Commentary
`
`T-DM1 adds to the armamentarium for
`targeting advanced HER2-positive breast
`cancer
`
`Maria Cristina Figueroa-Magalhães, MD, and Vered Stearns, MD
`The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
`
`The Food and Drug Administration recently ap-
`
`proved trastuzumab emtansine (T-DM1) as a
`single agent for patients with human epidermal
`growth factor receptor 2-positive metastatic breast cancer
`who have previously received trastuzumab and a taxane.1
`T-DM1 is a sophisticated antibody–drug conjugate con-
`sisting of the cytotoxic agent emtansine (DM1), which
`targets tubulin and suppressed microtubule dynamics, and
`the monoclonal antibody, trastuzumab. The agent, which
`is conjugated by a stable linker, is transmitted to malig-
`nant tissues while sparing normal tissues.2
`The approval was based on findings in the EMILIA
`trial, an instrumental phase 3 trial that is expected to
`change the management and outcomes of women with
`HER2-positive breast cancer.3 A total of 991 patients
`with HER2-positive advanced breast cancer who had
`previously received trastuzumab and a taxane were ran-
`domly assigned to T-DM1 (3.6 mg/kg IV) every 21 days
`or a combination of oral capecitabine (1,000 mg/m2 every
`12 hours on days 1-14 every 3 weeks) plus oral lapatinib
`(1,250 mg/day) until progressive disease or unmanageable
`toxicity. Women in the T-DM1 arm enjoyed superior
`median progression-free survival (PFS) compared with
`those in the capecitabine-plus-lapatinib arm (9.6 vs. 6.4
`months, respectively, hazard ratio [HR], 0.65; P ⬍ .001)
`and a higher objective response rate (43.6% vs. 30.8%,
`respectively; P ⬍ .001). However, the most striking result
`was a substantial improvement in median overall survival
`of 30.9 months among women who were treated with
`T-DM1, compared with 25.1 months in those treated
`with the capecitabine–lapatinib combination, with a re-
`duction of 32% in risk of death (HR, 0.68; P ⬍ .001).
`Perhaps as important was the finding that the patients
`
`Correspondence Vered Stearns, MD, The Sidney Kimmel Compre-
`hensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer
`Research Building, 1650 Orleans Street, Room 144, Baltimore, MD
`21231-1000 (vstearn1@jhmi.edu).
`Disclosures The authors have no disclosures.
`
`See Community Translations on page 71
`
`who were treated with T-DM1 had better tolerability of
`the agent than did those who received the capecitabine–
`lapatinib combination (grade 3 or 4 adverse events in 41%
`and 57%, respectively). The most common grade 3 or 4
`events with T-DM1 were thrombocytopenia (12.9% of
`patients) and elevated levels of the liver transaminases
`(2.9% for alanine aminotransferase; 4.3% for aspartate
`aminotransferase). The survival benefits observed in
`EMILIA, despite prior treatment with trastuzumab and
`taxane, were unprecedented. We join the oncology com-
`munity and our patients in the excitement and hope that
`T-DM1 and other designer agents will help achieve du-
`rable responses with limited side effects in women with
`HER2-positive metastatic disease.
`The challenge ahead is to better define the role of
`T-DM1 in the metastatic and adjuvant settings. The
`ongoing phase 3 MARIANNE trial will evaluate the
`efficacy and safety of the dual HER2 blockade using
`T-DM1-plus-pertuzumab or T-DM1-plus-placebo as
`first-line therapy in HER2-postive metastatic breast can-
`cer compared with trastuzumab plus a taxane.4 The
`TH3RESA study, another phase 3 trial, will provide data
`on the efficacy and safety of T-DM1 in heavily pretreated
`patients with HER2-positive disease.5
`T-DM1 is also under extensive investigation in the ad-
`juvant and neoadjuvant settings. In the ongoing ADAPT
`international study, pathological complete response (pCR)
`rates
`in patients with HER2-positive and hormone
`receptor-positive breast cancer who have been treated with
`preoperative T-DM1 with or without standard endocrine
`therapy and those who have been treated with trastuzumab
`with endocrine therapy.6 Another trial that is currently un-
`derway aims to assess the clinical safety and feasibility of
`T-DM1 after completion of anthracycline-based chemother-
`apy, as an adjuvant or neoadjuvant therapy for patients with
`early stage HER2-positive breast cancer.7
`
`Commun Oncol 2013;10:69-70
`
`© 2013 Frontline Medical Communications
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`March 2013 䡲 COMMUNITY ONCOLOGY 69
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`Commentary
`
`Other studies will help define the patient populations
`that are most likely to benefit from the agent and address
`rational combinations. An update of the CLEOPATRA
`trial, which compared treatment with trastuzumab and
`docetaxel with or without pertuzumab, revealed that mu-
`tations in PI3K were associated with poor prognosis in
`both treatment arms, although PFS continued to be su-
`perior in the pertuzumab arm. A benefit in the median
`overall survival was observed in the pertuzumab-treated
`group compared with the control group regardless of
`PI3K status (wild-type or mutated), however, the benefit
`was more substantial in the patients with wild-type PI3K
`compared with those harboring a mutation (21.8 vs 13.8
`months, respectively).8 Moreover, novel agents targeting
`HER2 are under investigation in women with metastatic
`HER2-positive disease, including afatinib, an oral irre-
`versible dual inhibitor of HER1 and HER2, and nera-
`tinib, an oral drug with activity against HER1, HER2,
`and HER4.
`Finally, women with metastatic HER2-positive breast
`cancer are at a higher risk for brain metastases.9 Although
`they can live for several years with advanced disease and
`brain metastases, the treatment options for brain metas-
`tases are more limited. Local approaches as well as sys-
`temic small-molecule agents such as lapatinib that can
`cross the blood–brain barrier should be considered in
`women with brain metastases. Ongoing studies aim to
`better assess susceptibility to early brain dissemination
`and to investigate new agents.
`In summary, the results from EMILIA have dem-
`onstrated a substantial improvement in survival out-
`comes and tolerability with T-DM1 in patients who
`have been previously exposed to other lines of treat-
`ment in the HER2-positive metastatic setting com-
`pared with capecitabine–lapatinib in the second-line
`setting. The FDA’s approval of T-DM1 extends the
`range of available therapeutic options for this tumor
`subtype. We await further studies that evaluate the role
`
`of T-DM1 in the first-line and neoadjuvant and adjuvant
`settings. We also expect additional knowledge regarding
`rational T-DM1-combinations, novel agents, and predictive
`biomarkers of response.
`
`References
`1. FDA approves new treatment for late-stage breast cancer. http://
`www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm
`340704.htm. Accessed March 1, 2013.
`2. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-
`positive breast cancer with trastuzumab-DM1, an antibody-
`cytotoxic drug conjugate. Cancer Res. 2008;68:9280-9290.
`3. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for
`HER2-positive advanced breast cancer. N Engl J Med. 2012;
`367:1783-1791.
`4. Ellis PA, Barrios CH, Im Y, et al. MARIANNE: A phase III,
`randomized study of trastuzumab-DM1 (T-DM1) with or with-
`out pertuzumab (P) compared with trastuzumab (H) plus taxane
`for first-line treatment of HER2-positive, progressive, or recurrent
`locally advanced or metastatic breast cancer (MBC) [ASCO
`abstract TPS102]. J Clin Oncol. 2011;29(suppl).
`5. National Institutes of Health. A study of trastuzumab emtansine in
`comparison with treatment of physician’s choice in patients with
`HER2-positive breast cancer who have received at least two prior
`regimens of HER2-directed therapy
`(TH3RESA). http://
`clinicaltrials.gov/show/NCT01419197. Updated July 6, 2012. Ac-
`cessed March 1, 2013.
`6. National Institutes of Health. A prospective, randomized multi-
`center, open-label
`comparison of preoperative
`trastuzumab
`emtansine (T-DM1) with or without standard endocrine therapy
`vs. trastuzumab with standard endocrine therapy given for twelve
`weeks in patients with operable HER2⫹/HR⫹ breast cancer
`within the ADAPT protocol.
`(ADAPT; T-DM1). http://
`clinicaltrials.gov/ct2/show/NCT01745965. Updated December 7,
`2012. Accessed March 1, 2013.
`7. National Institutes of Health. A study of trastuzumab emtansine
`(T-DM1) sequentially with anthracycline-based chemotherapy, as
`adjuvant or neoadjuvant therapy for patients with early stage
`HER2-positive
`breast
`cancer.
`http://clinicaltrials.gov/show/
`NCT01196052. Updated March 4, 2013. Accessed March 5,
`2013.
`8. Baselga J, Cortes J, Im SA, et al. Biomarker analyses in CLEOPATRA: a
`phase III, placebo-controlled study of pertuzumab in HER2-
`positive, first-line metastatic breast cancer (MBC) [San Antonio
`Breast Cancer Symposium abstract S5-1]. Cancer Res. 2012;
`72(suppl 3).
`9. Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin
`Cancer Res. 2007;13:1648-1655.
`
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`Community Translations
`
`Edited by Jame Abraham, MD
`
`Trastuzumab emtansine in advanced
`HER2-positive breast cancer
`Trastuzumab emtansine is an antibody⫺drug con-
`
`See Commentary on page 69
`
`What’s new, what’s important
`The development of antibody drug conjugates is a
`major advance in cancer treatment. Ado-trastuzumab
`emtansine, more commonly known as TDM-1, is the
`first ADC to be approved by the Food and Drug
`Administration for HER2/neu-positive patients who
`have progressed on prior therapy with trastuzumab.
`T-DM1 is an exciting development on many fronts.
`First, the concept and technology of combining a highly
`toxic drug (emtansine) with a targeted agent (trastuzumab)
`with a linker molecule will have a tremendous impact on
`future drug development. Second, and more importantly for
`many patients who progress on trastuzumab-containing
`regimens, this could be a highly viable option for improving
`progression free survival and improve overall survival for this
`population of patients. It is amazing to see that HER2-
`positive disease, which used to be considered an aggressive
`disease, has been redefined as a chronic disease in a short
`span of 10-12 years with the introduction of trastuzumab
`and other HER2- targeted agents.
`The dose of T-DM1 is 3.6 mg/kg infused (over 90
`minutes for the first dose, then over 30 minutes in sub-
`sequent treatments) every 3 weeks. Patients need to be
`carefully monitored for hepatic and cardiac toxicity.
`Thrombocytopenia is another T-DM1-associated side
`effect that was commonly seen in clinical trials. There
`should be appropriate dose reduction in the case of those
`toxicities. But overall, it is a well tolerated, extremely
`promising therapeutic option for patients with HER2-
`positive disease. Future clinical trials with T-DM1 in
`combination with pertuzumab and other PI3K inhibitors
`might provide us with more therapeutic options for pa-
`tients with trastuzumab-resistant disease.
`— Jame Abraham, MD
`
`jugate composed of trastuzumab (T) linked to a
`highly potent cytotoxic derivative of maytansine
`(DM1) by a stable linker (a nonreducible thioether,
`SMCC).1 DM1 binds to intracellular tubulin and pre-
`vents the assembly of microtubules, resulting in cell death.
`Trastuzumab targets the conjugate to the human epider-
`mal growth factor receptor 2 (HER2) protein and the
`stable linker releases the cytotoxic agent only when the
`compound is internalized through receptor endocytosis.
`Trastuzumab emtansine (T-DM1) has been in found to
`be active in trastuzumab- and lapatinib-resistant disease,
`as well as in trastuzumab-naïve tumors. The conjugate
`also seems to maintain the antitumor activity of trastu-
`zumab. Primary results of the phase 3 EMILIA trial that
`compared T-DM1 with capecitabine-plus-lapatinib in
`advanced HER2-positive breast cancer were reported at
`the 2012 American Society of Clinical Oncology meet-
`ing,2 with the findings indicating significant improvement
`in progression free survival (PFS) with the conjugate. It
`was on the basis of those findings that the Food and Drug
`Administration recently approved T-DM1 for the treat-
`ment of women with HER2-positive, late-stage meta-
`static breast cancer.
`In EMILIA, 991 patients with locally advanced or
`metastatic HER2-positive breast cancer who had previ-
`ously received trastuzumab and a taxane were randomized
`in open-label fashion to T-DM1 (3.6 mg/kg IV every 3
`weeks) alone or capecitabine (1,000 mg/m2 orally twice
`daily on days 1-14 every 3 weeks) plus lapatinib (1,250 mg
`orally daily) until progressive disease or unmanageable
`toxicity.2 The primary endpoint was PFS on independent
`review.
`Overall, 978 patients received the study treatments. Me-
`dian durations of follow-up were 12.9 months in the
`T-DM1 group and 12.4 months in the capecitabine⫺
`lapatinib group. Median PFS in the T-DM1 group was
`9.6 months,
`compared with 6.4 months
`in the
`capecitabine⫺lapatinib group, yielding a significant 35%
`reduction in risk for progression (hazard ratio [HR],
`0.650; 95% CI, 0.549-0.771; P ⬍ .0001).
`
`An interim overall survival (OS) analysis that was
`planned to occur at the time of the final PFS analysis had
`a prespecified efficacy boundary (HR, 0.617; P ⫽ .0003).
`At this interim analysis, median OS had not been reached
`in the T-DM1 group and it was 23.3 months in the
`
`Report prepared by Matt Stenger, MS.
`
`Commun Oncol 2013;10:71-73
`
`© 2013 Frontline Medical Communications
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`Volume 10/Number 3
`
`March 2013 䡲 COMMUNITY ONCOLOGY 71
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`IMMUNOGEN 2013, pg. 3
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`Community Translations
`
`How we treat metastatic HER2-positive breast cancer
`Until the Food and Drug Administration’s approvals of
`trastuzumab and cranial irradiation, about 21% of participants
`showed at least a 20% reduction in the brain tumor volume.4
`pertuzumab in 2012 and trastuzumab emtansine
`We would therefore consider lapatinib-based therapy in pa-
`(T-DM1) in early 2013, trastuzumab and lapatinib were
`tients with progressing brain metastases. Lapatinib can be
`the only commercially available targeted agents for the
`administered with a cytotoxic agent such as capecitabine, or in
`treatment of human epidermal growth factor receptor
`combination with trastuzumab in women with minimal dis-
`2-positive metastatic breast cancer. The anti-HER2
`tant metastases.
`agent is usually combined with a cytotoxic agent, or, in
`The approval of pertuzumab and T-DM1 presented new
`select women, with an aromatase inhibitor. Trastu-
`therapy options in the management of women with HER2-
`zumab and lapatinib can also be prescribed in combi-
`positive metastatic breast cancer. However, despite the im-
`nation. In women who are progressed on HER2-based
`pressive advances, most women will progress on available
`chemotherapy, clinicians would generally replace the
`therapies and succumb to their disease. We therefore strongly
`backbone while maintaining an anti-HER2 agent.
`recommend physicians and their patients consider participa-
`The history of metastatic HER2-positive tumors
`tion in clinical trials throughout the treatment continuum.
`has changed substantially in recent months. In the
`We anticipate that ongoing and future studies will help fur-
`CLEOPATRA trial, 808 patients with HER2-positive met-
`ther define the role of T-DM1 alone or in combination with
`astatic breast cancer were randomly assigned to first-line tras-
`tuzumab and docetaxel with or without pertuzumab.1 The
`other cytotoxic agents such as taxanes or with anti-HER2
`agents such as pertuzumab in the first-line treatment of met-
`primary endpoint, progression-free survival, was met with
`astatic disease or in the adjuvant or neo-adjuvant setting.
`significant improvement in median PFS in the dual anti-
`Women who have progressed after treatment with
`HER2 arm (18.5 vs. 12.4 months, respectively; hazard ratio
`[HR], 0.62; P ⬍ .001). In addition, the risk of death was
`pertuzumab-, trastuzumab-, T-DM1-, and lapatinib-based
`regimens should be considered for clinical trials with newer
`reduced by 46% favoring the dual HER2-blockade arm
`(HR, 0.64; P ⫽ .005). On the basis of the results from
`combinations, novel anti-HER2 agents such as neratinib or
`afatinib, or in studies in which anti-HER2 agents are com-
`CLEOPATRA, we would recommend trastuzumab, pertu-
`bined with PI3K inhibitors or other drugs that may reverse
`zumab, and docetaxel as first-line treatment for women with
`resistance.
`metastatic HER2-positive breast cancer.
`The recent additions to the treatment armamentarium
`In the EMILIA trial, T-DM1 was associated with sig-
`have helped redefine the natural history of metastatic HER2-
`nificant improvement in all primary endpoints compared with
`positive breast cancer. We are currently in uncharted territory,
`capecitabine-plus-lapatinib, including median PFS (9.6 vs.
`where women can live with the disease for many years and
`6.4 months, respectively; HR, 0.65; P ⬍ .001), and overall
`also expect an excellent quality of life.
`survival (30.9 vs. 25.1 months; HR, 0.68; P ⬍ .001).2 More
`importantly, T-DM1 was extremely well tolerated. On the
`— Maria Cristina Figueroa-Magalhães, MD, and
`basis of the EMILIA results and the recent approval of
`Vered Stearns, MD
`T-DM1, we recommend T-DM1 as second-line treatment
`in women with HER2-positive metastatic breast cancer.
`Lapatinib-based therapy should be considered in the third-
`line setting in women who progressed despite prior treatment
`with the trastuzumab, pertuzumab, and taxane combination,
`and T-DM1.
`Of note is that about 30% of women with HER2-positive
`tumors will develop brain metastasis.3 Lapatinib is a small
`molecule and is able to cross the blood–brain barrier. In a
`phase 2 study in patients who had been previously exposed to
`
`References
`1. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab
`plus docetaxel for metastatic breast cancer. N Engl J Med.
`2012;366:109-119.
`2. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for
`HER2-positive advanced breast cancer. N Engl J Med. 2012;
`367:1783-1791.
`3. Lin NU, Winer EP. Brain metastases: the HER2 paradigm.
`Clin Cancer Res. 2007;13:1648-1655.
`4. Lin NU, Diéras V, Paul D, et al. Multicenter phase II study of
`lapatinib in patients with brain metastases from HER2-
`positive breast cancer. Clin Cancer Res. 2009;15:1452-1459.
`
`capecitabine⫺lapatinib group, yielding an HR of 0.621
`(95% CI, 0.475-0.813; P ⫽ .0005). This difference did
`not cross the interim efficacy boundary and thus it cannot
`yet be concluded that T-DM1 treatment was associated
`with a significant OS benefit. OS rates were 84.7% (95% CI,
`
`80.8%-88.6%) in the T-DM1 group, compared with 77.0%
`in the capecitabine⫺lapatinib
`(95% CI, 72.4%-81.5%)
`group at 1 year (7.7% absolute difference), and 65.4%
`(95% CI, 58.7%-72.2%), compared with 47.5% (95% CI
`39.2%-55.9%) at 2 years (17.9% absolute difference).
`
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`Objective response was observed in 43.6% of T-DM1
`patients and in 30.8% of capecitabine⫺lapatinib patients.
`Median durations of response in patients with objective
`response were 12.6 months (95% CI, 8.4-20.8 months) in
`T-DM1 patients and 6.5 months (95% CI, 5.5-7.2
`months) in capecitabine⫺lapatinib patients.
`T-DM1 was well tolerated with no unexpected safety sig-
`nals. Adverse events of grade 3 or higher occurred in 40.8% of
`the T-DM1 group and 57.0% of the capecitabine⫺lapatinib
`group. The most common grade 3 or higher events in the
`T-DM1 group were thrombocytopenia (12.9% vs 0.2% in the
`capecitabine⫺lapatinib group), increased aspartate ami-
`notransferase levels (4.3% vs 0.8%), and increased alanine
`aminotransferase levels (2.9% vs 1.4%). The most common
`adverse events in the capecitabine⫺lapatinib group were
`diarrhea (20.7% vs 1.6% in the T-DM1 group), palmar
`plantar erythrodysesthesia (16.4% vs 0), and vomiting
`(4.5% vs 0.8%). Dose reduction was required in 16.3% of
`T-DM1 patients, and capecitabine and lapatinib dose
`reductions were required in 53.4% and 27.3%, respec-
`tively, of patients in the capecitabine⫺lapatinib group.
`
`T-DM1 is being evaluated in 2 additional phase 3
`trials in breast cancer — the MARIANNE trial, which
`compares T-DM1 with or without pertuzumab with tras-
`tuzumab plus a taxane in the first-line treatment of
`HER2-positive progressive or recurrent locally advanced
`or metastatic breast cancer; and the TH3RESA study,
`which compares T-DM1 with physician’s choice of treat-
`ment in patients with HER2-positive breast cancer who
`have received at least 2 prior regimens of HER2-directed
`therapy.
`
`References
`1. Hurvitz SA, Kakkar R. The potential for T-DM1 in human epider-
`mal growth factor receptor 2 positive metastatic breast cancer:
`latest evidence and ongoing studies. Ther Adv Med Oncol. 2012;4:
`235-245.
`2. Blackwell KL, Miles D, Gianni L, et al. Primary results from
`EMILIA, a phase III study of T-DM1 (T-DM1) versus capecit-
`abine (X) and lapatinib (L) in HER2-positive locally advanced or
`metastatic breast cancer (MBC) previously treated with trastu-
`zumab (T) and a taxane [ASCO abstract LBA1]. http://www.
`asco.org/ASCOv2/Meetings/Abstracts?&vmview⫽abst_detail_view
`&confID⫽114&abstractID⫽98675. Accessed February 26, 2013.
`
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