Evaluation of Sacituzumab Tirumotecan with Carboplatin/Paclitaxel and Pembrolizumab in High-Risk Early-Stage Triple-Negative or HR-Low/HER2-Negative Breast Cancer

The primary objective of this study is to compare the efficacy of **sacituzumab tirumotecan** (sac-TMT) followed by **carboplatin**/**paclitaxel** versus standard chemotherapy, both in combination with **pembrolizumab** as neoadjuvant therapy, in terms of the rate of pathological complete response (pCR) (ypT0/Tis ypN0) at the time of surgery. This is assessed by a local pathologist in all participants. Additionally, the study aims to evaluate event-free survival (EFS) as assessed by the investigator in all participants. These objectives are clinically relevant as they aim to improve treatment outcomes for patients with high-risk early-stage **triple-negative breast cancer** (TNBC) or hormone receptor-low positive/HER2-negative breast cancer, potentially leading to better survival rates and reduced recurrence.

Secondary objectives include: - Comparing sac-TMT followed by carboplatin/paclitaxel versus chemotherapy, both in combination with pembrolizumab as neoadjuvant therapy and pembrolizumab with optional adjuvant TPC, with respect to overall survival (OS) in all participants. - Evaluating the rate of pCR-no DCIS (ypT0 ypN0) at the time of surgery, as assessed by a local pathologist in all participants. - Assessing the rate of pCR (ypT0/Tis ypN0) at the time of surgery in participants with high-risk, early-stage TNBC. - Comparing EFS as assessed by the investigator in participants with high-risk, early-stage TNBC. - Evaluating OS in participants with high-risk, early-stage TNBC. - Assessing distant progression-free survival (DPDRFS) in all participants. - Evaluating mean change from baseline in health-related quality of life (HRQoL) assessments using EORTC QLQ-C30 and EORTC QLQ-BR42 questionnaires in both arms. - Evaluating the safety and tolerability of sac-TMT plus pembrolizumab followed by carboplatin/paclitaxel plus pembrolizumab.

The clinical trial involves a total of **2047 participants** diagnosed with **breast cancer**, specifically focusing on triple-negative breast cancer (TNBC) and hormone receptor (HR)-low positive/HER2 negative breast cancer. The study population includes both male and female subjects, with an age range that spans from young adults to older adults, categorized under age range codes 3 and 4. Participants were selected based on specific inclusion criteria, such as having previously untreated high-risk, early-stage, non-metastatic breast cancer, and a centrally confirmed diagnosis of TNBC or HR-low positive/HER2 negative breast cancer. Additionally, participants are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and a left ventricle ejection fraction of ≥50% or the institution's lower limit of normal. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to compare the efficacy of sac-TMT followed by carboplatin/paclitaxel versus chemotherapy, both in combination with pembrolizumab, as neoadjuvant therapy in terms of pathological complete response and event-free survival.

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of **sacituzumab tirumotecan** (MK-2870) followed by **carboplatin**/**paclitaxel** versus chemotherapy, both in combination with **pembrolizumab** as neoadjuvant therapy for high-risk early-stage **triple-negative breast cancer** (TNBC) or hormone receptor-low positive/HER2-negative breast cancer. The trial aims to compare the rate of pathological complete response (pCR) and event-free survival (EFS) between the treatment groups. The study is expected to commence recruitment on July 8, 2025, and conclude by December 29, 2034.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as tumor stage, performance status, and cardiac function. The trial will include multiple follow-up visits to monitor treatment response and safety, with assessments conducted by local pathologists and investigators. The end-of-study visit will evaluate the primary and secondary endpoints, including pCR and EFS, as well as overall survival and quality of life measures.

The expected duration of participant involvement in the trial is up to 54 weeks, depending on the treatment arm and response. Conditions that may lead to early termination from the study include the occurrence of adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of several experimental and non-experimental medications. **Carboplatin** is utilized in the study as a chemical agent with the pharmaceutical form PHF00230MIG. It is administered via **intravenous infusion** with a maximum daily dose of 225 mg and a total dose not exceeding 2700 mg over a treatment period of 12 weeks.

**Capecitabine** is another chemical agent used in the trial, presented in the pharmaceutical form PHF00009MIG. It is administered orally with a maximum daily dose of 1250 mg/m² and a total dose of up to 280,000 mg/m² over a 24-week period.

**Pembrolizumab**, a biological agent, is provided as a concentrate for solution for infusion. It is administered via intravenous infusion with a maximum daily dose of 400 mg and a total dose of 3600 mg over a 54-week period. This agent is marketed under the name Keytruda 25 mg/mL.

**Doxorubicin Hydrochloride** is administered as a chemical agent in the pharmaceutical form PHF00231MIG. It is delivered through intravenous infusion with a maximum daily dose of 60 mg/m² and a total dose of 240 mg/m² over a 12-week period.

**Dexamethasone Acetate** and **Phenol** are combined as a chemical agent in the pharmaceutical form PHF00036MIG. This combination is administered orally with a maximum daily dose of 2 mg and a total dose of 168 mg over a 12-week period.

**Cyclophosphamide** is used as a chemical agent in the pharmaceutical form PHF00231MIG. It is administered via intravenous infusion with a maximum daily dose of 600 mg/m² and a total dose of 2400 mg/m² over a 12-week period.

**Epirubicin Hydrochloride** is another chemical agent in the pharmaceutical form PHF00230MIG. It is administered through intravenous infusion with a maximum daily dose of 90 mg/m² and a total dose of 360 mg/m² over a 12-week period.

**Sacituzumab Tirumotecan**, a biological agent, is provided as a powder for solution for injection. It is administered via intravenous infusion with a maximum daily dose of 4 mg/kg and a total dose of 24 mg/kg over a 12-week period. This agent is also known by the sponsor product code MK-2870.

**Paclitaxel** is administered as a chemical agent in the pharmaceutical form PHF00230MIG. It is delivered through intravenous infusion with a maximum daily dose of 80 mg/m² and a total dose of 960 mg/m² over a 12-week period.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The study aims to evaluate the efficacy and safety of these treatments in combination with pembrolizumab as neoadjuvant therapy for high-risk early-stage triple-negative breast cancer or hormone receptor-low positive/HER2-negative breast cancer.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Pathological Complete Response (pCR)** rate, defined as ypT0/Tis ypN0, and **Event-Free Survival (EFS)**. These endpoints will be evaluated to compare the efficacy of Sacituzumab Tirumotecan (MK-2870) followed by Carboplatin/Paclitaxel versus chemotherapy, both in combination with Pembrolizumab as neoadjuvant therapy for high-risk early-stage triple-negative breast cancer or hormone receptor-low positive/HER2-negative breast cancer.

Secondary endpoints include **Overall Survival (OS)**, pCR without Ductal Carcinoma in Situ (DCIS) using the definition of ypT0 ypN0, and EFS in participants with high-risk, early-stage, triple-negative breast cancer. Additional secondary endpoints involve the assessment of distant progression or distant recurrence-free survival (DPDRFS), and changes from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) scores, including Global Health Status/Quality of Life (GHS/QoL), Physical Functioning, Role Functioning, and Fatigue scores. The EORTC QLQ-Breast Cancer Questionnaire (BR42) will also be used to evaluate systemic therapy side effects.

The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with assessments conducted by local pathologists and investigators. The trial will also monitor the number of participants experiencing adverse events and those who discontinue the study intervention due to adverse events. These comprehensive assessments will provide a robust evaluation of the efficacy of the treatment regimens under investigation.