Phase 3 Study of Sacituzumab Tirumotecan and Pembrolizumab Versus Physician's Choice in HR+/HER2- Unresectable Locally Advanced or Metastatic Breast Cancer

The primary objective of this study is to compare **MK-2870** to the treatment of physician's choice (TPC) with respect to progression-free survival (PFS) as assessed by blinded independent central review (BICR) in participants with hormone receptor-positive, HER2-negative unresectable locally advanced or metastatic breast cancer. This objective is clinically relevant as it aims to determine the efficacy of MK-2870 in delaying disease progression compared to standard treatment options, which is crucial for improving patient outcomes in this population.

Secondary objectives include:

• Comparing MK-2870 to TPC with respect to overall survival (OS) in all participants.
• Comparing MK-2870 plus pembrolizumab to TPC with respect to OS in all participants.
• Comparing MK-2870 plus pembrolizumab to MK-2870 with respect to PFS per RECIST 1.1 as assessed by BICR in all participants.
• Comparing MK-2870 plus pembrolizumab to MK-2870 with respect to OS in all participants.
• Comparing MK-2870 to TPC with respect to objective response rate (ORR) per RECIST 1.1 as assessed by BICR in all participants.
• Comparing MK-2870 plus pembrolizumab to TPC with respect to ORR per RECIST 1.1 as assessed by BICR in all participants.
• Evaluating MK-2870 to TPC with respect to duration of response (DOR) per RECIST 1.1 as assessed by BICR in all participants.
• Evaluating MK-2870 plus pembrolizumab to TPC with respect to DOR per RECIST 1.1 as assessed by BICR in all participants.
• Comparing MK-2870 to TPC with respect to mean change from baseline in health-related quality of life (HRQoL) using the EORTC QLQ-C30 in all participants.
• Comparing MK-2870 to TPC with respect to time to deterioration (TTD) in HRQoL using the EORTC QLQ-C30 in all participants.
• Comparing MK-2870 plus pembrolizumab to TPC with respect to mean change from baseline in HRQoL using the EORTC QLQ-C30 in all participants.
• Comparing MK-2870 plus pembrolizumab to TPC with respect to TTD in HRQoL using the EORTC QLQ-C30 in all participants.
• Evaluating the safety and tolerability of MK-2870, MK-2870 plus pembrolizumab, and chemotherapy.

The clinical trial involves a total of **831 participants** diagnosed with **hormone receptor positive breast cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having unresectable locally advanced or metastatic hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancer, and having experienced radiographic disease progression on one or more lines of endocrine therapy. All participants are required to be chemotherapy candidates and must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Additionally, participants must demonstrate adequate organ function. 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 ensures the inclusion of individuals with controlled HIV on antiretroviral therapy, and those with a history of Hepatitis B or C, provided they meet specific viral load conditions.

The clinical trial is designed as a **randomized**, **open-label**, Phase 3 study to evaluate the efficacy and safety of **MK-2870** as a single agent and in combination with **pembrolizumab** compared to the treatment of physician's choice in participants with hormone receptor-positive (HR+)/HER2-negative unresectable locally advanced or metastatic breast cancer. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), and changes in quality of life scores. The study is expected to commence recruitment on May 20, 2024, and conclude by April 12, 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as disease progression on prior endocrine therapy and adequate organ function. Following randomization, participants will receive either MK-2870, MK-2870 plus pembrolizumab, or a treatment of the physician's choice. Study visits will include regular assessments to monitor disease progression, adverse events, and overall health status. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 24 months, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. 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 **MK-2870**, a **powder for solution for injection**. The active substance in MK-2870 is **sacituzumab tirumotecan**, a humanized IgG1 monoclonal antibody against TROP2, conjugated to KL610023. The pharmaceutical form is a powder intended for intravenous infusion. The maximum daily dose is 4 mg/kg, with a total maximum dose of 104 mg/kg over a treatment period of 12 weeks. Participant compliance will be monitored through regular assessments of infusion administration.

**Pembrolizumab**, marketed as Keytruda, is used in combination with MK-2870. It is provided as a **concentrate for solution for infusion** with a concentration of 25 mg/mL. The active substance is pembrolizumab, a protein-based biological agent. The maximum daily dose is 400 mg, with a total maximum dose of 6933 mg over a 24-week treatment period. Administration is via intravenous infusion, and compliance is monitored through infusion records and participant follow-up.

**Doxorubicin hydrochloride, liposomal** is used as a comparator treatment. It is available as a **solution for infusion**. The active substance is doxorubicin hydrochloride, encapsulated in liposomes to enhance delivery. The maximum daily dose is 50 mg/m², with a total maximum dose of 650 mg/m² over 12 weeks. This treatment is administered intravenously, and compliance is tracked through infusion logs and participant monitoring.

**Paclitaxel** is another comparator treatment, provided as a **powder for dispersion for infusion**. The active substance is paclitaxel, a chemical agent used in chemotherapy. The maximum daily dose is 90 mg/m², with a total maximum dose of 3510 mg/m² over 12 weeks. Administration is via intravenous infusion, and compliance is ensured through infusion records and participant assessments.

**Capecitabine** is included as an oral comparator treatment. It is provided in a pharmaceutical form designated as PHF00009MIG. The active substance is capecitabine, a chemical agent used in chemotherapy. The maximum daily dose is 1000 mg/m², with a total maximum dose of 504000 mg/m² over 12 weeks. Compliance is monitored through pill counts and participant diaries.

**Dexamethasone acetate** is used as an auxiliary treatment. It is administered orally, with no specified maximum daily or total dose. The pharmaceutical form is designated as PHF00245MIG. Compliance is monitored through participant self-reporting and clinical assessments.

**H2-Receptor Antagonists** are also used as auxiliary treatments. They are administered orally, with no specified maximum daily or total dose. Compliance is monitored through participant self-reporting and clinical assessments.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will compare MK-2870 to the treatment of physician's choice (TPC), as well as MK-2870 combined with pembrolizumab versus TPC. This assessment will be conducted per RECIST 1.1 criteria and evaluated by a blinded independent central review (BICR) in all participants.

Secondary endpoints include **Overall Survival (OS)**, PFS comparing MK-2870 plus pembrolizumab to MK-2870 alone, **Objective Response Rate (ORR)**, and **Duration of Response (DOR)**. Additionally, changes from baseline in global health status and quality of life scores will be measured using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Specific domains such as physical functioning, emotional functioning, fatigue, and diarrhea will be evaluated. Time to first deterioration (TTD) in these domains will also be assessed.

The trial will also monitor the number of participants experiencing one or more adverse events (AEs) and those who discontinue study treatment due to an AE. These efficacy parameters will be collected and analyzed at various timepoints throughout the study, ensuring a comprehensive evaluation of the treatment's impact on participants with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) unresectable locally advanced or metastatic breast cancer.