Summary

This phase III trial compares the effect of usual treatment with trastuzumab emtansine (T-DM1) alone vs. T-DM1 in combination with tucatinib. T-DM1 is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors, and delivers DM1 to kill them. Tucatinib blocks HER2, which may help keep cancer cells from growing and may kill them. Giving T-DM1 in combination with tucatinib may work better in preventing breast cancer from relapsing in patients with HER2 positive breast cancer compared to T-DM1 alone.

Objectives

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. Overall survival (OS).
Ib. Breast cancer free survival (BCFS).
Ic. Distant recurrence-free survival (DRFS).
Id. Disease-free survival (DFS).
Ie. Brain metastases-free survival (BMFS).
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.

SECONDARY CORRELATIVE OBJECTIVES:
I. To evaluate the association of tumor infiltrating lymphocyte (TIL) levels in both the primary tumor and the residual disease specimen with iDFS.
II. To determine whether there is evidence of differential treatment benefit of T-DM1 and tucatinib compared to T-DM1 and placebo in high TIL cancers compared to low TIL cancers (assessed in both the pre-neoadjuvant tumor tissue and the residual cancer tissue).
III. To evaluate the association between iDFS and the presence of detectable circulating tumor cells (CTC) at baseline, at completion of study therapy and/or 1 year after completion of study therapy.
IV. To determine the difference in absolute magnitude of benefit of tucatinib (in terms of iDFS) in the subgroup of patients with detectable CTC at baseline and the subgroup of patients without detectable CTC at baseline.

LOCAL REGIONAL EXPLORATORY OBJECTIVES:
I. To determine local regional recurrence following breast conservation based on margin width (no ink on tumor, close, > 2 mm).
II. To determine local regional recurrence following breast conservation with or without boost.
III. To compare regional recurrence based on axillary surgery –sentinel lymph node biopsy (SLNB) vs. axillary lymph node dissection (ALND) – among patients with residual nodal disease.

PATIENT-REPORTED OUTCOMES:
I. To compare quality of life (QOL) after approximately 8 cycles of the study as assessed by the Functional Assessment of Cancer Therapy (FACT)-Breast Cancer (B) Trial Outcome Index between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Primary Objective)
II. To compare QOL after approximately 13 cycles of the study as assessed by the FACT-B Trial Outcome Index between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Secondary Objective)
III. To compare various QOL domains after approximately 8 and 13 cycles of the study as assessed by the 5 subscales of the FACT-B questionnaire between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Exploratory Objective)
IV. To compare self-reported patient adherence and reasons for non-adherence after 1, 4, 8, and 13 cycles of the study as assessed by the Voils instrument (Domains of Subjective Extent of Nonadherence [DOSE-Nonadherence]) between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Exploratory Objective)
V. To compare self-reported symptomatic adverse events after 1, 4, 8, and 13 cycles of the study assessed by the Patient-Reported Outcomes (PRO) - Common Terminology Criteria for Adverse Events (CTCAE) between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Exploratory Objective)

TO-BE-DETERMINED CORRELATIVE OBJECTIVES:
I. To evaluate the association of circulating tumor deoxyribonucleic acid (ctDNA) tumor-specific mutations (at baseline and after completion of adjuvant HER2-directed therapy) with iDFS.
II. To evaluate the association of breast cancer intrinsic subtype and other transcriptional signatures in both the primary tumor and the residual disease specimen with iDFS.

PHARMACOKINETIC OBJECTIVES:
I. To characterize the pharmacokinetic (PK) of T-DM1 in all patients.
II. To characterize the PK of tucatinib in tucatinib-treated patients.
III. To investigate exposure–effect (efficacy and safety) relationships in tucatinib-treated patients.

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. Patients undergo blood sample collection throughout the study.

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. Patients undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, then every 6 months for 10 years.

Eligibility

1. 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.
2. 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)
3. Patients with residual HR-negative, HER2+ disease in the breast and/or lymph nodes per the surgical pathology report are eligible. Patients with HR-positive, HER2+ disease must have disease in their lymph node(s) 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 node-positive patients
4. 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
5. 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
6. 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
7. 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
8. 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 registration. Note: Patients who complete at least nine of a planned twelve doses of weekly paclitaxel, or three of a planned four doses of docetaxel, or four of a planned six cycles of docetaxel, 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).
9. 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)
10. 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
11. Toxicities related to prior systemic treatment should have resolved or be at baseline, apart from alopecia and peripheral neuropathy =< grade 1
12. 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 for residual disease, no further axillary treatment is necessary. If patients have a sentinel lymph node biopsy and sentinel nodes are positive for residual nodal disease, then ALND is strongly encouraged. If ALND is not performed, then nodal irradiation to the level I/II axilla is required. If patients have micro- or macro-metastatic nodal disease, regional nodal irradiation is required.
13. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
14. Age >= 18 years (male or female)
15. Absolute neutrophil count (ANC) >= 1,000/mm^3
16. Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted to achieve eligibility)
17. Platelet count >= 100,000/mm^3
18. Creatinine =< 1.5 x upper limit of normal (ULN)
19. Total bilirubin =< 1.0 x upper limit of normal (ULN) or direct bilirubin within the institutional normal range for patients with Gilbert’s syndrome
20. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
21. 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

Treatment Sites in Georgia