HER2-Positive Primary Breast Cancer, Residual Invasive Breast Cancer
Conditions
Keywords
HER2-Positive Primary Breast Cancer, Residual Invasive Breast Cancer, Trastuzumab Deruxtecan, Trastuzumab Emtansine
Brief summary
Patients with HER2-positive primary breast cancer (BC) who do not achieve complete response after appropriate neoadjuvant therapy are at higher risk of disease recurrence. More effective treatment options are needed for this patient population. This study will examine the efficacy and safety of trastuzumab deruxtecan (T-DXd) compared with trastuzumab emtansine (T-DM1) in high-risk patients with residual invasive breast cancer following neoadjuvant therapy.
Detailed description
This study will examine trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2-positive primary BC who have residual invasive disease in breast or axillary lymph nodes with higher risk of recurrence, which includes patients who were inoperable at disease presentation or had pathological node-positive status after neoadjuvant therapy. The primary objective is to compare invasive disease-free survival (IDFS) between T-DXd and T-DM1 treatment arms in this population. The key secondary objective of the study is to evaluate disease-free survival (DFS).
Interventions
DRUGDS-8201a
Administered initially as an intravenous (IV) infusion at a dose of 5.4 mg/kg on Day 1 of each 21-day cycle
DRUGT-DM1
Administered initially as an intravenous (IV) infusion at a dose of 3.6 mg/kg on Day 1 of each 21-day cycle
Sponsors
Daiichi Sankyo
AstraZeneca
NSABP Foundation Inc
GBG Forschungs GmbH
Spanish Breast Cancer Research Group (SOLTI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adults ≥18 years old (local regulatory requirements will apply if the legal age of consent for study participation is \>18 years old). * Pathologically documented HER2-positive breast cancer (BC): * HER2-positive expression defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) confirmed prior to study randomization. * Histologically confirmed invasive breast carcinoma. * Clinical stage at disease presentation: T1-4, N0-3, M0; patients presenting with T1N0 tumors are not eligible. * Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes following completion of neoadjuvant therapy meeting one of the following high-risk criteria: * Inoperable breast cancer at presentation (prior to neoadjuvant therapy), defined as clinical stages T4, N0-3, M0 or T1-3, N2-3, M0. * Operable at presentation, defined as clinical stages T1-3,N0-1,M0, with axillary node positive disease (ypN1-3) following neoadjuvant therapy. * Completion of neoadjuvant systemic therapy, including taxane-based chemotherapy and HER2-directed treatment prior to surgery. * Systemic therapy must consist of at least 6 cycles of neoadjuvant therapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab (± pertuzumab) and at least 9 weeks of taxane-based chemotherapy to be completed prior to surgery. Patients may have received an anthracycline as part of neoadjuvant therapy in addition to taxane chemotherapy. * Adequate excision as confirmed per medical records: surgical removal of all clinically evident disease in the breast and axillary lymph nodes. * An interval of no more than 12 weeks between the date of last surgery and the date of randomization. * Known hormone receptor (HR) status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR positive status defined by either positive estrogen receptor (ER) and/or positive progesterone receptor (PR). status. HR-negative status defined by both known negative ER and known negative PR. * Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening. * Has adequate organ function within 14 days before randomization. Key
Exclusion criteria
* Stage IV (metastatic) BC. * History of any prior (ipsi- or contralateral) breast cancer except lobular carcinoma in situ (LCIS). * Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery. * Prior treatment with T-DXd, T-DM1 or other anti-HER2 antibody-drug conjugate (ADC) or prior enrollment in a clinical study of T-DXd (regardless of treatment arm) * History of exposure to the following cumulative doses of anthracyclines: * Doxorubicin \> 240 mg/m\^2 * Epirubicin or Liposomal Doxorubicin-Hydrochloride \> 480 mg/m\^2 * For other anthracyclines, exposure equivalent to doxorubicin \> 240 mg/m\^2 * History of other malignancy within the last 5 years except for appropriately treated CIS of the cervix, nonmelanoma skin carcinoma, Stage I melanoma skin carcinoma, Stage I uterine cancer, or other appropriately treated non-breast malignancies with an outcome similar to those mentioned above. * History of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids and/or has ILD/pneumonitis noted on computed tomography (CT) scan of the chest at Screening (asymptomatic interstitial changes confined to recent radiation therapy fields are not excluded). * Known pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months prior to randomization, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease). * Any autoimmune, connective tissue or inflammatory disorders (eg, Rheumatoid arthritis, Sjogren's, sarcoidosis, etc) where there is documented or a suspicion of pulmonary involvement or pneumonectomy at the time of screening. * Medical history of myocardial infarction (MI) within 6 months before randomization, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), troponin levels consistent with MI as defined according to the manufacturer 28 days prior to randomization.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Invasive Disease-free Survival (IDFS) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment | Randomization to date of invasive local, axillary or distant recurrence, invasive contralateral breast cancer or death from any cause (whichever occurs first), up to approximately 57 months postdose |
Secondary
| Measure | Time frame |
|---|---|
| Disease-free Survival (DFS) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment | Randomization to date of the first occurrence of an IDFS event including second primary non-breast cancer event or contralateral or ipsilateral ductal carcinoma in situ (whichever occurs first), up to approximately 81 months postdose |
| Overall Survival (OS) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment | Randomization to date of death from any cause, up to approximately 81 months postdose |
| Distant Recurrence-free Interval (DRFI) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment | Randomization to date of distant recurrence, up to approximately 81 months postdose |
| Brain Metastases-free Interval (BMFI) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment | Randomization to date of brain metastasis, up to approximately 81 months postdose |
| Percentage of Treatment-emergent Adverse Events in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment | Baseline up to approximately 81 months postdose |
| Serum Concentrations of Trastuzumab Deruxtecan (T-DXd), total anti-HER2 antibody, and Active Metabolite MAAA-1181a | Pre-dose on Day 1 of Cycles 1, 4 and 10 and within 15 minutes post-dose on Day 1 of Cycles 1 and 4 (each cycle is 21 days) |
| Percentage of Participants Positive for Treatment-emergent Anti-drug Antibodies (ADAs) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) | Baseline up to approximately 81 months postdose |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Czechia, Denmark, France, Germany, Greece, Hong Kong, Ireland, Israel, Italy, Japan, Mexico, Netherlands, Peru, Poland, Portugal, Romania, Russia, Singapore, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORGlobal Clinical Leader
Daiichi Sankyo
Outcome results
None listed