Phase III Randomized Study of Datopotamab Deruxtecan and Durvalumab in Neoadjuvant and Adjuvant Settings for Triple-Negative or Hormone Receptor-Low/HER2-Negative Breast Cancer

The primary objective of this study is to demonstrate the superiority of **neoadjuvant** Datopotamab Deruxtecan (Dato-DXd) plus Durvalumab followed by adjuvant Durvalumab, with or without chemotherapy, compared to neoadjuvant Pembrolizumab plus chemotherapy followed by adjuvant Pembrolizumab, with or without chemotherapy, in participants with previously untreated **Triple-Negative Breast Cancer (TNBC)** or hormone receptor-low/HER2-negative breast cancer. This will be assessed by central evaluation of pathological complete response (pCR) and investigator assessment of event-free survival (EFS). The clinical relevance of this objective lies in potentially improving treatment outcomes for patients with these aggressive subtypes of breast cancer, which are often associated with poorer prognoses and limited treatment options.

Secondary objectives include: - Demonstrating the superiority of the same treatment regimen by assessing overall survival (OS) in the same patient population. - Assessing the effectiveness of the treatment regimen by evaluating distant disease-free survival (DDFS) in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer.

The clinical trial involves a total of **1245 participants** diagnosed with **Triple Negative or Hormone Receptor low/HER2-negative Breast Cancer**. The study population includes both male and female subjects, aged 18 years and older, with a histologically confirmed diagnosis of Stage II or III unilateral or bilateral primary invasive breast cancer. Participants are required to have an **ECOG Performance Status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on the provision of an acceptable tumor sample and adequate bone marrow reserve and organ function. Contraceptive use is mandated in accordance with local regulations and protocol requirements. The study also includes vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy of neoadjuvant **datopotamab deruxtecan** plus **durvalumab** followed by adjuvant durvalumab with or without chemotherapy, compared to neoadjuvant **pembrolizumab** plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy. The trial targets adult patients with previously untreated **triple-negative breast cancer** or hormone receptor-low/HER2-negative breast cancer. The primary objectives are to assess the superiority of the investigational regimen in terms of pathological complete response (pCR) and event-free survival (EFS). The trial is expected to commence recruitment on March 11, 2024, and conclude by August 30, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of cancer, and adequate organ function. Following randomization, participants will receive the assigned treatment regimen. The trial includes multiple follow-up visits to monitor treatment response and safety, with assessments conducted by both central and investigator evaluations. The end-of-study visit will occur after the completion of the adjuvant therapy phase, where final assessments of efficacy and safety will be performed.

The expected duration of participant involvement spans from the initial screening through the end-of-study visit, with the total duration varying based on individual treatment response and progression. Conditions that may lead to early termination from the study include disease progression precluding surgery, unacceptable toxicity, or withdrawal of consent. The trial's design ensures rigorous monitoring and evaluation to achieve its primary and secondary endpoints, contributing valuable data to the treatment landscape of breast cancer.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Datopotamab deruxtecan** is an investigational drug used in this study. It is provided as a solution for infusion and is administered intravenously. The dosing is based on milligrams per kilogram (mg/kg) of body weight. The maximum treatment period is set to an extensive duration, allowing for long-term administration as required by the study protocol.

**Durvalumab**, marketed as IMFINZI, is used as a comparator in the trial. It is a concentrate for solution for infusion, administered intravenously. The dosing is measured in milligrams (mg), and the treatment period is similarly extensive, aligning with the study's requirements for prolonged administration.

**Pembrolizumab** is another comparator used in the study. It is provided as a solution for infusion and administered intravenously. The dosing is in milligrams, with a treatment period designed to accommodate the study's long-term objectives.

**Cyclophosphamide** is utilized in the trial as a powder for solution for injection. It is administered intravenously, with dosing based on milligrams per square meter (mg/m²) of body surface area. The treatment period is extensive, ensuring flexibility in administration duration.

**Olaparib**, marketed as Lynparza, is used in two formulations: 100 mg and 150 mg film-coated tablets. Both are administered orally. The 100 mg tablet has a yellow film coat due to the absence of iron oxide, while the 150 mg tablet is unmarked and packed in HDPE bottles to facilitate blinding in placebo-controlled studies. The dosing is in milligrams, with a treatment period that supports the study's long-term goals.

**Mycophenolate mofetil** is included in the study in various forms, including hard capsules and film-coated tablets, all administered orally. The dosing is in milligrams, with an extensive treatment period to accommodate the study's requirements.

**Doxorubicin** is provided as a concentrate for solution for infusion, administered intravenously. The dosing is based on milligrams per square meter (mg/m²) of body surface area, with a treatment period designed for long-term administration.

**Epirubicin** and **Carboplatin** are both administered as concentrates for solution for infusion, given intravenously. The dosing for epirubicin is in mg/m², while carboplatin is dosed in milligrams per milliliter (mg/mL). Both have extensive treatment periods to align with the study's objectives.

**Capecitabine** is used in the study as a film-coated tablet, administered orally. The dosing is based on mg/m², with a treatment period that supports the study's long-term administration needs.

**Paclitaxel** is provided as a concentrate for solution for infusion, administered intravenously. The dosing is in mg/m², with a treatment period designed for extended administration.

**Infliximab** is included as a powder for concentrate for solution for infusion, administered intravenously. The dosing is in milligrams, with a treatment period that accommodates the study's requirements for long-term administration.

Participant compliance is monitored throughout the study to ensure adherence to the dosing schedules and administration routes as specified in the protocol. The study design includes both experimental and comparator treatments to evaluate the efficacy and safety of the investigational drugs in comparison to established therapies.

The efficacy of the clinical trial will be assessed using primary and secondary endpoints. The primary endpoints include the **pathological complete response (pCR) rate** and **event-free survival (EFS)**. The pCR rate is defined as the proportion of participants with no evidence of residual invasive disease or lymphovascular invasion in the resected breast specimen and all sampled regional lymph nodes, as determined by blinded central evaluation following neoadjuvant systemic therapy. EFS is defined as the time from randomization to the first occurrence of disease progression precluding surgery, disease recurrence, second primary invasive cancer, relapse from prior malignancy, or death by any cause.

Secondary endpoints include **overall survival (OS)** and **distant disease-free survival (DDFS)**. OS is defined as the time from randomization until death from any cause. DDFS is defined as the time from randomization until the first occurrence of distant metastasis, second primary invasive cancer, relapse from prior malignancy, or death by any cause. These efficacy parameters will be measured and analyzed at specified timepoints throughout the trial to determine the superiority of the treatment regimens being tested.