Phase III Evaluation of Trastuzumab Deruxtecan ± Pertuzumab Versus Taxane, Trastuzumab, and Pertuzumab in HER2-Positive Metastatic Breast Cancer

The primary objective of this Phase III study is to evaluate the **efficacy** of Trastuzumab Deruxtecan (T-DXd) with or without Pertuzumab compared to the combination of Taxane, Trastuzumab, and Pertuzumab (THP) in terms of progression-free survival (PFS) as assessed by blinded independent central review (BICR) in participants with HER2-positive, first-line metastatic breast cancer (mBC). This objective is clinically relevant as it aims to determine the potential of T-DXd, a novel antibody-drug conjugate, to improve PFS, which is a critical endpoint in the management of metastatic breast cancer, potentially offering a more effective treatment option for patients.

Secondary objectives include: - Assessing the efficacy of T-DXd ± Pertuzumab relative to THP by evaluating PFS according to investigator assessment, overall survival (OS), objective response rate (ORR), and duration of response (DoR) according to BICR and investigator assessment. - Evaluating PFS2 according to investigator assessment. - Assessing the effect of T-DXd ± Pertuzumab on patient-reported pain and treatment tolerability. - Evaluating the pharmacokinetics (PK) of T-DXd and Pertuzumab. - Investigating the immunogenicity of T-DXd.

The clinical trial involves a total of **991 participants** diagnosed with **HER2-positive metastatic breast cancer**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including having pathologically documented advanced or metastatic breast cancer that is HER2-positive and either hormone receptor-positive or negative in the metastatic setting. Eligible participants have not received prior chemotherapy or HER2-targeted therapy for advanced or metastatic breast cancer, except for one previous line of endocrine therapy in the metastatic setting. Those who have undergone chemotherapy or HER2-targeted therapy in the neo-adjuvant or adjuvant setting are eligible if more than six months have passed since treatment to metastatic diagnosis. Participants must also have protocol-defined adequate organ and bone marrow function and an **ECOG performance status** of 0 or 1. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of **trastuzumab deruxtecan** with or without **pertuzumab** compared to a regimen of **taxane**, **trastuzumab**, and **pertuzumab** in patients with **HER2-positive metastatic breast cancer**. The primary objective is to assess progression-free survival (PFS) as determined by blinded independent central review (BICR) using RECIST 1.1 criteria. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DoR), and health-related quality of life (HRQoL) among others. The trial is expected to run until December 2029, with recruitment having commenced in April 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented HER2-positive status, and adequate organ function. Following randomization, participants will receive intravenous infusions of the investigational products or comparators. Regular follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetics, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the final treatment cycle or upon early termination.

The expected duration of participant involvement is up to 99 weeks, contingent upon disease progression or unacceptable toxicity. Conditions that may lead to early termination from the study include withdrawal of consent, protocol non-compliance, or adverse events that compromise participant safety. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the integrity and scientific validity of the data collected.

The clinical trial involves the administration of **trastuzumab deruxtecan**, marketed under the name DS-8201a, which is an **antibody drug conjugate**. This experimental medication is provided as a **solution for infusion** and is administered via **intravenous use**. The dosing schedule and frequency are determined by the study protocol, with a maximum treatment period of 99 weeks. Participant compliance with the dosing regimen is monitored throughout the trial.

In addition to the experimental treatment, the study includes several comparator treatments. **Trastuzumab**, a **monoclonal antibody**, is also administered as a **solution for infusion** via **intravenous use**. The dosing schedule is consistent with standard clinical practice, and the treatment period is aligned with the study's maximum duration of 99 weeks.

**Docetaxel**, classified as a **taxane**, is another comparator used in the trial. It is provided as a **solution for infusion** and administered intravenously. The dosing regimen follows established guidelines for its use in clinical settings, with a treatment period not exceeding 99 weeks.

Similarly, **paclitaxel**, also a **taxane**, is included as a comparator treatment. It is supplied as a **concentrate for solution for infusion** and administered via **intravenous use**. The dosing schedule is in accordance with standard medical practice, with a maximum treatment duration of 99 weeks.

**Pertuzumab**, another **monoclonal antibody**, is used as a comparator in the study. It is administered as a **solution for infusion** through **intravenous use**. The dosing and administration are consistent with its approved use, with a treatment period of up to 99 weeks.

A **placebo** in the form of saline 0.9% (weight per volume; w/v) is used for **pertuzumab**. This placebo is locally sourced by investigational sites and serves as a control to evaluate the efficacy of the experimental and comparator treatments. The administration route and dosing schedule are designed to match those of the active comparator.

The efficacy of the investigational product **trastuzumab deruxtecan** (T-DXd), with or without pertuzumab, will be assessed in a Phase III clinical trial involving participants with HER2-positive, first-line metastatic breast cancer. The primary endpoint for evaluating efficacy is progression-free survival (PFS), defined as the time from randomization until objective radiological disease progression or death by any cause, as determined by blinded independent central review (BICR) using RECIST 1.1 criteria.

Secondary endpoints include PFS as assessed by investigators, overall survival (OS), objective response rate (ORR), duration of response (DoR), time to second progression or death (PFS2), health-related quality of life (HRQoL) using the European Organisation for Research and Treatment of Cancer (EORTC) tools, serum concentration of trastuzumab deruxtecan and pertuzumab, and immunogenicity of trastuzumab deruxtecan, alone or with pertuzumab. Safety and tolerability will also be evaluated.

Data collection will occur at specified timepoints throughout the trial, with assessments conducted using validated scales and laboratory tests. The trial is designed to provide comprehensive data on the efficacy of T-DXd in comparison to a regimen of taxane, trastuzumab, and pertuzumab (THP) in the specified patient population.