Phase 3 Multicenter Randomized Study of Trastuzumab Deruxtecan vs. Trastuzumab Emtansine in High-Risk HER2-Positive Breast Cancer with Residual Disease

The primary objective of this study is to evaluate the **invasive disease-free survival (IDFS)** with Trastuzumab Deruxtecan (T-DXd) treatment as compared to Trastuzumab Emtansine (T-DM1) in patients with high-risk HER2-positive breast cancer who have residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy. This is clinically relevant as IDFS is a critical endpoint in assessing the efficacy of adjuvant therapies in reducing the risk of cancer recurrence.

Secondary objectives include:

• Evaluating **disease-free survival (DFS)** with T-DXd treatment as compared to T-DM1.
• Evaluating **overall survival (OS)** with T-DXd treatment as compared to T-DM1.
• Evaluating **distant recurrence-free interval (DRFI)** with T-DXd treatment as compared to T-DM1.
• Evaluating **brain metastasis-free interval (BMFI)** with T-DXd treatment as compared to T-DM1.
• Evaluating the **safety** of T-DXd.
• Evaluating the **pharmacokinetics (PK)** of T-DXd.
• Evaluating the **immunogenicity** of T-DXd.

The clinical trial involves a total of **371 participants** diagnosed with **High-Risk HER2-Positive Breast Cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have completed neoadjuvant systemic therapy, including taxane-based chemotherapy and HER2-directed treatment prior to surgery. Participants were selected based on specific criteria, including a histologically confirmed invasive breast carcinoma and adequate organ function. The trial population is characterized by a **left ventricular ejection fraction (LVEF) ≥ 50%** and an **Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1**. Lifestyle considerations such as the use of contraception and restrictions on sperm and ova donation are mandated for participants of reproductive potential. The trial includes a vulnerable population, ensuring comprehensive representation of the affected demographic. The selection process adhered to stringent inclusion criteria to ensure the reliability and validity of the study outcomes.

The clinical trial is a **Phase 3**, multicenter, randomized, open-label, active-controlled study designed to evaluate the efficacy of **trastuzumab deruxtecan** (T-DXd) compared to **trastuzumab emtansine** (T-DM1) in subjects with high-risk **HER2-positive breast cancer** who have residual invasive disease in the breast or axillary lymph nodes following neoadjuvant therapy. The primary objective is to assess invasive disease-free survival (IDFS) with T-DXd treatment as compared to T-DM1. The trial is expected to conclude by March 31, 2028, with recruitment having started on December 30, 2020.

The trial involves a sequence of study visits, beginning with an inclusion (screening) visit where participants are assessed for eligibility based on criteria such as known hormone receptor status, left ventricular ejection fraction, and adequate organ function. Participants must be adults aged 18 years or older with histologically confirmed invasive breast carcinoma and must have completed neoadjuvant systemic therapy. Following the screening, eligible participants are randomized to receive either T-DXd or T-DM1, both administered as a **solution for infusion** via intravenous use.

Participants will undergo regular follow-up visits to monitor treatment efficacy and safety, including assessments of IDFS, disease-free survival (DFS), overall survival (OS), and other secondary endpoints. These visits will include physical examinations, laboratory tests, and imaging studies as necessary. The end-of-study visit will occur after the completion of the treatment period, which is a maximum of 11 cycles, or upon early termination from the study.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as required. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The study is conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial.

The clinical trial involves the administration of **trastuzumab emtansine**, marketed under the name Kadcyla, which is available in two formulations: 100 mg and 160 mg powder for concentrate for solution for infusion. This medication is administered via **intravenous use**. The pharmaceutical form is a solution for infusion, and it is of biological/biotechnological origin. The maximum daily dose is 3.6 mg/kg, with a total maximum dose of 50.4 mg/kg over a treatment period of 11 cycles. The product is manufactured by Roche Registration GmbH and is not a pediatric formulation. The medication is relabeled for the trial, and its role is as a comparator in the study.

The experimental medication in the trial is **trastuzumab deruxtecan**, known by the sponsor product code DS-8201a. This medication is also administered as a solution for infusion via the **intravenous route**. It is of biological/biotechnological origin and is produced by Daiichi Sankyo, Inc. The maximum daily dose for trastuzumab deruxtecan is 5.4 mg/kg, with a total maximum dose of 75.6 mg/kg over the same treatment period of 11 cycles. This product is not a pediatric formulation and serves as the test drug in the trial.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Invasive Disease-Free Survival (IDFS)**, which is defined as the time from randomization to invasive local, axillary, or distant recurrence, invasive contralateral breast cancer, or death from any cause. IDFS will be determined based on disease recurrence as assessed by the investigator using all available clinical assessments.

Secondary endpoints include Disease-Free Survival (DFS), Overall Survival (OS), Distant Recurrence-Free Interval (DRFI), and Brain Metastasis-Free Interval (BMFI). DFS is defined as the time between randomization and the first occurrence of an IDFS event, including second primary non-breast cancer events or contralateral or ipsilateral ductal carcinoma in situ (DCIS). OS is defined as the time from randomization to death due to any cause. DRFI is the time between randomization and the date of distant breast cancer recurrence, while BMFI is the time from randomization to documentation of central nervous system involvement by metastatic cancer.

Additional assessments will include adverse events (AEs), serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and adverse events of special interest (AESIs). These will be evaluated through physical examination findings, Eastern Cooperative Oncology Group (ECOG) performance status, vital sign measurements, standard clinical laboratory parameters, electrocardiogram (ECG) parameters, echocardiogram (ECHO)/multigated acquisition (MUGA) findings, and computed tomography (CT) scans. Pharmacokinetic (PK) assessments will measure serum concentrations of Trastuzumab Deruxtecan (T-DXd), total anti-HER2 antibody, and MAAA 1181a in the PK sampling cohort. The percentage of subjects positive for anti-drug antibodies (ADAs) at baseline, post-baseline, and treatment-emergent ADA positivity will also be determined, including titer and neutralizing antibody (NAb) assessments for positive ADA samples.