PRIMARY OBJECTIVE:
I. To determine if the invasive disease-free survival (iDFS) with T-DM1 and tucatinib is
superior to the iDFS in the control arm (T-DM1 + placebo) when administered to high risk
patients with HER2-positive breast cancer and residual disease after neoadjuvant
HER2-directed therapy.
SECONDARY OBJECTIVES:
I. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1
alone (T-DM1 plus placebo) improves the following:
Ia. Breast cancer free survival (BCFS). Ib. Distant recurrence-free survival (DRFS). Ic.
Brain metastases-free survival (BMFS). Id. Overall survival (OS). II. To evaluate whether
treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus
placebo) reduces the incidence of brain metastases.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive T-DM1 intravenously (IV) over 30-90 minutes on day 1 and placebo
orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 14
cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days
1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 6 months
for 10 years.
Inclusion Criteria:
- HER2-positive status will be based on pretreatment biopsy material and defined as an
immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH)
according to current American Society of Clinical Oncology (ASCO) College of American
Pathologists (CAP) guidelines. Central testing is not required
* Known hormone receptor (HR) status as defined by ASCO/CAP guidelines. Hormone
receptor positive status can be determined by either known positive estrogen receptor
(ER) or known positive progesterone receptor (PR) status; hormone receptor negative
status must be determined by both known negative ER and known negative PR
- Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or
lymph nodes per the surgical pathology report are eligible; however, patients with HR+
HER2+ cancers must have node-positive residual disease per the surgical pathology
report in order to qualify for the study. The presence of residual invasive disease in
the breast is not mandatory for these patients. Note: The presence of micrometastases
in lymph nodes after preoperative therapy counts as residual disease, whereas the
presence of isolated tumor cells does not
- Patients with synchronous bilateral invasive disease are eligible provided both
lesions were confirmed to be HER2-positive, and at least one of the lesions meets the
criteria outlined above. Multifocal disease is allowed, as long as the largest
biopsied breast tumor was HER2-positive
- Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive
disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0
tumors are not eligible)
- Patients must have received neoadjuvant chemotherapy with one of the following
regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin
(TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P));
docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P));
fluorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab
(FAC-TH(P)), or
fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)).
Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is
acceptable
- Patients may have received =< 2 cycles of T-DM1 in the adjuvant setting. Note: These
patients will be randomized to receive a further 14 cycles of T-DM1 and
tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been
administered =< 5 weeks prior to registration
* N.B: Both of the following two criteria need to be met for the patient to be
eligible for this study
- An interval of no more than 12 weeks between the completion date of the last
definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither
given, breast surgical date) and the date of registration
- Patients must be registered on study within =< 180 days of the date of the most
recent definitive breast cancer surgery (not including reconstructive surgery)
- All systemic chemotherapy should have been completed preoperatively unless
participating in EA1181 (CompassHER2 pathologic complete response [pCR])
- Toxicities related to prior systemic treatment should have resolved or be at baseline,
apart from alopecia and peripheral neuropathy =< grade 1
- Adequate excision: surgical removal of all clinically evident disease in the breast
and lymph nodes as follows:
- Breast surgery: total mastectomy with no gross residual disease at the margin of
resection, or breast-conserving surgery with histologically negative margins of
excision
- For patients who undergo breast-conserving surgery, the margins of the resected
specimen must be histologically free of invasive tumor and ductal carcinoma in
situ (DCIS) as determined by the local pathologist. If pathologic examination
demonstrates tumor at the line of resection, additional operative procedures may
be performed to obtain clear margins. If tumor is still present at the resected
margin after re-excision(s), the patient must undergo total mastectomy to be
eligible. Patients with margins positive for classic lobular carcinoma in situ
(LCIS) are eligible without additional resection
- Lymph node surgery ** The axilla needs to be evaluated with either sentinel node
biopsy or axillary lymph node dissection. If patients have a sentinel lymph node
biopsy and sentinel nodes are negative, no further axillary treatment is
necessary. If patients have isolated tumor cells (ITCs) in the setting of
residual breast disease, at least one of the following is required: axillary
lymph node dissection (ALND) or planned nodal irradiation. If patients have
micro- or macro-metastatic nodal disease, an ALND is required
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Absolute neutrophil count (ANC) >= 1,000/mm^3
- Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted
to achieve eligibility)
- Platelet count >= 100,000/mm^3
- Creatinine =< 1.5 x upper limit of normal (ULN)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin within the
institutional normal range for patients with Gilbert's syndrome
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN)
- Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or
multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no
decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or,
if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55% after
completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated once up
to 3 weeks following the initial screening assessment to assess eligibility
Exclusion Criteria:
- Prior receipt of T-DM1 in the neoadjuvant setting is not allowed
- Systemic therapy must have consisted of at least 9 weeks of preoperative taxane
and trastuzumab (or Food and Drug Administration [FDA]-approved biosimilar) with
or without pertuzumab. Patients who have received at least 9 weeks of
preoperative taxane, pertuzumab and margetuximab are also eligible. Note:
Patients who complete at least nine of a planned twelve doses of weekly
paclitaxel, or three of a planned four doses of docetaxel, but discontinue
prematurely due to toxicity (i.e. peripheral neuropathy =< grade 1) are eligible.
Patients receiving dose-dense chemotherapy regimens are also eligible. Prior use
of nab-paclitaxel (Abraxane) instead of paclitaxel or docetaxel is permitted.
Prior use of subcutaneous trastuzumab (Hylecta) is also allowed
- Patients who received neoadjuvant systemic therapy which included experimental
HER2-targeted therapy/therapies are potentially eligible, as long as the
investigational agent was not a HER2-targeted antibody-drug conjugate (e.g.
T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase
inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib)
- No adjuvant treatment with any anti-cancer investigational drug within 28 days prior
to registration
- Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing
potential only, a negative serum pregnancy test done =< 7 days prior to registration
is required
- Patients with known active and/or untreated hepatitis B or hepatitis C or chronic
liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has
been treated and cleared and normal liver function are eligible to participate in the
study if the other eligibility parameters are met
- Stage IV (metastatic) breast cancer
- History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of
registration
- Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the
surgical pathology report
- Evidence of recurrent disease following preoperative therapy and surgery
- Patients for whom radiotherapy would be recommended for breast cancer treatment but
for whom it is contraindicated because of medical reasons (e.g., connective tissue
disorder or prior ipsilateral breast radiation)
- History of exposure to the following cumulative doses of anthracyclines: doxorubicin >
240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2.
For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2
- Cardiopulmonary dysfunction as defined by any of the following:
- History of National Cancer Institute (NCI) CTCAE version (v) 5.0 grade >= 3
symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA)
criteria class >= II
- Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not
controlled by adequate medication, severe conduction abnormality, or clinically
significant valvular disease
- High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate >
100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or
higher-grade atrioventricular block (AV)-block (second degree AV-block type 2
[Mobitz 2] or third degree AV-block)
- Significant symptoms (grade >= 2) relating to left ventricular dysfunction,
cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative
therapy
- History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with
prior trastuzumab treatment (e.g., during preoperative therapy)
- Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure > 100 mmHg)
- Current severe, uncontrolled systemic disease
- Major surgical procedure unrelated to breast cancer or significant traumatic injury
within 28 days prior to registration or anticipation of the need for major surgery
during the course of study treatment
- History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity
to trastuzumab or murine proteins or any components of the product
- Peripheral neuropathy of any etiology that exceeds grade 1
- Assessment by the investigator as being unable or unwilling to comply with the
requirements of the protocol
- Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4
or CYP2C8 inducer within 5 days prior to registration is prohibited. Please note that
use of sensitive CYP3A substrates should be avoided two weeks before registration and
during study treatment. Additionally, CYP3A4 or CYP2C8 inducers are prohibited as
concomitant medications within 5 days following discontinuation of tucatinib treatment
