pegram, M. D.; Konecny, G. E.; O’Callaghan, C.; Beryt, M.; Pietras, R.; Slamon, D. J. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer J. Natl. Cancer Inst. 2004, 96, 739– 7492https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkt1Sqsbo%253D&md5=1fb831bd3fbb62277de025c4a99f383dRational Combinations of Trastuzumab With Chemotherapeutic Drugs Used in the Treatment of Breast CancerPegram, Mark D.; Konecny, Gottfried E.; O'Callaghan, Carminda; Beryt, Malgorzata; Pietras, Richard; Slamon, Dennis J.Journal of the National Cancer Institute (2004), 96 (10), 739-749CODEN: JNCIEQ; ISSN:0027-8874. (Oxford University Press)Trastuzumab, a humanized anti-HER2 antibody, increases the clin. benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress HER2. We characterized interactions between trastuzumab and chemotherapeutic agents commonly used in the treatment of breast cancer. Multiple drug effect/combination index isobologram anal. was used to study the efficacy of chemotherapeutic drug plus trastuzumab combinations tested against four HER2-overexpressing breast cancer cell lines (SK-BR-3, BT-474, MDA-MB-361, and MDA-MB-453). Combination index values were derived from parameters of the median effect plots, and statistical tests were used to det. whether the mean combination index values at multiple effect levels were statistically significantly different from a combination index value of 1.0. Values less than 1.0 indicate synergistic interactions, values greater than 1.0 indicate antagonistic interactions, and values equal to 1.0 indicate additive interactions. At a wide range of clin. achievable drug concns., synergistic interactions were obsd. in all four breast cancer cell lines for trastuzumab plus carboplatin (mean combination index values ranged from 0.32 [P<.001] to 0.53 [P<.001]), 4-hydroxycyclophosphamide (mean combination index values ranged from 0.38 [P<.001] to 0.73 [P = .010]), docetaxel (mean combination index values ranged from 0.30 [P<.001] to 0.62 [P<.001]), and vinorelbine (mean combination index values ranged from 0.24 [P<.001] to 0.78 [P<.034]). Additive interactions were obsd. in all four cell lines with trastuzumab plus doxorubicin, epirubicin, and paclitaxel. Interactions between trastuzumab and gemcitabine were synergistic at low concns. of gemcitabine and antagonistic at high concns. A synergistic interaction was obsd. with a three-drug combination of docetaxel plus carboplatin plus trastuzumab in SK-BR-3 cells (mean combination index value = 0.09; P<.001). Consistent synergistic interactions of trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine across a wide range of clin. relevant concns. in HER2-overexpressing breast cancer cells indicate that these are rational combinations to test in human clin. trials.
- 3Shepard, H. M.; Lewis, G. D.; Sarup, J. C.; Fendly, B. M.; Maneval, D.; Mordenti, J.; Figari, I.; Kotts, C. E.; Palladino, M. A., Jr.; Ullrich, A. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic J. Clin. Immunol. 1991, 11, 117– 1273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmsFent7w%253D&md5=8c323a0c6d081fc00a2b3328a8711f75Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinicShepard, H. Michael; Lewis, Gail D.; Sarup, Jay C.; Fendly, Brian M.; Maneval, Daniel; Mordenti, Joyce; Figari, Irene; Kotts, Claire E.; Palladino, Michael A., Jr.; et al.Journal of Clinical Immunology (1991), 11 (3), 117-27CODEN: JCIMDO; ISSN:0271-9142.A review, with 35 refs., on: the HER2 protoncogene and human cancer; derivation of muMAb 4D5; in vivo preclin. efficacy; and mechanism of action.
- 4Spector, N. L.; Blackwell, K. L. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer J. Clin. Oncol. 2009, 27, 5838– 58474https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVWitro%253D&md5=d54f228c3b69c973238fb1279ee8572dUnderstanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancerSpector, Neil L.; Blackwell, Kimberly L.Journal of Clinical Oncology (2009), 27 (34), 5838-5847CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)A review. Purpose: Targeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) -pos. breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clin. benefit also is discussed. Methods: An extensive literature review of trastuzumab and proposed mechanisms of action was performed. Results: At least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclin. setting. These include activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, redn. of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clin. benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated. The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway. Targeting both HER2, with various approaches, and other pathways may enhance the clin. benefit obsd. with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1). Conclusion: Trastuzumab is the foundation of care for patients with HER2-pos. BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clin. benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.
- 5Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; Baselga, J.; Norton, L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N. Engl. J. Med. 2001, 344, 783– 7925https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXisVGktrc%253D&md5=81112f11ffc66fc3a898b61e104322b6Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2Slamon, Dennis J.; Leyland-Jones, Brian; Shak, Steven; Fuchs, Hank; Paton, Virginia; Bajamonde, Alex; Fleming, Thomas; Eiermann, Wolfgang; Wolter, Janet; Pegram, Mark; Baselga, Jose; Norton, LarryNew England Journal of Medicine (2001), 344 (11), 783-792CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 % of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive std. chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addn. of trastuzumab to chemotherapy was assocd. with a longer time to disease progression (median, 7.4 vs. 4.6 mo; P<0.001), a higher rate of objective response (50 % vs. 32 %, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 mo; P<0.001), a lower rate of death at 1 yr (22 % vs. 33 %, P=0.008), longer survival (median survival, 25.1 vs. 20.3 mo; P=0.046), and a 20 % redn. in the risk of death. The most important adverse event was cardiac dysfunction, which occurred in 27 % of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 % of the group given an anthracycline and cyclophosphamide alone; 13 % of the group given paclitaxel and trastuzumab; and 1 % of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with std. medical management. Trastuzumab increases the clin. benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.
- 6Nahta, R.; Esteva, F. J. HER-2-targeted therapy: lessons learned and future directions Clin. Cancer Res. 2003, 9, 5078– 50846https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXovVOgtb4%253D&md5=0c48944fbc257ee35c8197d04b31595fHER-2-Targeted Therapy: Lessons Learned and Future DirectionsNahta, Rita; Esteva, Francisco J.Clinical Cancer Research (2003), 9 (14), 5078-5084CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. HER-2 is overexpressed in 20-25% of invasive breast cancers and is assocd. with an aggressive tumor phenotype and reduced survival rates. The HER-2 status of a tumor is the crit. determinant of response to the HER-2-targeted antibody trastuzumab. Thus, accurate assessment of HER-2 expression levels is essential for identifying breast cancer patients who will benefit from HER-2-targeted therapy. Trastuzumab combined with chemotherapy increases response rates, time to progression, and survival. However, the majority of cancers that initially respond to trastuzumab begin to progress again within 1 yr. This minireview describes HER-2 targeting strategies currently in use or in stages of development for the treatment of breast cancer.
- 7Metzger-Filho, O.; Winer, E. P.; Krop, I. Pertuzumab: optimizing HER2 blockade Clin. Cancer Res. 2013, 19, 5552– 55567https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ahurzK&md5=a72443fe22216b25ad4b438bd604f44ePertuzumab: Optimizing HER2 BlockadeMetzger-Filho, Otto; Winer, Eric P.; Krop, IanClinical Cancer Research (2013), 19 (20), 5552-5556CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. Pertuzumab has been approved by the U.S. Food and Drug Administration for use in combination with trastuzumab and docetaxel for the first-line treatment of patients with advanced HER2-pos. (HER2+) breast cancer. Pertuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2 and inhibits heterodimerization of HER2 with other HER family members, including EGF receptor (EGFR), HER3, and HER4. The HER2-HER3 heterodimer is a robust activator of phosphoinositide 3-kinase (PI3K) pathway signaling and functions as the most transforming and mitogenic of the receptor complexes formed by the HER family of proteins; thus, blockade of HER2-HER3 likely represents the most relevant action of pertuzumab. In the seminal phase III study, patients with HER2+ metastatic breast cancer were randomized to receive trastuzumab and docetaxel, with or without pertuzumab: Addn. of pertuzumab significantly prolonged progression-free survival with an increase of 6.1 mo (12.4 vs. 18.5 mo, resp.). In a subsequent anal. with 30 mo of median follow-up, pertuzumab conferred a 34% redn. in the risk of mortality. Here, we review the mechanism of action of pertuzumab, the rationale for combining it with trastuzumab/pertuzumab, clin. data, and future directions for this work. Clin Cancer Res; 19(20); 5552-6. ©2013 AACR.
- 8Chari, R. V.; Miller, M. L.; Widdison, W. C. Antibody–drug conjugates: an emerging concept in cancer therapy Angew. Chem., Int. Ed. 2014, 53, 3796– 3827There is no corresponding record for this reference.
- 9Blattler, W. A.; Chari, R. V. J. Methods of treatment using anti-ERBB antibody–maytansinoid conjugates. U.S. Patent 8,337,856, 2012.There is no corresponding record for this reference.
- 10Sedlacek, H. H. Antibodies as Carriers of Cytotoxicity; Karger: Basel, Switzerland, 1992; pp 1– 145.There is no corresponding record for this reference.
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- 12Kupchan, S. M.; Komoda, Y.; Branfman, A. R.; Sneden, A. T.; Court, W. A.; Thomas, G. J.; Hintz, H. P.; Smith, R. M.; Karim, A.; Howie, G. A.; Verma, A. K.; Nagao, Y.; Dailey, R. G., Jr.; Zimmerly, V. A.; Sumner, W. C., Jr. The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides J. Org. Chem. 1977, 42, 2349– 2357There is no corresponding record for this reference.
- 13Widdison, W. C.; Wilhelm, S. D.; Cavanagh, E. E.; Whiteman, K. R.; Leece, B. A.; Kovtun, Y.; Goldmacher, V. S.; Xie, H.; Steeves, R. M.; Lutz, R. J.; Zhao, R.; Wang, L.; Blattler, W. A.; Chari, R. V. Semisynthetic maytansine analogues for the targeted treatment of cancer J. Med. Chem. 2006, 49, 4392– 440813https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFent7o%253D&md5=a06c19d2d5166b0ca806babf9624c48bSemisynthetic Maytansine Analogs for the Targeted Treatment of CancerWiddison, Wayne C.; Wilhelm, Sharon D.; Cavanagh, Emily E.; Whiteman, Kathleen R.; Leece, Barbara A.; Kovtun, Yelena; Goldmacher, Victor S.; Xie, Hongsheng; Steeves, Rita M.; Lutz, Robert J.; Zhao, Robert; Wang, Lintao; Blaettler, Walter A.; Chari, Ravi V. J.Journal of Medicinal Chemistry (2006), 49 (14), 4392-4408CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clin. trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
- 14Issell, B. F.; Crooke, S. T. Maytansine Cancer Treat. Rev. 1978, 5, 199– 20714https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE1M7gsFektw%253D%253D&md5=73ec733c0581edc2085d87aa26291f26MaytansineIssell B F; Crooke S TCancer treatment reviews (1978), 5 (4), 199-207 ISSN:0305-7372.There is no expanded citation for this reference.
- 15Kupchan, S. M.; Sneden, A. T.; Branfman, A. R.; Howie, G. A.; Rebhun, L. I.; McIvor, W. E.; Wang, R. W.; Schnaitman, T. C. Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids J. Med. Chem. 1978, 21, 31– 37There is no corresponding record for this reference.
- 16Chari, R. V.; Martell, B. A.; Gross, J. L.; Cook, S. B.; Shah, S. A.; Blattler, W. A.; McKenzie, S. J.; Goldmacher, V. S. Immunoconjugates containing novel maytansinoids: promising anticancer drugs Cancer Res. 1992, 52, 127– 13116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xht1Snu7s%253D&md5=33e7613da2a71800fc13e0b2bc6e21f1Immunoconjugates containing novel maytansinoids: promising anticancer drugsChari, Ravi V. J.; Martell, Bridget A.; Gross, Jonathan L.; Cook, Sherrilyn B.; Shah, Sudhir A.; Blattler, Walter A.; McKenzie, Sara J.; Goldmacher, Victor S.Cancer Research (1992), 52 (1), 127-31CODEN: CNREA8; ISSN:0008-5472.The potential of immunoconjugates of cytotoxic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concns. of these drugs to the target cells. In an effort to overcome this problem the authors have synthesized maytansinoids that have 100- to 1000-fold higher cytotoxic potency than clin. used anticancer drugs. These maytansinoids are linked to antibodies via disulfide bonds, which ensures the release of fully active drug inside the cells. The conjugates show high antigen-specific cytotoxicity for cultured human cancer cells (50% inhibiting concn., 10 to 40 pM), low systemic toxicity in mice, and good pharmacokinetic behavior.
- 17Kellogg, B. A.; Garrett, L.; Kovtun, Y.; Lai, K. C.; Leece, B.; Miller, M.; Payne, G.; Steeves, R.; Whiteman, K. R.; Widdison, W.; Xie, H.; Singh, R.; Chari, R. V.; Lambert, J. M.; Lutz, R. J. Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage Bioconjugate Chem. 2011, 22, 717– 72717https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsFKnsro%253D&md5=ef2969ceaaea23e81da2edf06f62ea7eDisulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkageKellogg, Brenda A.; Garrett, Lisa; Kovtun, Yelena; Lai, Katharine C.; Leece, Barbara; Miller, Michael; Payne, Gillian; Steeves, Rita; Whiteman, Kathleen R.; Widdison, Wayne; Xie, Hongsheng; Singh, Rajeeva; Chari, Ravi V. J.; Lambert, John M.; Lutz, Robert J.Bioconjugate Chemistry (2011), 22 (4), 717-727CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to redn. of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to redn. by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two Me groups on the maytansinoid side of the disulfide bond and no Me groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addn. to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity obsd. for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one addnl. factor contributing to the activity of these conjugates in vivo.
- 18Wakankar, A.; Chen, Y.; Gokarn, Y.; Jacobson, F. S. Analytical methods for physicochemical characterization of antibody drug conjugates mAbs 2011, 3, 161– 172There is no corresponding record for this reference.
- 19Wakankar, A. A.; Feeney, M. B.; Rivera, J.; Chen, Y.; Kim, M.; Sharma, V. K.; Wang, Y. J. Physicochemical stability of the antibody–drug conjugate trastuzumab-DM1: changes due to modification and conjugation processes Bioconjugate Chem. 2010, 21, 1588– 159519https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVyltbk%253D&md5=6c67fb904a35f97adfeb62ec69b7d4bePhysicochemical Stability of the Antibody-Drug Conjugate Trastuzumab-DM1: Changes due to Modification and Conjugation ProcessesWakankar, Aditya A.; Feeney, Maria B.; Rivera, Javier; Chen, Yan; Kim, Michael; Sharma, Vikas K.; Wang, Y. JohnBioconjugate Chemistry (2010), 21 (9), 1588-1595CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)In the manuf. of the antibody-drug conjugate Trastuzumab-DM1 (T-DM1), the lysine residues on the antibody trastuzumab (Tmab) are modified to form the intermediate Tmab-MCC (T-MCC) and then conjugated with the drug DM1. Our goal is to understand the effects of modification and conjugation steps on the physicochem. stability of the antibody. The structural stability of Tmab relative to its modified and conjugated forms was assessed, employing thermally induced stress conditions to formulations contg. Tmab, T-MCC, and T-DM1. DSC, SEC, CE-SDS, and LC-MS were used to study the stability of Tmab, T-MCC, and T-DM1 to thermal stress. The DSC thermograms show a decrease in melting temp. for the CH2 transition, in the order Tmab > T-MCC > T-DM1. As per SEC anal., a significant increase in level of aggregation was detected in T-MCC (∼32%) and T-DM1 (∼5%) after 14 days at 40°. Tmab did not show significant aggregate formation. CE-SDS and LC-MS data demonstrate that the aggregation in the case of T-MCC is largely covalent and involves mechanisms other than formation of intermol. disulfide crosslinks. The aggregation obsd. for T-MCC was significantly inhibited upon addn. of amino acids with nucleophilic side chains contg. thiol (Cys) and hydroxyl moieties (Ser, Tyr). The covalent aggregation obsd. for T-MCC and the ability of nucleophilic amino acids, particularly Cys, to inhibit it indicate that the maleimide moiety in the MCC linker may react to form intermol. covalent crosslinks between T-MCC mols., possibly through a Michael addn. mechanism. In addn., DSC results demonstrate that the conjugation of the drug moiety DM1 to Tmab results in destabilization of the CH2 domain of the antibody.
- 20Lewis Phillips, G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Blattler, W. A.; Lambert, J. M.; Chari, R. V.; Lutz, R. J.; Wong, W. L.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate Cancer Res. 2008, 68, 9280– 929020https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlOmt7rK&md5=e86e8687d5f8884f8e28514299dcbbf1Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug ConjugateLewis Phillips, Gail D.; Li, Guangmin; Dugger, Debra L.; Crocker, Lisa M.; Parsons, Kathryn L.; Mai, Elaine; Blaettler, Walter A.; Lambert, John M.; Chari, Ravi V. J.; Lutz, Robert J.; Wong, Wai Lee T.; Jacobson, Frederic S.; Koeppen, Hartmut; Schwall, Ralph H.; Kenkare-Mitra, Sara R.; Spencer, Susan D.; Sliwkowski, Mark X.Cancer Research (2008), 68 (22), 9280-9290CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-pos. breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We detd. in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymg. agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was detd. in mouse breast cancer models, and toxicity was assessed in rats as measured by body wt. loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concns. of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was obsd. on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addn., trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clin. development.
- 21Erickson, H. K.; Lewis Phillips, G. D.; Leipold, D. D.; Provenzano, C. A.; Mai, E.; Johnson, H. A.; Gunter, B.; Audette, C. A.; Gupta, M.; Pinkas, J.; Tibbitts, J. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates Mol. Cancer Ther. 2012, 11, 1133– 114221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xms1yrtLs%253D&md5=e7485e8164a5bf3210f6c68f174df112The Effect of Different Linkers on Target Cell Catabolism and Pharmacokinetics/Pharmacodynamics of Trastuzumab Maytansinoid ConjugatesErickson, Hans K.; Lewis Phillips, Gail D.; Leipold, Douglas D.; Provenzano, Carmela A.; Mai, Elaine; Johnson, Holly A.; Gunter, Bert; Audette, Charlene A.; Gupta, Manish; Pinkas, Jan; Tibbitts, JayMolecular Cancer Therapeutics (2012), 11 (5), 1133-1142CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-pos. metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions. The efficacy findings are unique, as other disulfide-linked antibody-drug conjugates (ADC) have shown greater efficacy than thioether-linked designs. To explore this further, the in vitro and in vivo activity, PK, and target cell activation of T-DM1 and the disulfide-linked T-SPP-DM1 were examd. Both ADCs showed high in vitro potency, with T-DM1 displaying greater potency in two of four breast cancer cell lines. In vitro target cell processing of T-DM1 and T-SPP-DM1 produced lysine-N.vepsiln.-MCC-DM1, and lysine-N.vepsiln.-SPP-DM1 and DM1, resp.; in vivo studies confirmed these results. The in vitro processing rates for the two conjugate to their resp. catabolites were similar. In vivo, the potencies of the conjugates were similar, and T-SPP-DM1 had a faster plasma clearance than T-DM1. Slower T-DM1 clearance translated to higher overall tumor concns. (conjugate plus catabolites), but unexpectedly, similar levels of tumor catabolite. These results indicate that, although the ADC linker can have clear impact on the PK and the chem. nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor. Mol Cancer Ther; 11(5); 1133-42.
- 22Junttila, T. T.; Li, G.; Parsons, K.; Phillips, G. L.; Sliwkowski, M. X. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer Breast Cancer Res. Treat. 2011, 128, 347– 35622https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnslehsbo%253D&md5=f3b04d9b9bb099007f338c619dd65f00Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancerJunttila, Teemu T.; Li, Guangmin; Parsons, Kathryn; Phillips, Gail Lewis; Sliwkowski, Mark X.Breast Cancer Research and Treatment (2011), 128 (2), 347-356CODEN: BCTRD6; ISSN:0167-6806. (Springer)Trastuzumab (Herceptin) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clin. benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine deriv.). Currently T-DM1 is being tested in multiple clin. trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcγ receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.
- 23Barok, M.; Tanner, M.; Koninki, K.; Isola, J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer Cancer Lett. 2011, 306, 171– 17923https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsV2nt7k%253D&md5=b3c549e901da81d69ccdf85af4808310Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancerBarok, Mark; Tanner, Minna; Koeninki, Katri; Isola, JormaCancer Letters (New York, NY, United States) (2011), 306 (2), 171-179CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)Background: A novel antibody-drug conjugate (trastuzumab-DM1, T-DM1) is currently in clin. trials for patients with trastuzumab resistant HER2-pos. breast cancer. Since no clin. data is available from gastric cancer, we studied T-DM1 on HER2-pos. human gastric cancer cells and xenograft tumors. Methods: Effects of T-DM1 were studied in four HER2-pos. gastric cancer cell lines (N-87, OE-19, SNU-216 and MKN-7) in vitro. Xenograft tumors from N-87 and OE-19 were studied to det. the effect of T-DM1 in vivo. Results: T-DM1 was found more effective than trastuzumab in N-87 and OE-19, and moderately effective in MKN-7 cells. On SNU-216 cells both trastuzumab and T-DM1 showed limited efficacy. In xenograft tumor expts., complete pathol. response was obsd. in all OE-19 xenografted mice and in half of the N-87 xenografted mice. The results were equally good irresp. of the tumor burden at therapy initiation, or preceding trastuzumab treatment. T-DM1 treatment showed direct effects (apoptotic cell death and aberrant mitosis) as well as it mediated antibody-dependent cellular cytotoxcity (ADCC). Conclusions: T-DM1 showed a promising anti-tumor effect in HER2-pos. gastric cancer cell lines in vitro and in vivo, even in tumors which had developed resistance to trastuzumab. T-DM1 therapy may warrant clin. trials for HER2-pos. gastric cancer patients.
- 24Kovtun, Y. V.; Audette, C. A.; Mayo, M. F.; Jones, G. E.; Doherty, H.; Maloney, E. K.; Erickson, H. K.; Sun, X.; Wilhelm, S.; Ab, O.; Lai, K. C.; Widdison, W. C.; Kellogg, B.; Johnson, H.; Pinkas, J.; Lutz, R. J.; Singh, R.; Goldmacher, V. S.; Chari, R. V. Antibody–maytansinoid conjugates designed to bypass multidrug resistance Cancer Res. 2010, 70, 2528– 2537There is no corresponding record for this reference.
- 25Guo, J.; Li, G.; Lewis Phillips, G. D. Role of multidrug resistance transporters in the biological response to trastuzumab–cytotoxic drug conjugates Cancer Res. 2010, 70 (Suppl. 1) Abstract 618There is no corresponding record for this reference.
- 26Jumbe, N. L.; Xin, Y.; Leipold, D. D.; Crocker, L.; Dugger, D.; Mai, E.; Sliwkowski, M. X.; Fielder, P. J.; Tibbitts, J. Modeling the efficacy of trastuzumab–DM1, an antibody drug conjugate, in mice J. Pharmacokinet. Pharmacodyn. 2010, 37, 221– 24226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnslyktLw%253D&md5=28bac6e680530a3aeba7b44607669c8cModeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in miceJumbe, Nelson L.; Xin, Yan; Leipold, Douglas D.; Crocker, Lisa; Dugger, Debra; Mai, Elaine; Sliwkowski, Mark X.; Fielder, Paul J.; Tibbitts, JayJournal of Pharmacokinetics and Pharmacodynamics (2010), 37 (3), 221-242CODEN: JPPOAH; ISSN:1567-567X. (Springer)Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer. One challenge in oncol. drug development is detg. the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using exptl. data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-pos. breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concn. required for tumor stasis.
- 27Kaur, S.; Xu, K.; Saad, O. M.; Dere, R. C.; Carrasco-Triguero, M. Bioanalytical assay strategies for the development of antibody–drug conjugate biotherapeutics Bioanalysis 2013, 5, 201– 226There is no corresponding record for this reference.
- 28Poon, K. A.; Flagella, K.; Beyer, J.; Tibbitts, J.; Kaur, S.; Saad, O.; Yi, J. H.; Girish, S.; Dybdal, N.; Reynolds, T. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability Toxicol. Appl. Pharmacol. 2013, 273, 298– 31328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslGlsbbO&md5=f2ae6f6fc865d8ad027752e1301be3ccPreclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerabilityPoon, Kirsten Achilles; Flagella, Kelly; Beyer, Joseph; Tibbitts, Jay; Kaur, Surinder; Saad, Ola; Yi, Joo-Hee; Girish, Sandhya; Dybdal, Noel; Reynolds, TheresaToxicology and Applied Pharmacology (2013), 273 (2), 298-313CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we present results from preclin. studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, resp., in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (~ 4400 μg DM1/m2) and 30 mg/kg (~ 6000 μg DM1/m2) in rats and monkeys, resp. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μg DM1/m2). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic index. In addn., T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematol. (primarily platelet), lymphoid organ, and neuronal toxicities, and increased nos. of cells of epithelial and phagocytic origin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date.
- 29Sun, X.; Widdison, W.; Mayo, M.; Wilhelm, S.; Leece, B.; Chari, R.; Singh, R.; Erickson, H. Design of antibody–maytansinoid conjugates allows for efficient detoxification via liver metabolism Bioconjugate Chem. 2011, 22, 728– 73529https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFyitL4%253D&md5=042dafa46e287f5a8a76af8714c124ceDesign of Antibody-Maytansinoid Conjugates Allows for Efficient Detoxification via Liver MetabolismSun, Xiuxia; Widdison, Wayne; Mayo, Michele; Wilhelm, Sharon; Leece, Barbara; Chari, Ravi; Singh, Rajeeva; Erickson, HansBioconjugate Chemistry (2011), 22 (4), 728-735CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Antibody-maytansinoid conjugates (AMCs) are targeted chemotherapeutic agents consisting of a potent microtubule-depolymg. maytansinoid (DM1 or DM4) attached to lysine residues of a monoclonal antibody (mAb) using an uncleavable thioether linker or a stable disulfide linker. Most of the administered dose of an antibody-based therapeutic is slowly catabolized by the liver and other tissues of the reticuloendothelial system. Maytansinoids released from an AMC during this catabolic process could potentially be a source of toxicity. To investigate this, we isolated and identified liver metabolites in mice for three different [3H]AMCs with structures similar to those currently undergoing evaluation in the clinic. We then synthesized each metabolite to confirm the identification and assessed their cytotoxic potencies when added extracellularly. We found that the uncleavable mAb-SMCC-[3H]DM1 conjugate was degraded to a single major maytansinoid metabolite, lysine-SMCC-[3H]DM1, that was nearly 50-fold less cytotoxic than maytansine. The two disulfide-linked conjugates, mAb-SPP-[3H]DM1 and mAb-SPDB-[3H]DM4, were also catabolized to the analogous lysine-linked maytansinoid metabolites. However, subsequent redn., S-methylation, and NADPH-dependent oxidn. steps in the liver yielded the corresponding S-Me sulfoxide and S-Me sulfone derivs. The cytotoxic potencies of the oxidized maytansinoids toward several human carcinoma cell lines were 5- to 50-fold less potent than maytansine. Our results suggest that liver plays an important role in the detoxification of both cleavable and uncleavable AMCs.
- 30Fishkin, N.; Maloney, E. K.; Chari, R. V.; Singh, R. A novel pathway for maytansinoid release from thioether linked antibody–drug conjugates (ADCs) under oxidative conditions Chem. Commun. 2011, 47, 10752– 10754There is no corresponding record for this reference.
- 31Krop, I. E.; Beeram, M.; Modi, S.; Jones, S. F.; Holden, S. N.; Yu, W.; Girish, S.; Tibbitts, J.; Yi, J. H.; Sliwkowski, M. X.; Jacobson, F.; Lutzker, S. G.; Burris, H. A. Phase I study of trastuzumab–DM1, an HER2 antibody–drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer J. Clin. Oncol. 2010, 28, 2698– 270431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslykt7c%253D&md5=98ba29a289f4ac0ea38c37a9b6bd0c5dPhase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancerKrop, Ian E.; Beeram, Muralidhar; Modi, Shanu; Jones, Suzanne F.; Holden, Scott N.; Yu, Wei; Girish, Sandhy; Tibbitts, Jay; Yi, Joo-Hee; Sliwkowski, Mark X.; Jacobson, Fred; Lutzker, Stuart G.; Burris, Howard A.Journal of Clinical Oncology (2010), 28 (16), 2698-2704CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-pos. cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-pos. breast cancer. Patients and Methods: Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by std. solid-tumor phase I methods. Results: Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-wk schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the max.-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade ≤ 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clin. benefit rate (objective response plus stable disease at 6 mo) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. Conclusion: At the MTD of 3.6 mg/kg every 3 wk, T-DM1 was assocd. with mild, reversible toxicity and substantial clin. activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-pos. breast cancer are under way.
- 32Baselga, J. Phase I and II clinical trials of trastuzumab Ann. Oncol. 2001, 12 (Suppl. 1) S49– S55There is no corresponding record for this reference.
- 33Beeram, M.; Krop, I. E.; Burris, H. A.; Girish, S. R.; Yu, W.; Lu, M. W.; Holden, S. N.; Modi, S. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer Cancer 2012, 118, 5733– 5740There is no corresponding record for this reference.
- 34Burris, H. A., 3rd; Rugo, H. S.; Vukelja, S. J.; Vogel, C. L.; Borson, R. A.; Limentani, S.; Tan-Chiu, E.; Krop, I. E.; Michaelson, R. A.; Girish, S.; Amler, L.; Zheng, M.; Chu, Y. W.; Klencke, B.; O’Shaughnessy, J. A. Phase II study of the antibody drug conjugate trastuzumab–DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy J. Clin. Oncol. 2011, 29, 398– 40534https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFWmsrc%253D&md5=94f0c939a12a7875590fc02f3f056d65Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapyBurris, Howard A., III; Rugo, Hope S.; Vukelja, Svetislava J.; Vogel, Charles L.; Borson, Rachel A.; Limentani, Steven; Tan-Chiu, Elizabeth; Krop, Ian E.; Michaelson, Richard A.; Girish, Sandhya; Amler, Lukas; Zheng, Maoxia; Chu, Yu-Waye; Klencke, Barbara; O'Shaughnessy, Joyce A.Journal of Clinical Oncology (2011), 29 (4), 398-405CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biol. activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2) -overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the max.-tolerated dose of 3.6 mg/kg every 3 wk, with evidence of efficacy, in patients with HER2-pos. metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of i.v. T-DM1 (3.6 mg/kg every 3 wk) in patients with HER2-pos. MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. With a follow-up of ≥ 12 mo among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 mo), and median progression-free survival time was 4.6 mo (95% CI, 3.9 to 8.6 mo). The response rates were higher among patients with confirmed HER2-pos. tumors (immunohistochem. 3+ or fluorescent in situ hybridization pos.) by retrospective central testing (n = 74). Higher response rates were also obsd. in patients whose tumors expressed ≥ median HER2 levels by quant. reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-pos. MBC and is well tolerated at the recommended phase II dose.
- 35Krop, I. E.; LoRusso, P.; Miller, K. D.; Modi, S.; Yardley, D.; Rodriguez, G.; Guardino, E.; Lu, M.; Zheng, M.; Girish, S.; Amler, L.; Winer, E. P.; Rugo, H. S. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine J. Clin. Oncol. 2012, 30, 3234– 324135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKrsL%252FJ&md5=e3c54c63b8a2c6a585818e35c0e4aab9A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabineKrop, Ian E.; LoRusso, Patricia; Miller, Kathy D.; Modi, Shanu; Yardley, Denise; Rodriguez, Gladys; Guardino, Ellie; Lu, Michael; Zheng, Maoxia; Girish, Sandhya; Amler, Lukas; Winer, Eric P.; Rugo, Hope S.; Krop, Ian E.; Winer, Eric P.Journal of Clinical Oncology (2012), 30 (26), 3234-3241CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose. To det. whether the antibody-drug conjugate trastuzumab emtansine (T-DM1), which combines human epidermal growth factor receptor 2 (HER2) -targeted delivery of the potent antimicrotubule agent DM1 with the antitumor activity of trastuzumab, is effective in patients with HER2-pos. metastatic breast cancer (MBC) who have previously received all std. HER2-directed therapies. Patients and Methods. In this single-arm phase II study, T-DM1 3.6 mg/kg was administered i.v. every 3 wk to patients with HER2-pos. MBC who had prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. The primary objectives were overall response rate (ORR) by independent review and safety. Results. Among 110 pretreated patients (median, seven prior agents for MBC; median follow-up, 17.4 mo), the ORR was 34.5% (95% CI, 26.1% to 43.9%), clin. benefit rate was 48.2% (95% CI, 38.8% to 57.9%), median progression-free survival (PFS) was 6.9 mo (95% CI, 4.2 to 8.4 mo), and median duration of response was 7.2 mo (95% CI, 4.6 mo to not estimable). In patients with confirmed HER2-pos. tumors (n = 80 by retrospective central testing), the response rate was 41.3% (95% CI, 30.4% to 52.8%), and median PFS was 7.3 mo (95% CI, 4.6 to 12.3 mo). Most adverse events were grades 1 to 2; the most frequent grade ≥ 3 events were thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%). Conclusion. T-DM1 is well tolerated and has single-agent activity in patients with HER2-pos. MBC who have previously received both approved HER2-directed therapies and multiple chemotherapy agents. T-DM1 may be an effective new treatment for this patient population.
- 36Hurvitz, S. A.; Dirix, L.; Kocsis, J.; Bianchi, G. V.; Lu, J.; Vinholes, J.; Guardino, E.; Song, C.; Tong, B.; Ng, V.; Chu, Y. W.; Perez, E. A. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer J. Clin. Oncol. 2013, 31, 1157– 116336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVyhtbs%253D&md5=95cd6eb05ce016e971b2af745d1b587fPhase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancerHurvitz, Sara A.; Dirix, Luc; Kocsis, Judit; Bianchi, Giulia V.; Lu, Janice; Vinholes, Jeferson; Guardino, Ellie; Song, Chunyan; Tong, Barbara; Ng, Vivian; Chu, Yu-Waye; Perez, Edith A.Journal of Clinical Oncology (2013), 31 (9), 1157-1163CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clin. activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting. Patients and Methods: Patients (N = 137) with HER2-pos. MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clin. benefit rate, and quality of life. Results: Median PFS was 9.2 mo with HT and 14.2 mo with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approx. 14 mo in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile vs. HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approx. 23 mo in both arms. Conclusion: In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-pos. MBC provided a significant improvement in PFS, with a favorable safety profile, vs. HT.
- 37Suter, T. M.; Procter, M.; van Veldhuisen, D. J.; Muscholl, M.; Bergh, J.; Carlomagno, C.; Perren, T.; Passalacqua, R.; Bighin, C.; Klijn, J. G.; Ageev, F. T.; Hitre, E.; Groetz, J.; Iwata, H.; Knap, M.; Gnant, M.; Muehlbauer, S.; Spence, A.; Gelber, R. D.; Piccart-Gebhart, M. J. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial J. Clin. Oncol. 2007, 25, 3859– 386537https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFanu7zE&md5=9aa4ecb50b0566677b2552e7c645b2f2Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trialSuter, Thomas M.; Procter, Marion; van Veldhuisen, Dirk J.; Muscholl, Michael; Bergh, Jonas; Carlomagno, Chiara; Perren, Timothy; Passalacqua, Rodolfo; Bighin, Claudia; Klijn, Jan G. M.; Ageev, Fail T.; Hitre, Erika; Greetz, Juergen; Iwata, Hiroji; Knap, Malgorzata; Gnant, Michael; Muehlbauer, Susanne; Spence, Alison; Gelber, Richard D.; Piccart-Gebhart, Martine J.Journal of Clinical Oncology (2007), 25 (25), 3859-3865CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: The purpose of this anal. was to investigate trastuzumab-assocd. cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Patients and Methods: The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 wk with observation in patients with HER-2-pos. breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF ≥ 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. Results: Data were available for 1,693 patients randomly assigned to 1 yr trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 mo. Patients with trastuzumab-assocd. cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index. Conclusion: Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.
- 38Verma, S.; Miles, D.; Gianni, L.; Krop, I. E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D. Y.; Dieras, V.; Guardino, E.; Fang, L.; Lu, M. W.; Olsen, S.; Blackwell, K. Trastuzumab emtansine for HER2-positive advanced breast cancer N. Engl. J. Med. 2012, 367, 1783– 179138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1ekt73M&md5=3be5bac27a81b530442dc8a6b4a1f82eTrastuzumab emtansine for HER2-positive advanced breast cancerVerma, Sunil; Miles, David; Gianni, Luca; Krop, Ian E.; Welslau, Manfred; Baselga, Jose; Pegram, Mark; Oh, Do-Youn; Dieras, Veronique; Guardino, Ellie; Fang, Liang; Lu, Michael W.; Olsen, Steven; Blackwell, KimNew England Journal of Medicine (2012), 367 (19), 1783-1791CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor 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. METHODS: We randomly assigned patients with HER2-pos. advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 mo with T-DM1 vs. 6.4 mo with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim anal. crossed the stopping boundary for efficacy (30.9 mo vs. 25.1 mo; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all addnl. secondary end points favored T-DM1. Rates of grade 3 or above were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-pos. advanced breast cancer previously treated with trastuzumab and a taxane.
- 39Krop, I. E.; Kim, S. B.; Gonzalez-Martin, A.; LoRusso, P. M.; Ferrero, J. M.; Smitt, M.; Yu, R.; Leung, A.; Wildiers, H. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomized open-label phase 3 trial Lancet Oncol. 2014, 15, 689– 69939https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntl2gs7o%253D&md5=975dd9e786d96360b163c2583aefc4b8Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trialKrop, Ian E.; Kim, Sung-Bae; Gonzalez-Martin, Antonio; LoRusso, Patricia M.; Ferrero, Jean-Marc; Smitt, Melanie; Yu, Ron; Leung, Abraham C. F.; Wildiers, HansLancet Oncology (2014), 15 (7), 689-699CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare trastuzumab emtansine, an antibody-drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients.This randomised, open-label, phase 3 trial took place in medical centers in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncol. Group performance status 0-2) with progressive HER2-pos. advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg i.v. every 21 days) or physician's choice using a permuted block randomization scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), no. of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS anal. and the first interim overall survival anal. This study is registered with ClinicalTrials.gov, no. NCT01419197.From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 mo (IQR 5·0-10·1 mo) in the trastuzumab emtansine group and 6·5 mo (IQR 4·1-9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 mo [95% CI 5·59-6·87] vs 3·3 mo [2·89-4·14]; stratified hazard ratio [HR] 0·528 [0·422-0·661]; p<0·0001). Interim overall survival anal. showed a trend favoring trastuzumab emtansine (stratified HR 0·552 [95% CI 0·369-0·826]; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events [32%] in 403 patients vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [<1%] vs eight [4%]), and febrile neutropenia (one [<1%] vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Trastuzumab emtansine should be considered as a new std. for patients with HER2-pos. advanced breast cancer who have previously received trastuzumab and lapatinib.Genentech.
- 40Baselga, J.; Cortes, J.; Kim, S. B.; Im, S. A.; Hegg, R.; Im, Y. H.; Roman, L.; Pedrini, J. L.; Pienkowski, T.; Knott, A.; Clark, E.; Benyunes, M. C.; Ross, G.; Swain, S. M. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N. Engl. J. Med. 2012, 366, 109– 11940https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFSlt7Y%253D&md5=8f8a05c82e4722049923dd069f1863b4Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancerBaselga, Jose; Cortes, Javier; Kim, Sung-Bae; Im, Seock-Ah; Hegg, Roberto; Im, Young-Hyuck; Roman, Laslo; Pedrini, Jose Luiz; Pienkowski, Tadeusz; Knott, Adam; Clark, Emma; Benyunes, Mark C.; Ross, Graham; Swain, Sandra M.New England Journal of Medicine (2012), 366 (2), 109-119CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)BACKGROUND The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-pos. metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-pos. breast cancer. METHODS We randomly assigned 808 patients with HER2-pos. metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS The median progression-free survival was 12.4 mo in the control group, as com pared with 18.5 mo in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P < 0.001). The interim anal. of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-pos. metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.
- 41Phillips, G. D.; Fields, C. T.; Li, G.; Dowbenko, D.; Schaefer, G.; Miller, K.; Andre, F.; Burris, H. A., 3rd; Albain, K. S.; Harbeck, N.; Dieras, V.; Crivellari, D.; Fang, L.; Guardino, E.; Olsen, S. R.; Crocker, L. M.; Sliwkowski, M. X. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy Clin. Cancer Res. 2014, 20, 456– 46841https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFKrs7c%253D&md5=71f2be1c5fccaee1d613d09c0eaf48b5Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination TherapyPhillips, Gail D. Lewis; Fields, Carter T.; Li, Guangmin; Dowbenko, Donald; Schaefer, Gabriele; Miller, Kathy; Andre, Fabrice; Burris, Howard A.; Albain, Kathy S.; Harbeck, Nadia; Dieras, Veronique; Crivellari, Diana; Fang, Liang; Guardino, Ellie; Olsen, Steven R.; Crocker, Lisa M.; Sliwkowski, Mark X.Clinical Cancer Research (2014), 20 (2), 456-468CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-pos. cancers. We investigated combining the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta). Exptl. Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-pos. locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed std. pertuzumab dose in a 3+3 phase Ib/II study design. Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addn. of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the max. tolerated dose (MTD; 3.6 mg/kg every 3 wk) with std. dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clin. activity. Conclusions: Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456-68. ©2013 AACR.
- 42Lu, D.; Burris, H. A., 3rd; Wang, B.; Dees, E. C.; Cortes, J.; Joshi, A.; Gupta, M.; Yi, J. H.; Chu, Y. W.; Shih, T.; Fang, L.; Girish, S. Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer Curr. Drug Metab. 2012, 13, 911– 92242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1OlurrO&md5=ee2756eb89baee7a08a95ff9d43eb736Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancerLu, Dan; Burris, Howard A., III; Wang, Bei; Dees, E. Claire; Cortes, Javier; Joshi, Amita; Gupta, Manish; Yi, Joo-Hee; Chu, Yu-Waye; Shih, Ted; Fang, Liang; Girish, SandhyaCurrent Drug Metabolism (2012), 13 (7), 911-922CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (deriv. of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-pos., locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estd. by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-pos. MBC. T-DM1 clearance and vol. of distribution in the central compartment, as estd. by population PK anal., were also comparable between this study and historical single-agent studies in patients with HER2-pos. MBC. Summary statistics of pertuzumab trough and maximal exposure (concns. at predose and 15-30 min after the end of infusion at cycle 1 and at steady state) were similar with those obsd. in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
- 43Bartsch, R.; Berghoff, A. S.; Preusser, M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1 J. Neuro-Oncol. 2014, 116, 205– 20643https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c%252Fht1SlsA%253D%253D&md5=cb5391468373267301aadd8c16fc8e06Breast cancer brain metastases responding to primary systemic therapy with T-DM1Bartsch Rupert; Berghoff Anna S; Preusser MatthiasJournal of neuro-oncology (2014), 116 (1), 205-6 ISSN:.There is no expanded citation for this reference.
- 44Girish, S.; Gupta, M.; Wang, B.; Lu, D.; Krop, I. E.; Vogel, C. L.; Burris, H. A., III; LoRusso, P. M.; Yi, J. H.; Saad, O.; Tong, B.; Chu, Y. W.; Holden, S.; Joshi, A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer Cancer Chemother. Pharmacol. 2012, 69, 1229– 124044https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmt1Kru70%253D&md5=f4b2a4ef4aaa79a96adbb1810a0c44d9Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancerGirish, Sandhya; Gupta, Manish; Wang, Bei; Lu, Dan; Krop, Ian E.; Vogel, Charles L.; Burris, Howard A., III; LoRusso, Patricia M.; Yi, Joo-Hee; Saad, Ola; Tong, Barbara; Chu, Yu-Waye; Holden, Scott; Joshi, AmitaCancer Chemotherapy and Pharmacology (2012), 69 (5), 1229-1240CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymn. inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 wk (q3w) were assessed in aggregate. Methods: Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liq. chromatog. tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calcd. using std. noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concns.). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays. Results: PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were obsd. between T-DM1 exposure and efficacy, thrombocytopenia, or increased concns. of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w. Conclusions The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clin. responses or key adverse events.
- 45Lu, D.; Joshi, A.; Wang, B.; Olsen, S.; Yi, J. H.; Krop, I. E.; Burris, H. A.; Girish, S. An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer Clin. Pharmacokinet. 2013, 52, 657– 67245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVSnu7jI&md5=b5b591684a66774da1b9161926217f32An Integrated Multiple-Analyte Pharmacokinetic Model to Characterize Trastuzumab Emtansine (T-DM1) Clearance Pathways and to Evaluate Reduced Pharmacokinetic Sampling in Patients with HER2-Positive Metastatic Breast CancerLu, Dan; Joshi, Amita; Wang, Bei; Olsen, Steve; Yi, Joo-Hee; Krop, Ian E.; Burris, Howard A.; Girish, SandhyaClinical Pharmacokinetics (2013), 52 (8), 657-672CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)Background and Objective: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 (HER2)-pos. metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. It comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to the HER2-targeted humanized monoclonal antibody trastuzumab via a stable linker. To characterize the pharmacokinetics of T-DM1 in patients with metastatic breast cancer, concns. of multiple analytes were quantified, including serum concns. of T-DM1 conjugate and total trastuzumab (the sum of conjugated and unconjugated trastuzumab), as well as plasma concns. of DM1. The clearance of T-DM1 conjugate is approx. 2 to 3 times faster than its parent antibody, trastuzumab. However, the clearance pathways accounting for this faster clearance rate are unclear. An integrated population pharmacokinetic model that simultaneously fits the pharmacokinetics of T-DM1 conjugate and total trastuzumab can help to elucidate the clearance pathways of T-DM1. The model can also be used to predict total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data, thereby reducing the frequency of pharmacokinetic sampling. Methods: T-DM1 conjugate and total trastuzumab serum concn. data, including baseline trastuzumab concns. prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes. Results: The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degrdn. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estd. to be ∼0.4 L/day. Proteolytic degrdn. clearances for T-DM1 and trastuzumab were similar (∼0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one addnl. steady state cycle. Conclusions: This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degrdn. and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance vs. that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.
- 46Chudasama, V. L.; Schaedeli Stark, F.; Harrold, J. M.; Tibbitts, J.; Girish, S. R.; Gupta, M.; Frey, N.; Mager, D. E. Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer Clin. Pharmacol. Ther. 2012, 92, 520– 52746https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtl2iurfP&md5=1d04057bdead10453770c704e5ed28f4Semi-mechanistic Population Pharmacokinetic Model of Multivalent Trastuzumab Emtansine in Patients with Metastatic Breast CancerChudasama, V. L.; Schaedeli Stark, F.; Harrold, J. M.; Tibbitts, J.; Girish, S. R.; Gupta, M.; Frey, N.; Mager, D. E.Clinical Pharmacology & Therapeutics (New York, NY, United States) (2012), 92 (4), 520-527CODEN: CLPTAT; ISSN:0009-9236. (Nature Publishing Group)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple mols. of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-pos. metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclin. modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concn. profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclin. studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems. Clin. Pharmacol. & Therapeutics (2012); 92 4, 520-527. doi:10.1038/clpt.2012.153.
- 47Bender, B. C.; Schaedeli-Stark, F.; Koch, R.; Joshi, A.; Chu, Y. W.; Rugo, H.; Krop, I. E.; Girish, S.; Friberg, L. E.; Gupta, M. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer Cancer Chemother. Pharmacol. 2012, 70, 591– 60147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVentbjN&md5=52d01f2d24af314edf8c54d87304af23A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancerBender, Brendan C.; Schaedeli-Stark, Franziska; Koch, Reinhold; Joshi, Amita; Chu, Yu-Waye; Rugo, Hope; Krop, Ian E.; Girish, Sandhya; Friberg, Lena E.; Gupta, ManishCancer Chemotherapy and Pharmacology (2012), 70 (4), 591-601CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-pos. cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. Methods: A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concn.-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEM 7 software was used for model development. Data from a sep. phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. Results: The model described the platelet data well and predicted the incidence of grade ≥3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 wk (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. Conclusions: This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the ∼8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or redns. for TCP.
- 48Shen, B. Q.; Bumbaca, D.; Saad, O.; Yue, Q.; Pastuskovas, C. V.; Khojasteh, S. C.; Tibbitts, J.; Kaur, S.; Wang, B.; Chu, Y. W.; LoRusso, P. M.; Girish, S. Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism Curr. Drug Metab. 2012, 13, 901– 91048https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1OlurrN&md5=faf70e5692e4d6a5a7789a0510705837Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolismShen, Ben-Quan; Bumbaca, Daniela; Saad, Ola; Yue, Qin; Pastuskovas, Cinthia V.; Khojasteh, S. Cyrus; Tibbitts, Jay; Kaur, Surinder; Wang, Bei; Chu, Yu-Waye; LoRusso, Patricia M.; Girish, SandhyaCurrent Drug Metabolism (2012), 13 (7), 901-910CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clin. development for the treatment of human epidermal growth factor receptor 2 (HER2)-pos. cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metab., and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concns. were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1-carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-pos. metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 wk) in a phase 2 clin. study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-contg. catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.
- 49Thon, J. N.; Devine, M. T.; Begonja, A. J.; Tibbitts, J.; Italiano, J. E., Jr. High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)-mediated inhibition of platelet production Blood 2012, 120, 1975– 1984There is no corresponding record for this reference.
- 50Sendur, M. A.; Aksoy, S.; Altundag, K. Cardiotoxicity of novel HER2-targeted therapies Curr. Med. Res. Opin. 2013, 29, 1015– 102450https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFeqsL%252FN&md5=a5a593ec4ce6bbbb95584eb1e1d38d05Cardiotoxicity of novel HER2-targeted therapiesSendur, Mehmet A. N.; Aksoy, Sercan; Altundag, KadriCurrent Medical Research and Opinion (2013), 29 (8), 1015-1024CODEN: CMROCX; ISSN:0300-7995. (Informa Healthcare)A review. Background: Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the std. treatment for both early and metastatic HER2-pos. breast cancer. In addn. to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-pos. early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely assocd. with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Scope: Novel HER2-targeted therapies showed favorable results in HER2 pos. metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstrs. were searched until Jan. 2013 using the following search keywords; trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib mols. are evaluated in the study. Findings: In a comprehensive anal., 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was obsd. only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addn. of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was obsd. with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T-DM1 group experienced redn. of left ventricular ejection fraction (LVEF) and grade III LVEF redn. developed only in one patient (0.2%) in the T-DM1 group compared to the lapatinib plus capecitabine group. In phase I-II trials with neratinib no cardiotoxicity was reported whereas cardiotoxicity was seen between 0-5.3% with afatinib treatment. Conclusion: Although cardiac toxicity has been reported as an adverse event for novel HER2-targeted therapies, cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastuzumab did not significantly increase the cardiac adverse events.