Phase 3 Randomized Study of Datopotamab Deruxtecan ± Durvalumab vs. Investigator's Choice in Stage I-III Triple-negative Breast Cancer with Residual Disease

The primary objective of this study is to demonstrate the superiority of **Datopotamab Deruxtecan** (Dato-DXd) in combination with **Durvalumab** relative to the investigator's choice of therapy (ICT) by assessing invasive disease-free survival (iDFS) in participants with Stage I-III **Triple-negative Breast Cancer** (TNBC) who have residual invasive disease at surgical resection following neoadjuvant therapy. This objective is clinically relevant as it aims to improve outcomes in a patient population with limited treatment options and high risk of recurrence.

Secondary objectives include:

• Demonstrating the superiority of Dato-DXd + Durvalumab relative to ICT by assessing distant disease-free survival (DDFS) and overall survival (OS).
• Demonstrating the superiority of Dato-DXd relative to ICT by assessing iDFS.
• Assessing the efficacy of Dato-DXd relative to ICT by evaluating DDFS and OS.
• Assessing the efficacy of Dato-DXd relative to ICT by evaluating iDFS, DDFS, and OS.
• Assessing the efficacy of Dato-DXd + Durvalumab relative to Dato-DXd by evaluating iDFS and DDFS.
• Evaluating participant-reported outcomes such as physical function and quality of health status/quality of life (QHS/QoL) with Dato-DXd +/- Durvalumab versus ICT.
• Assessing patient-reported fatigue with Dato-DXd +/- Durvalumab versus ICT.
• Evaluating the pharmacokinetics and immunogenicity of Dato-DXd.
• Assessing the safety and tolerability of Dato-DXd +/- Durvalumab versus ICT.

The clinical trial involves a total of **797 participants** diagnosed with **Stage I-III Triple-negative Breast Cancer** with residual invasive disease following neoadjuvant systemic therapy. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including histologically confirmed invasive triple-negative breast cancer (TNBC) and the presence of residual invasive disease in the breast and/or axillary lymph nodes at surgical resection after completing at least six cycles of neoadjuvant therapy. The trial excludes individuals with known germline BRCA1 or BRCA2 pathogenic mutations and requires participants to have adequate organ and bone marrow function, with a left ventricular ejection fraction (LVEF) of 50% or higher. The trial does not involve a vulnerable population, and participants must not have received adjuvant systemic therapy. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The sponsor has not provided additional information regarding lifestyle considerations.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy of **datopotamab deruxtecan** with or without **durvalumab** compared to the investigator's choice of therapy in patients with Stage I-III **triple-negative breast cancer** who have residual invasive disease following neoadjuvant systemic therapy. The trial aims to demonstrate the superiority of the combination therapy by assessing invasive disease-free survival (iDFS) as the primary endpoint. Secondary endpoints include distant disease-free survival (DDFS), overall survival (OS), and various clinical outcome assessments. The trial is expected to commence recruitment on March 28, 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 invasive **triple-negative breast cancer**, and completion of neoadjuvant therapy. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will occur after the final assessment of the primary and secondary endpoints. The expected duration of participant involvement is contingent upon the occurrence of any primary endpoint events or the completion of the study timeline.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdrawal of consent. Additionally, any deviation from the inclusion criteria or the emergence of exclusion criteria during the study may lead to early termination. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

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 via **intravenous use**. The dosing is based on **mg/kg** (milligrams per kilogram) of body weight. The specific dosing schedule and frequency are determined by the study protocol, and participant compliance is monitored throughout the trial. This drug is identified by the sponsor product code DS-1062a and is developed by Daiichi Sankyo, Inc.

**Durvalumab**, marketed as **IMFINZI**, is another investigational treatment in this trial. It is a **concentrate for solution for infusion** and is also administered intravenously. The active substance, **durvalumab**, is a protein of other origin. The dosing schedule is determined by the study protocol, and compliance is monitored. This product is authorized under the marketing authorization number EU/1/18/1322/001 and is manufactured by AstraZeneca AB.

**Capecitabine** is used as a comparator treatment in the study. It is provided in the form of a **film-coated tablet** and is administered orally. The dosage is calculated in **mg/m²** (milligrams per square meter) of body surface area. The specific dosing schedule and frequency are outlined in the study protocol, with compliance monitoring in place to ensure adherence.

**Pembrolizumab** is another comparator treatment, provided as a **solution for infusion** and administered intravenously. The active substance, **pembrolizumab**, is a protein of other origin. The dosing schedule is determined by the study protocol, and participant compliance is monitored throughout the trial.

**Infliximab** is used as an auxiliary treatment in the study. It is supplied as a **powder for concentrate for solution for infusion** and administered intravenously. The dosing schedule and frequency are specified in the study protocol, with compliance monitoring to ensure adherence.

**Mycophenolate mofetil** is also used as an auxiliary treatment. It is provided in **capsule** form and administered orally. The dosing schedule and frequency are determined by the study protocol, and compliance is monitored to ensure participant adherence. This drug is classified as an immunosuppressive agent.

The efficacy of the clinical trial will be assessed primarily through the measurement of **invasive disease-free survival (iDFS)**. iDFS is defined as the time from randomization until the date of the first event, which may include local, regional, contralateral, or distant breast cancer recurrence, the occurrence of a second primary non-breast invasive cancer, or death from any cause. This endpoint will be based on investigator assessment and will include all randomized participants, regardless of withdrawal or receipt of another anticancer therapy. The measure of interest is the hazard ratio (HR) of iDFS for the combination of Datopotamab Deruxtecan (Dato-DXd) and durvalumab versus Investigator's Choice of Therapy (ICT).

Secondary endpoints include **distant disease-free survival (DDFS)**, which is defined as the time from randomization to the date of the first distant recurrence, occurrence of a second primary non-breast invasive cancer, or death from any cause. DDFS will also be determined based on investigator assessment and will include all randomized participants. The HR of DDFS will be measured for various comparisons, including Dato-DXd versus ICT and Dato-DXd plus durvalumab versus Dato-DXd alone. **Overall survival (OS)**, defined as the time from randomization until the date of death due to any cause, will also be assessed, with the HR of OS being a key measure of interest.

Additional efficacy assessments will include patient-reported outcomes (PROs) such as time to deterioration (TTD) and actual scores in physical function, measured by the PROMIS Physical Function Short Form 8c, and global health status/quality of life (GHS/QoL), measured by the GHS/QoL scale from the EORTC IL172. Fatigue levels will be evaluated using the PROMIS Fatigue Short Form 7a, with assessments at 3, 6, and 12 months. Pharmacokinetics and immunogenicity of Dato-DXd, as well as safety and tolerability, will also be monitored throughout the trial.