A Double-Blinded, Phase III Randomized Trial of T-DM1 Compared with T-DM1 and Tucatinib.

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 (based on

pretreatment biopsy material). 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 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 at initial breast cancer diagnosis are not eligible)

- 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

- Patients with weakly ER-positive (1-10%) breast cancer (based on the pretreatment core

biopsy) are eligible even if they have node-negative disease per the surgical

pathology report

- The residual disease tissue (breast and/or lymph nodes) is not required to be

HER2-positive, as eligibility for NCI-2020-03770 (A011801) is based on a positive HER2

status at the time of the initial breast cancer diagnosis

* 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 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

- Prior receipt of T-DM1 in the neoadjuvant setting is not allowed.

- Prior treatment must have consisted of >= 6 cycles of chemotherapy and

HER2-directed therapy, with a total duration of >= 12 weeks, including at least 9

weeks of preoperative taxane and trastuzumab with or without pertuzumab (or Food

and Drug Administration [FDA]-approved biosimilars). Patients who have received

at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also

eligible if they received >= 6 cycles of systemic therapy prior to enrollment.

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 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) and subcutaneous trastuzumab and pertuzumab (Phesgo) 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).

- Patients may have received =< 1 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

* Note: 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. Concurrent radiation

therapy is permitted while receiving study treatment

- 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]) or the BIG

DECRESCENDO Trial (which is very similar to CompassHER2 pCR in terms of study design,

drugs, and eligibility). However, patients who received 4 cycles of neoadjuvant THP

off study can receive a further 2-4 cycles of chemotherapy postoperatively to meet

eligibility for A011801. Patients who participated in EA1181 or MA41 and proceeded to

surgery immediately after the de-escalated trial regimen must receive postoperative

chemotherapy to complete a total of >= 6 cycles of systemic treatment prior to

enrollment on A011801, as outlined above (e.g. 4 cycles pre-operatively, and 2 cycles

post-operatively). The postoperative chemotherapy regimen prescribed is at the

discretion of the treating oncologist (i.e. 2-4 cycles AC or THP, other). Continuation

of trastuzumab + pertuzumab (HP) pre- or post-operatively as maintenance therapy

(while awaiting a surgical date or an official pathology report) is allowed for all

study participants

- 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, ALND and planned nodal irradiation are

required. Of note, co-enrollment on Alliance A011202 is not allowed

- 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 =< 1.0 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 percentage 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

- 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. Patients who require medications that are

known to be sensitive substrates of CYP3A4 with a narrow therapeutic window

should be excluded.