NcXHF

ANTIBODY-DRUG CONJUGATES AND T-DM1
regimens 32 and as fırst-line therapy for HER2MBC. 33-35 Lapatinib
is approved in combination with capecitabine for patients
whose tumors have progressed on trastuzumab-based therapy.
36 A combination of lapatinib and trastuzumab has been
shown to improve overall survival rates in patients with HER2
MBC who have experienced progression after multiple regimens.
37 For details regarding the management of HER2
MBC, please refer to the American Society of Clinical Oncology
(ASCO) clinical practice guideline. 38 On the basis of the results
of the EMILIA randomized trial described below, 39 the FDAapproved
T-DM1 (Kadcyla, Genentech, South San Francisco)
in February 2013 for the treatment of patients with HER2-
overexpressing MBC who have received prior treatment with
trastuzumab and a taxane.
T-DM1: PATIENT SELECTION
All clinical trials of T-DM1 used HER2 protein overexpression
and/or HER2 gene amplifıcation as one of the key inclusion
criteria. As with all other HER2-directed therapies,
T-DM1 appears to be effective only against HER2 tumors.
Ongoing clinical trials are evaluating the role of T-DM1 in
other solid tumors that either overexpress HER2 protein
and/or amplify the HER2 oncogene (e.g., gastric cancer) or
carry HER2 mutations (e.g., NCI-MATCH trial).
Phase I and phase II trials of T-DM1 showed objective responses
in patients with HER2 MBC with an acceptable
toxicity profıle, leading to the design of pivotal phase III, randomized
trial (EMILIA). In this study, patients with HER2-
positive MBC were randomly assigned to T-DM1 or to
capecitabine in combination with lapatinib. One of the key
inclusion criteria was prior trastuzumab- and taxane-based
chemotherapy. In this study, T-DM1 therapy improved response
rate, time to progression, and overall survival rate
compared with the combination of capecitabine and lapatinib.
39 In addition, T-DM1 was better tolerated than capecitabine
plus lapatinib.
The TH3RESA global trial was launched to determine the
effectiveness of T-DM1 in heavily pretreated patients (beyond
second line) who had HER2 MBC. In this study, more
than 600 patients with progressive MBC who had been previously
treated with trastuzumab and lapatinib were randomly
assigned to either T-DM1 or to a standard treatment
of the physician’s choice. The fınal results showed a 3-month
improvement in the median progression-free survival time
in the T-DM1 group. Response rates were improved in the
T-DM1 group (31% in T-DM1 vs. 9% in control group). 40 There
was a suggestion of an improved overall survival rate for patients
treated with T-DM1, although the data are not mature. Importantly,
T-DM1 was better tolerated than other standard chemotherapies.
On the basis of these results, T-DM1 is now
considered a new standard treatment after multiple lines of therapy
for patients who have HER2 MBC.
After obtaining regulatory approval for T-DM1 when progression
develops after trastuzumab treatment, the next logical
step was to evaluate the effıcacy of this novel ADC in the
fırst-line setting. The MARIANNE trial recruited more than
1,000 patients with HER2 MBC who had not received any
chemotherapy in the metastatic setting. In this study, patients
were randomly assigned to receive a taxane/trastuzumab,
T-DM1, or T-DM1 plus pertuzumab (Perjeta;
Genentech/Roche, South San Francisco, CA). However, this
trial did not include a comparator arm with taxane, trastuzumab,
and pertuzumab, which is the standard fırst-line
therapy for HER2 MBC. 33 Though detailed data have not
yet been shared, the sponsor recently announced that the
MARIANNE trial did not reach its primary endpoint. 41
On the basis of the encouraging results reported in patients
with metastatic disease, there is great interest in testing the
effıcacy of T-DM1 for early-stage breast cancer. An ongoing,
single-arm, phase II trial (NCT01196052) is evaluating the
effıcacy of T-DM1 in the adjuvant or neoadjuvant setting.
After completion of an anthracycline-based adjuvant/neoadjuvant
chemotherapy regimen (doxorubicin/cyclophosphamide
[AC] or 5-fluorouracil/epirubicin/cyclophosphamide
[FEC]), 153 patients will be treated with T-DM1 instead of
the conventional taxane/trastuzumab combination for 17 cycles.
In the ATEMPT trial (NCT01853748), 500 patients with
stage I breast cancer will be randomly assigned to T-DM1
versus paclitaxel plus trastuzumab. In the KAITLIN trial
(NCT01966471), 2,500 patients will be randomly assigned after
adjuvant AC/FEC to either a taxane, trastuzumab plus
pertuzumab, or T-DM1 plus pertuzumab. A randomized,
phase III trial (KATHERINE; NCT01772472) will evaluate
the effıcacy of T-DM1 in patients who have residual disease
after neoadjuvant, trastuzumab-containing regimens. In this
study, patients are randomly assigned to continuation of
trastuzumab (standard treatment) or to T-DM1. This study
has a planned enrollment of more than 1,400 patients. The
KRISTINE trial will examine the combination of docetaxel,
carboplatin, trastuzumab, and pertuzumab (one of the FDAapproved
neoadjuvant pertuzumab-containing regimens)
versus T-DM1 plus pertuzumab. All of these trials will provide
key data to integrate T-DM1 in the treatment of HER2
early-stage breast cancer.
MANAGEMENT OF T-DM1 OFF-TARGET TOXICITIES
It is important to understand common off-target toxicities
caused by T-DM1 and to manage them appropriately (Table 2).
Thrombocytopenia was reported in phase I and phase II
clinical trials of T-DM1. In the EMILIA trial, the incidence of
grade 3 or worse thrombocytopenia was 12.9% in the
T-DM1–treated group and was 0.2% in the lapatinib/capecitabine
group (overall incidence, 28% and 2.5%, respectively).
The mechanism of T-DM1–induced thrombocytopenia is
puzzling, because platelets do not overexpress HER2. Recent
data indicate that thrombocytopenia may be mediated in part
by DM1-induced impairment of megakaryocytic differentiation,
with a less-pronounced effect on mature megakaryocytes.
42 For most patients receiving T-DM1, thrombocytopenia
is asymptomatic and can be monitored without any changes
in treatment. Platelet counts should be monitored before ini-
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