T r a s t u z u m a b E m t a n s i n e ( T - D M 1 ) : H i t c h i n g a
`R i d e o n a T h e r a p e u t i c A n t i b o d y
`
`By Howard A. Burris III, MD
`
`The treatment of cancers with chemotherapy is
`Overview:
`frequently limited by side effects. The effectiveness may be
`improved by the use of monoclonal antibodies to deliver
`cytotoxic agents to cancer cells while limiting exposure to
`normal tissues. The use of antibody-drug conjugates (ADCs) is
`one such strategy: a drug connected by a linker to an antibody
`specific for a tumor antigen is the basic makeup of an ADC.
`Overexpression and amplification of HER2 is associated with
`clinically aggressive breast cancers, and the use of trastu-
`zumab to target HER2 has been highly effective. That said,
`most patients with HER2-positive metastatic breast cancer
`will eventually have disease progression during targeted ther-
`apy. Trastuzumab emtansine (T–DM1)
`is a novel ADC that
`combines the humanized antibody trastuzumab and the potent
`antimicrotubule agent T-DM1 (derivative of maytansine) using
`a unique and highly stable linker. The potential of maytansine
`was found in the 1970s with clinical responses noted against
`breast cancer; however, substantial toxicity prohibited further
`development. DM1 possesses in vitro cytotoxicity 10 to 200
`times greater than that of taxanes and vinca alkaloids. A phase
`I trial of T-DM1 for patients with heavily pretreated HER2-
`positive breast cancer determined a recommended dose of 3.6
`
`THE TREATMENT of many cancers is often based on the
`
`use of standard chemotherapy agents and regimens.
`The effectiveness of this approach is frequently limited by
`substantial systemic toxicities associated with these agents.
`The therapeutic index can be markedly improved with the
`use of monoclonal antibodies to deliver potent cytotoxic
`agents to cancer cells, thus minimizing the exposure of the
`agents to normal tissues. The use of antibody-drug conju-
`gates (ADCs) is one such strategy; a cytotoxic drug con-
`nected by a chemical linker to a monoclonal antibody specific
`for a tumor antigen is the basic makeup of an ADC. More
`stable linkers and different cytotoxic agents have enabled a
`new generation of ADCs to enter the clinic. First and
`foremost, the design of an ADC centers on the selection of an
`antigen that is tumor-specific and accessible to antibody
`binding at the tumor cell.
`Overexpression and amplification of HER2 is associated
`with clinically aggressive breast cancers that have histori-
`cally had an overall poor prognosis and therapeutic resis-
`tance to traditional drugs. The use of trastuzumab to target
`the extracellular domain of HER2 has been highly effective
`in the treatment of this type of breast cancer. Multiple
`mechanisms for the efficacy of trastuzumab have been
`proposed, including inhibition of the PI3K signal transduc-
`tion pathway, antibody-dependent cell-mediated cytotoxic-
`ity (ADCC), and induction of apoptosis. When combined with
`chemotherapy, trastuzumab improves the time to disease
`progression and overall survival for patients with HER2-
`positive metastatic breast cancer. Furthermore, mature
`data from four large phase III trials in which trastuzumab
`was evaluated in the adjuvant setting, have demonstrated
`marked improvements in both disease-free and overall sur-
`vival. That said, most patients with HER2-positive meta-
`static breast cancer will eventually have disease progression
`during targeted therapy while the cancer continues to both
`
`mg per kilogram delivered every 3 weeks. Responses were
`seen in multiple patients. T-DM1 was then studied in phase II
`trials of patients with HER2-positive metastatic breast cancer.
`In a studies of 112 and 110 patients in whom disease had
`progressed during HER2-directed therapy, T-DM1 was asso-
`ciated with objective response rates of 26% and 34%, respec-
`tively. The agent was well tolerated in both trials, with most
`toxicities being grade 1 and 2, and no bleeding episodes or
`cardiac events occurring. Additional phase II and III trials are
`now evaluating T-DM1 in the first-line setting.
`In one such
`trial, T-DM1 was compared with standard dosing of trastu-
`zumab every 3 weeks plus docetaxel every 3 weeks. Objective
`response rates were comparable and grade 3 or4 adverse
`events were substantially reduced in the T-DM1 arm. The
`anticipated selective activity and reduction in side effects
`were thus noted. Randomized multicenter phase III trials are
`ongoing,
`including the EMILIA trial, an open-label
`trial of
`T-DM1 compared with the U.S. Food & Drug Administration-
`approved regimen of capecitabine plus lapatinib. The results
`of studies completed to date suggest T-DM1 is active in
`patients who have cancer resistant
`to trastuzumab-based
`combinations.
`
`express HER2 and demonstrate sensitivity to antimicrotu-
`bule agents.
`T-DM1 is a novel ADC that combines the humanized
`antibody trastuzumab and the potent antimicrotubule agent
`DM1 (derivative of maytansine) using a unique and highly
`stable linker.1 T-DM1, with its ability to bind HER2 with the
`same affinity as trastuzumab, maintains the activity of
`trastuzumab in addition to providing intracellular delivery
`of the antimicrotubule agent DM1. It is hypothesized that
`when T-DM1 binds to HER2 receptors, a portion of them
`undergo receptor internalization, followed by lysosomal deg-
`radation. Activated DM1 is then released from lysosome into
`the cellular cytoplasm after antibody degradation, inhibiting
`microtubule assembly and causing cell death. Potent cyto-
`toxic agents are needed to maximize the role of drug conju-
`gates. In addition, the drug must be inactive and nontoxic in
`the conjugated form to avoid systemic toxicities. Few agents
`are able to fulfill these characteristics, including the inhib-
`itors of tubulin polymerization (the maytansinoids and the
`auristatins).
`The potential of maytansine as an anticancer agent was
`originally discovered in the 1970s with clinical responses
`noted against breast cancer. However, substantial and ran-
`dom toxicities of neuropathy and myelosuppression were
`prohibitive of further clinical development. Recently, an
`attempt at improving the therapeutic index through conju-
`gation with trastuzumab was undertaken, leading to the
`
`From the Sarah Cannon Research Institute, Nashville, TN.
`Author’s disclosures of potential conflicts of interest are found at the end of this article.
`Address reprint requests to Howard A. Burris, MD, Tennessee Oncology/Sarah Cannon
`Research Institute, 250 25th Avenue N., Suite 110, Nashville, TN 37203; email:
`Howard.burris@scresearch.net
`© 2012 by American Society of Clinical Oncology.
`1092-9118/10/1-10
`
`159
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`IMMUNOGEN 2188, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

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`Table 1. Summary of Clinical Efficacy Data from Trastuzumab Emtasine (T-DM1) Clinical Trials
`
`HOWARD A. BURRIS III
`
`Trial and Reference
`
`TDM3569g2
`
`TDM4258g3
`
`TDM4374g4
`
`TDM4373g5
`
`TDM4450g6
`
`Treatment Regimens
`
`T-DM1 0.3 tp 4.8 mg/kg q3w for previously treated HER2⫹
`MBC after previous chemotherapy and disease progression
`on trastuzumab
`T-DM1 3.6 mg/kg q3w for HER2-positive MBC after previous
`chemotherapy and disease progression on HER2-targeted
`therapy
`T-DM1 3.6 mg/kg q3w for HER2-positive MBC after previous
`exposure to an anthracycline, a taxane, capecitabine and 2
`HER2-directed therapies in the metastatic setting
`T-DM1 3.6 mg/kg q3w ⫹ pertuzumab 840 mg loading dose
`then 420 mg q3w, for HER2⫹ MBC first-line treatment or
`after previous chemotherapy and HER2-directed therapy
`T-DM1 3.6 mg/kg q3w
`Or
`Trastuzumab 8 mg/kg loading dose then 6 mg/kg q3w ⫹
`docetaxel 75 mg/m2 or 100 mg/m2 q3w
`
`Number of
`Patients
`
`24
`
`112
`
`110
`
`67
`
`67
`70
`
`ORR, Number of
`Patients (%)
`
`6/24 (25.0)
`
`29 (26)
`
`38 (34.5)
`
`First line: 9/22 (41),
`Relapsed: 19/45 (42)
`
`32 (47.8)
`29 (41.4)
`
`Abbreviations: MBC, metastatic breast cancer; MTD, maximum tolerated dose; NR, not reported; ORR, objective response rate; q3w, every 3 weeks.
`
`development of DM1 (derivative of maytansine 1). DM1
`possesses in vitro cytotoxicity that is 10 to 200 times greater
`than that of other tubulin inhibitors, such as taxanes and
`vinca alkaloids. A suitable linker is critical to this process,
`and it must have a higher degree of stability in the circula-
`tion and allow efficient release of the potent cytotoxic agent
`once inside the tumor cell. The cytotoxic drug DM1 is
`conjugated to lysine residues of trastuzumab using a unique
`hetero-bifunctional
`reagent,
`N-succinimidyl
`4-(N-
`maleimidomethyl) cyclohexane-1-carboxylate (SMCC), in a
`two-step process. Trastuzumab is initially reacted with
`SMCC to form trastuzuamb-MCC. Next, T-MCC is then
`conjugated to DM1 to make T-DM1. The thioether linker
`was developed to provide a bond between trastuzumab and
`
`KEY POINTS
`● The therapeutic index for treating patients can be
`improved by the use of monoclonal antibodies to
`deliver potent cytotoxic agents to cancer cells while
`minimizing exposure of the agents to normal tissues.
`● The use of antibody-drug conjugates (ADCs) is one
`such strategy; a cytotoxic drug connected by a chem-
`ical linker to a monoclonal antibody specific for a
`tumor antigen is the basic makeup of an ADC.
`● Trastuzumab emtansine (T–DM1) is a novel ADC
`that combines the humanized antibody trastuzumab
`and the potent antimicrotubule agent T-DM1 (deriv-
`ative of maytansine) with use of a unique and highly
`stable linker.
`● In phase II studies of patients in whom metastatic
`breast cancer previously progressed during multiple
`HER2-directed therapies, T-DM1 was associated
`with response rates of 26% to 34% and was reason-
`ably well tolerated.
`● The results of phase II studies suggest T-DM1 can
`improve outcomes for patients with cancers that are
`resistant to trastuzumab-based combinations, and
`phase III trials are underway.
`
`160
`
`DM1 that is more stable than hydrazone or disulfide linkers.
`The therapeutic index of DM1 is thus enhanced by minimiz-
`ing systemic exposure to free DM1 and improving exposure
`to T-DM1. Before development in the clinic, the conjugate
`was extensively studied in preclinical models. The effective-
`ness of T-DM1 was established in three murine models of
`HER2-expressing human breast carcinoma. In contrast,
`little activity was seen in the normal human cells or breast
`cancer cells not overexpressing HER2, demonstrating the
`specificity of the ADC.1
`T-DM1 was the first HER2-targeted ADC with this unique
`SMCC linker to be studied in patients. A phase I trial in
`patients with HER2-positive breast cancer that had pro-
`gressed during prior trastuzumab-based therapy deter-
`mined a maximum tolerated dose of 3.6 mg per kilogram,
`delivered every 3 weeks.2 The dose-limiting toxicity was
`grade 4 thrombocytopenia that was rapidly reversible and
`not associated with clinically meaningful bleeding events.
`No cardiac events or left ventricular ejection fraction de-
`clines were noted. In addition, no alopecia greater than
`grade 1 was noted, further evidence for the lack of systemic
`toxicity.
`Six of the 24 patients had an objective partial response.
`All patients had previously been treated with trastuzumab,
`with a median exposure of approximately 2 years, as well as
`microtubulin inhibiting agents. Of the six responses, four
`occurred in the nine patients treated at the maximum
`tolerated dose. The trial pharmacokinetics demonstrated
`peak free (unconjugated) DM1 plasma concentrations imme-
`diately after dosing which were low on all time points,
`suggesting that any systemic toxicity was unrelated to
`circulating unconjugated DM1. Weekly dosing was also
`explored and was both active and well tolerated, but it
`showed no particular advantage from either a dose intensity
`or density standpoint.
`After these results, T-DM1 was studied in phase II trials
`of patients with HER2-positive metastatic breast cancer at
`the recommended dose of 3.6 mg per kilogram every 3 weeks.
`In a study of 112 patients who had disease progression
`during HER2-directed therapy, T-DM1 was associated with
`an objective response rate of 26% based on independent
`review, and progression-free survival of 4.6 months.3 The
`
`IMMUNOGEN 2188, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`T-DM1 AND THERAPEUTIC ANTIBODIES
`
`agent was well tolerated, with most toxicities being grade 1
`and 2, and no bleeding episodes or cardiac events.
`A second trial was conducted in 110 patients with HER2-
`positive metastatic breast cancer who had received prior
`treatment with an anthracycline, a taxane, capecitabine,
`trastuzumab, and lapatinib (and had had disease progres-
`sion during treatment with the most recent regimen).4
`T-DM1 demonstrated an objective response rate of 34.5%
`and a median progression-free survival of 6.9 months,
`based on independent reviews. The agent was again well
`tolerated in this heavily pretreated population, and no
`cardiac toxicity signals were noted. During these phase II
`trials, central review for HER2-positivity was required.
`Response rates were higher amongpatients with centrally
`verified HER2-positive tumors, whereas few responses were
`noted among patients with tumors that tested negatively on
`central review, confirming the relationship with drug activ-
`ity.
`Additional trials are now being done to evaluat T-DM1
`asfirst-line treatment. One such trial involved 137 patients
`who received either T-DM1 or standard dosing of trastu-
`zumab every 3 weeks plus docetaxel 75 or 100 mg/m2 every
`3 weeks.5 Objective response rates were comparable, at 48%
`and 41%, respectively. Of note, grade 3 or 4 adverse events
`were substantially reduced in the T-DM1 arm (37% com-
`pared with 75%). The selective activity and proposed reduc-
`tion in side effects were demonstrated in this randomized
`phase II trial.
`Two randomized multicenter phase III trials are ongoing
`to evaluate the role of T-DM1 in earlier lines of therapy.
`MARIANNE is designed to compare the efficacy and safety
`of single-agent T-DM1, alone or in combination with pertu-
`
`Author’s Disclosures of Potential Conflicts of Interest
`
`zumab, with the standard trastuzumab plus a taxane (pac-
`litaxel or docetaxel). The exposure to pertuzumab is blinded,
`and the standard arm is open-label.6
`Another study, EMILIA, is an open-label trial in which
`T-DM1 is being compared with the U.S. Food and Drug
`Administration (FDA)-approved regimen of capecitabine
`plus lapatinib in patients previously treated with both a
`taxane and trastuzumab. Interestingly, in another trial,
`T-DM1 is being compared with physician’s choice of treat-
`ment in patients who had disease progression after multiple
`prior regimens. Trastuzumab alone or with chemotherapy is
`allowed in the physician’s-choice arm.
`
`Conclusion
`
`The discovery of HER2 gene amplification and the subse-
`quent development of trastuzumab has markedly improved
`the prognosis for patients with HER2-positive breast cancer.
`Unfortunately, not all patients have a response to trastu-
`zumab, and disease will progress in most patients with
`metastatic HER2-positive disease. T-DM1 meets the criteria
`for a successful ADC by combining the targeted effect of
`trastuzumab with the cytotoxic potency of DM1 using a
`stable linker and minimizing systemic toxicity. In addition,
`other tumor histologies, such as gastrointestinal cancers
`that are HER2-positive may be sensitive to this agent. The
`results of phase II studies suggest T-DM1 can improve
`outcomes for patients with cancers that are resistant to
`trastuzumab-based combinations. An aggressive portfolio of
`phase II and III clinical trials will help determine the role
`of T-DM1 in earlier lines of therapy or with combinations of
`other targeted agents.
`
`Employment or
`Leadership
`Positions
`
`Author
`Howard A. Burris III*
`
`*No relevant relationships to disclose.
`
`Consultant or
`Advisory Role
`
`Stock
`Ownership
`
`Honoraria
`
`Research
`Funding
`
`Expert
`Testimony
`
`Other
`Remuneration
`
`REFERENCES
`1. Burris HA. Trastuzumab emtansine: A novel antibody-drug conjugate
`anthracycline, a taxane, capecitabine, lapatinib, and trastuzumab. Paper
`for HER2-positive breast cancer. Expert Opin Bio Ther. 2011;11:807-819.
`presented at: the European Society for Medical Oncology. October 10, 2010,
`2. Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-
`Milan, Italy, abstract 277O.
`DM1, a HER2 antibody-drug conjugate, given every 3 weeks to patients
`5. Perez EA, Dirix L, Kocsis J, et al. Efficacy and safety of trastuzumab-
`with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28:2698-
`DM1 versus trastuzumab plus docetaxel in HER2-positive metastatic breast
`2704.
`cancer patients with no prior chemotherapy for metastatic disease: Prelimi-
`3. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody
`nary results of a randomized, multicenter open-label phase 2 (TDM4450g).
`drug conjugate trastuzumab-DM1 for the treatment of human epidermal
`Ann Oncol. 2010; 21 Suppl 8:LBA3.
`growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-
`6. A study of trastuzumab-MCC-DM1 (T-DM1) in combination with pertu-
`directed therapy. J Clin Oncol. 2011;29:398-405.
`zumab administered to patients with HER2-positive locally advanced or
`4. Krop I, Lorusso P, Miller KD, et al. A phase II study of trastuzumab-
`metastatic breast cancer who have previously received trastuzumab. http://
`www.clinicaltrials.gov/ct2/show/NCT00875979?term⫽t-dm1⫹4373&rank⫽1.
`DM1 (T-DM1), a novel HER2 antibody-drug conjugate, in patients with
`HER2-positive metastatic breast cancer who were previously treated with an
`Accessed August 3, 2010.
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`IMMUNOGEN 2188, pg. 3
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`IPR2014-00676
`
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