Breast cancer is the most common cancer in US women, affecting approximately 1 in
8 women over the course of a
lifetime. Nearly 40,000 women die of breast cancer every year (Siegel, Naishadham,
& Jemal, 2013). In the past decade,
we have come to understand that breast cancer is a heterogeneous disease, comprising
subtypes that are defined by
gene expression profiling (Perou et al., 2000). Treatment choices such as chemotherapy,
endocrine therapy, and
therapies targeted toward specific genetic alterations have resulted in improved survival.
Approximately 25% of all breast cancers are classified as HER2 positive, in which
there is overexpression of the HER2
protein (as measured by immunohistochemistry) and/or amplification of the HER2 gene
(determined by fluorescence in
situ hybridization). HER2 activation triggers an intracellular signaling cascade,
which results in cell proliferation, survival,
invasion, and angiogenesis. HER2-positive breast cancers have an aggressive phenotype.
However, with the advent of
HER2-targeted therapy, the natural history of HER2-positive breast cancer has been
dramatically improved (Ferretti,
Fabi, Felici, & Papaldo, 2010; Dawood, Broglio, Buzdar, Hortobagyi, & Giordano, 2010).
HER2-Directed Therapies
Trastuzumab (Herceptin) is a monoclonal antibody that targets the HER2 receptor tyrosine
kinase. In a study of 469
patients with meta-static breast cancer randomized to receive standard chemotherapy
vs. chemotherapy plus
trastuzumab, the group receiving trastuzumab demonstrated response rates of 50% vs.
32% and median survival times
of 25.1 vs. 20.3 months, respectively (Slamon et al., 2001). Trastuzumab was approved
by the US Food and Drug
Administration (FDA) for use in patients with metastatic breast cancer in 1998. It
was subsequently evaluated in the
nonmetastatic setting and showed striking benefits in relapse-free survival and overall
survival (OS), leading to its
approved use in patients with early-stage HER2-positive breast cancer in 2006 (Romond
et al., 2005; Piccart-Gebhart,
2005).
Despite the benefits of adjuvant trastuzumab for HER2-positive breast cancer, recurrences
do occur. For these
patients, resistance to trastuzumab ultimately develops, and they eventually succumb
to their disease. Therefore, there
was a need to develop other drugs for patients who develop trastuzumab resistance.
Lapatinib (Tykerb) was the second HER2-directed agent approved by the FDA for use
in metastatic breast cancer. It is
a small-molecule tyrosine kinase inhibitor that targets the intracellular portion
of the HER2 receptor. Its approval was
largely based on a study of patients with advanced breast cancer whose disease had
progressed on an anthracycline, a
taxane, and trastuzumab; patients were randomized to receive either capecitabine or
capecitabine with lapatinib. The
addition of lapatinib improved median time to progression from 4.4 to 8.4 months,
and the combination was approved
by the FDA in March 2007 (Geyer et al., 2006). Since that time, studies evaluating
the use of trastuzumab with varying
chemotherapeutic agents have been performed, and it has been incorporated into widespread
use (Slamon et al.,
2011). The use of lapatinib in combination with endocrine therapy has also been evaluated
and is approved for use in
metastatic HER2-positive breast cancer.
In June 2012, pertuzumab (Perjeta), a new monoclonal antibody that binds and blocks
the action of the HER2
receptor in a manner complementary to that of trastuzumab, was approved for use in
first-line metastatic HER2-
positive breast cancer in combination with taxane chemotherapy and trastuzumab. This
approval was based on a
demonstrable benefit in progression-free survival (PFS; 18.5 vs. 12.4 months) when
pertuzumab was added to docetaxel
and trastuzumab (Baselga et al., 2012).
The newest agent in the armamentarium against HER2-positive breast cancer is ado-trastuzumab
emtansine
(Kadcyla), also known as T-DM1, which earned FDA approval in February 2013 for metastatic
HER2-positive breast
cancer that has progressed on a trastuzumab-containing regimen (Genentech, 2013).
See the Table on the next page for
a summary of key information.
Table 1
Table. Ado-Trastuzumab Emtansine: Key Information
Mechanism of Action
Ado-trastuzumab emtansine is described as an antibody drug conjugate (ADC). It contains
trastuzumab attached to
a chemotherapy molecule (DM1) by a stable linker molecule. Trastuzumab is a humanized,
anti-HER2 IgG1 antibody.
The DM1 chemotherapy molecule is a maytansine derivative that was studied in the 1970s
at the National Cancer
Institute. Development was halted at that time due to unacceptable toxicity in human
trials. However, in ado-
trastuzumab emtansine, a thioether linker (MCC) stabilizes the compound so that the
DM1 chemotherapy molecule is
targeted to the HER2+ cancer cell. The chemotherapy is internalized and released into
that cell only after it is attached
to the HER2+ cell. Therefore, the cancer cells are destroyed, and surrounding normal
tissue is spared the toxicity of the
chemotherapy.
Ado-trastuzumab emtansine demonstrates mechanisms of action of both trastuzumab and
DM1. In vitro, similar to
trastuzumab, it inhibits HER2 receptor signaling and enhances antibody-dependent cell-mediated
cytotoxicity. Ado-
trastuzumab emtansine, like trastuzumab, inhibits shedding of the HER2 extracellular
domain, which is a known
mechanism of resistance to trastuzumab. The DM1 chemotherapy molecule, upon internalization
and release into the
cancer cell, inhibits microtubule function, thereby interfering with progression through
the cell cycle (Baselga et al.,
2012).
Clinical Studies
A phase I, multicenter, open-label, dose-escalation study of single-agent ado-trastuzumab
emtansine was initiated
to assess its safety, tolerability, and pharmacokinetics in patients with HER2-positive
metastatic breast cancer who had
previously received trastuzumab (Krop et al., 2010).
Twenty-four patients were treated at doses ranging from 0.3 to 4.8 mg/kg. In this
study, 3.6 mg/kg was identified as
the maximum tolerated dose (MTD). The dose-limiting toxicity was thrombocytopenia,
yet it was usually mild (grade 1
or 2) and rapidly reversible upon discontinuation of therapy. Platelet count usually
dropped starting 1 day after ado-
trastuzumab emtansine administration, with a nadir around day 8 and recovery by day
15. There were no bleeding
events that required transfusion or any other intervention.
Overall, the most commonly reported adverse events (AEs) were thrombocytopenia (54.2%),
elevated
transaminases (41.7%), fatigue (37.5%), anemia (29.2%), and nausea (25.0%). No patients
experienced grade > 1
nausea, vomiting, alopecia, or neuropathy. The overall response rate (ORR) was 44%
in the 9 patients with measurable
disease treated at the MTD. The clinical benefit rate (CBR) was 73% (ORR + stable
disease) among the 15 patients
treated at the MTD. The median duration of treatment was 238 days for these 15 patients.
Based on the favorable phase I safety and efficacy profile, the clinical development
of ado-trastuzumab emtansine
continued. A phase II, open-label, single-arm study of ado-trastuzumab emtansine (TDM4374g)
included 110 patients
who had previously been treated with trastuzumab, lapatinib, an anthracycline, a taxane,
and capecitabine. The
primary objectives were ORR and safety. On average, patients had been treated for
metastatic breast cancer with seven
prior agents. The ORR was 34.5% and the CBR was 48.2%. The median PFS was 6.9 months
in this heavily pretreated
group of patients (Krop et al., 2012). In another phase II, open-label, single-arm
study of ado-trastuzumab emtansine
(TDM4258g) that included 112 patients, ORR was 26% and median PFS was 4.6 months (Burris
et al., 2011).
The EMILIA study was a phase III, randomized, multicenter, open-label trial of ado-trastuzumab
emtansine vs.
capecitabine plus lapatinib in 991 women with metastatic HER2-positive breast cancer
who progressed on or within 6
months of having received trastuzumab and who had received taxane chemotherapy (Verma
et al., 2012). Patients were
randomly allocated (1:1) to receive ado-trastuzumab emtansine 3.6 mg/kg once every
21 days or oral lapatinib 1,250
mg/day once daily plus oral capecitabine 1,000 mg/m2 twice daily for 14 of every 21
days. The primary endpoints
were PFS and OS. A total of 88% of the patients had received prior systemic treatment
in the metastatic setting; 12% of
the patients had prior treatment only in the neoadjuvant or adjuvant setting with
disease relapse within 6 months.
Patients received a median of three systemic agents for metastatic disease.
Median PFS was 9.6 months in the ado-trastuzumab emtansine group vs. 6.4 months in
the lapatinib plus
capecitabine group. The hazard ratio for PFS was 0.65 with ado-trastuzumab emtansine
vs. capecitabine plus lapatinib.
Median duration of survival was 30.9 months in the ado-trastuzumab emtansine group
vs. 25.1 months in the lapatinib
plus capecitabine group (Verma et al., 2010).
More recently, results from TDM4450g, a phase II, multicenter, open-label study of
ado-trastuzumab emtansine in
the first-line setting, were published. This was the first trial to directly compare
ado-trastuzumab emtansine with a
standard trastuzumab plus chemotherapy regimen in patients who had not received treatment
for metastatic disease.
In this trial, 137 patients with advanced HER2-positive breast cancer were randomized
in a 1:1 ratio to receive ado-
trastuzumab emtansine 3.6 mg/kg IV once every 3 weeks vs. trastuzumab 8 mg/kg loading
dose then 6 mg/kg IV and
docetaxel 75 or 100 mg/m2 (HT) at the investigator’s discretion, once every 3 weeks.
The primary endpoint was PFS
and safety. Secondary endpoints included OS, ORR, duration of response (DOR), CBR,
and quality of life (QOL). Of note,
only 27.1% and 17.9% of patients in the ado-trastuzumab emtansine and HT groups, respectively,
had received prior
trastuzumab in the adjuvant or neoadjuvant setting. The ado-trastuzumab emtansine
group demonstrated a median
PFS of 14.2 months compared with 9.2 months in the HT group. The hazard ratio for
PFS was 0.59 with ado-
trastuzumab emtansine vs. HT. The ORR and CBR in the ado-trastuzumab emtansine group
was 64.2% vs. 58% in the HT
group (Hurvitz et al., 2013).
Adverse Events
In the single-arm, phase II study TDM4374g, fatigue (61.8%), nausea (37.3%), and thrombocytopenia
(38.2%) were
among the most common adverse events (AEs) seen. Thrombocytopenia (9.1%), fatigue
(4.5%), and cellulitis (3.6%)
were the most common grade 3 adverse events. In TDM4258g, the other single-arm phase
II study, the most frequent
grade 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%; Krop
et al., 2012).
In the EMILIA study, grade 3 adverse events were more common with capecitabine plus
lapatinib vs. ado-
trastuzumab emtansine (57% vs. 40.8%). The most commonly reported grade 3 AEs in the
capecitabine plus lapatinib
group were diarrhea (20.7%) and palmar-plantar erythrodysesthesia (16.4%). Thrombocytopenia
and elevated serum
concentrations of aspartate transaminase (AST) and alanine transaminase (ALT) were
the most commonly reported
grade 3 adverse events in the ado-trastuzumab emtansine group, affecting 12.9%, 4.3%,
and 2.9% of patients,
respectively.
While thrombocytopenia is a common side effect of ado-trastuzumab emtansine, it led
to discontinuation of
therapy in only 2% of patients in the EMILIA study. Thrombocytopenia was usually seen
in the first two cycles of
therapy, responded to dose reductions, and was rarely associated with significant
bleeding. The rate of grade 3 or 4
bleeding events was low overall in the ado-trastuzumab emtansine group (1.4%, vs.
0.8% in the capecitabine plus
lapatinib group).
In the phase II TDM4450g trial, treatment with ado-trastuzumab emtansine also resulted
in fewer grade ≥ 3 adverse
events than with the comparator—in that case, HT (AEs: 46.4% vs. 90.9%). Grade 4 AEs
occurred in 57.6% of patients
receiving HT vs. 5.8% in patients receiving ado-trastuzumab emtansine. A total of
40.9% of patients in the HT group
experienced AEs leading to treatment discontinuation (of either drug) vs. 7.2% in
the ado-trastuzumab emtansine
group. In the HT group, the most common AEs of any grade were alopecia, neutropenia,
diarrhea, and fatigue. The most
common AEs in the ado-trastuzumab emtansine group were fatigue, nausea, increase in
serum AST, fever, and
headache. A notable difference in side-effect profile between ado-trastuzumab emtansine
and taxane-based
chemotherapy with trastuzumab is the lack of alopecia seen with ado-trastuzumab emtansine.
Consistent with the AE
profile of both study arms, QOL assessments in this study favored ado-trastuzumab
emtansine over HT (Hurvitz et al.,
2013).
Cardiotoxicity
Studies of therapy with ado-trastuzumab emtansine took special note of cardiac events
due to the known potential
for trastuzumab-associated cardiotoxicity. With trastuzumab, this cardiotoxicity,
manifest by decreases in left
ventricular ejection fraction (LVEF), is usually asymptomatic and readily reversible.
Additionally, trastuzumab-associated
cardiotoxicity is worsened in patients receiving concurrent or prior anthracycline
therapy (Romond et al., 2012).
In a single-arm phase II study (TDM4374g), at a median follow-up of 17.4 months, no
left ventricular ejection
fraction decline to ≤ 45% or symptomatic congestive heart failure was observed, and
no patients discontinued
treatment because of cardiotoxicity. Similarly, in TDM4258g, there was no dose-limiting
cardiotoxicity observed (Burris
et al., 2011). In the randomized TDM4450g trial, there were no clinically significant
cardiac events in either group. At a
median follow-up of 23 months, 3 patients—1 in the ado-trastuzumab emtansine group
and 2 in the HT group—had an
asymptomatic decline in LVEF to ≤ 40% (Hurvitz et al., 2013).
Primarily because it contains trastuzumab, the FDA-approved prescribing information
recommends that all patients
treated with ado-trastuzumab emtansine have a baseline LVEF assessment at baseline
and at regular intervals (e.g.,
every 3 months) during treatment (Genentech, 2013). At least temporary discontinuation
of therapy is recommended if
the LVEF falls to < 40% or is 40% to 45% with a 10% absolute decrease below the pretreatment
value. In this case, LVEF
should be rechecked 3 weeks later. If it has not improved or worsened, then permanent
discontinuation is
recommended. However, if there is improvement, it is acceptable to restart ado-trastuzumab
emtansine with close
cardiac monitoring.
Summary
In a phase III study of patients with HER2-positive metastatic breast cancer previously
treated with trastuzumab,
ado-trastuzumab emtansine resulted in a 35% reduction in the risk of progressive disease
compared with standard
treatment (Verma et al., 2012). In the phase II trial of ado-trastuzumab emtansine
used in the first-line setting, there
was a 41% reduction in risk of progressive disease compared with a standard therapy
(Hurvitz et al., 2013). Remarkably,
these improvements in efficacy came with a decrease in toxicity vs. the comparator
arm.
Ado-trastuzumab emtansine is an effective, tolerable, IV, "smart" therapy, now approved
for use in patients with
HER2-positive breast cancer who have progressed on or within 6 months of a trastuzumab-containing
treatment
regimen. Ongoing studies are evaluating its use as first-line therapy for metastatic
disease, in combination with other
HER2-directed therapies and in the neoadjuvant setting. The use of ado-trastuzumab
emtansine may be expanded if
these trials demonstrate safety and efficacy in these studies. Therefore, the use
of ado-trastuzumab emtansine is
expected to increase dramatically. In light of this, it is essential for the oncology
advanced practitioner to understand its
mechanism of action, efficacy, and adverse event profile.