Phase 3 Study of Sacituzumab Tirumotecan With/Without Pembrolizumab in PD-L1 CPS <10 Triple-Negative Breast Cancer

The primary objective of this study is to evaluate the efficacy of **sacituzumab tirumotecan** (sac-TMT) compared to the treatment of physician's choice (TPC) in terms of **progression-free survival** (PFS) as assessed by **RECIST 1.1** criteria in participants with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) expressing **PD-L1** at a combined positive score (CPS) of less than 10. Additionally, the study aims to compare sac-TMT plus **pembrolizumab** to TPC with respect to PFS, and to compare sac-TMT to TPC regarding **overall survival** (OS) in all participants. These objectives are clinically relevant as they aim to determine the potential benefits of sac-TMT, alone or in combination with pembrolizumab, in improving survival outcomes in a challenging patient population with limited treatment options.

Secondary objectives include:

• Comparing sac-TMT plus pembrolizumab to TPC with respect to OS in all participants.
• Comparing sac-TMT plus pembrolizumab to sac-TMT with respect to PFS per RECIST 1.1 as assessed by **BICR** in all participants.
• Comparing sac-TMT to TPC with respect to **objective response rate** (ORR) per RECIST 1.1 as assessed by BICR in all participants.
• Comparing sac-TMT plus pembrolizumab to TPC with respect to ORR per RECIST 1.1 as assessed by BICR in all participants.
• Comparing sac-TMT plus pembrolizumab to sac-TMT with respect to OS in all participants.
• Evaluating sac-TMT, sac-TMT plus pembrolizumab, and TPC with respect to **duration of response** (DOR) per RECIST 1.1 as assessed by BICR in all participants.
• Comparing sac-TMT 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 sac-TMT plus pembrolizumab to TPC with respect to mean change from baseline in HRQoL using the EORTC QLQ-C30 in all participants.
• Evaluating the safety and tolerability of sac-TMT, sac-TMT plus pembrolizumab, and TPC.

The clinical trial involves a total of **680 participants** diagnosed with **locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC)**, with tumors expressing PD-L1 at a cut-off of CPS <10. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including those who have not received systemic treatment for their condition and those who have completed prior therapy for early-stage breast cancer at least six months before recurrence. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include being a candidate for treatment with pembrolizumab and one of the treatment options of the physician's choice, such as paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin. Participants with controlled HIV on antiretroviral therapy, those with hepatitis B on antiviral therapy with undetectable viral load, and those with a history of hepatitis C with undetectable viral load are eligible. The trial does not focus on any specific lifestyle habits or conditions beyond the medical criteria outlined.

The clinical trial is a **Phase III** study designed to evaluate the efficacy and safety of **sacituzumab tirumotecan** as a monotherapy and in combination with **pembrolizumab** compared to the treatment of physician's choice in participants with previously untreated locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) expressing PD-L1 at a combined positive score (CPS) of less than 10. The trial employs a randomized, open-label design, ensuring that participants are randomly assigned to treatment groups, but both participants and investigators are aware of the treatment being administered. The trial is expected to commence recruitment on March 24, 2025, and conclude by February 10, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as the absence of prior systemic treatment for locally recurrent unresectable or metastatic TNBC and the ability to receive pembrolizumab and one of the treatment options of physician's choice, which include **paclitaxel**, **nab-paclitaxel**, or **gemcitabine** plus **carboplatin**. Following the screening, participants will be enrolled and randomized into one of the treatment arms. Regular follow-up visits will be scheduled to monitor progression-free survival (PFS) and overall survival (OS), as well as to assess any adverse events (AEs) and changes in quality of life scores using the EORTC QLQ-C30 questionnaire. The end-of-study visit will mark the completion of the participant's involvement in the trial.

The expected duration of participant involvement is up to 60 weeks, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include the occurrence of unacceptable AEs, disease progression, or withdrawal of consent by the participant. The primary endpoints of the trial are PFS and OS, while secondary endpoints include objective response rate (ORR), duration of response (DOR), and changes in quality of life scores. The trial aims to provide comprehensive data on the comparative effectiveness of sacituzumab tirumotecan, both as a standalone treatment and in combination with pembrolizumab, against standard treatment options in this patient population.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Gemcitabine hydrochloride** is utilized in the study as a chemical agent. It is administered in the form of a pharmaceutical preparation coded as PHF00230MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 1000 mg/m² and a total maximum dose of 173,333 mg/m² over a treatment period of 60 days. The route of administration is via **intravenous infusion**.

**Carboplatin** is another chemical agent used in the trial, also in the form of PHF00230MIG. The maximum daily dose is 300 mg, with a total maximum dose of 52,020 mg over the same 60-day treatment period. Administration is conducted through intravenous infusion.

**Paclitaxel** is included in the study as a chemical agent, administered in the form of PHF00230MIG. The dosing is based on body surface area, with a maximum daily dose of 90 mg/m² and a total maximum dose of 20,800 mg/m² over 60 days. The administration route is intravenous infusion.

**Pembrolizumab**, marketed as Keytruda, is a biological agent used in the trial. It is provided as a 25 mg/mL concentrate for solution for infusion. The maximum daily dose is 600 mg, with a total maximum dose of 10,800 mg over a treatment period of 108 days. Administration is via intravenous infusion.

**Sacituzumab tirumotecan**, also known as MK-2870, is a biological agent administered as a powder for solution for injection. The dosing is based on body weight, with a maximum daily dose of 4 mg/kg and a total maximum dose of 520 mg over 60 days. The route of administration is intravenous infusion.

**Paclitaxel albumin-bound** is used as a chemical agent in the form of a powder for dispersion for infusion. The dosing is based on body surface area, with a maximum daily dose of 100 mg/m² and a total maximum dose of 19,500 mg/m² over 60 days. Administration is conducted through intravenous infusion.

Additionally, **glucocorticoids** are included in the study as a comparator treatment. The pharmaceutical form is coded as PHF00170MIG, and the route of administration is categorized as "other use." The maximum treatment period for glucocorticoids is 1 day, with no specified maximum daily or total dose.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS will be evaluated by comparing sacituzumab tirumotecan (sac-TMT) to the treatment of physician's choice (TPC), as well as sac-TMT plus pembrolizumab to TPC. OS will be assessed by comparing sac-TMT to TPC. These endpoints will be measured according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by blinded independent central review (BICR).

Secondary endpoints include OS for sac-TMT plus pembrolizumab versus TPC, PFS for sac-TMT plus pembrolizumab versus sac-TMT, and Objective Response Rate (ORR). Additional secondary endpoints involve the Duration of Response (DOR) and changes from baseline in various scores on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), including global health status/quality of life, physical functioning, emotional functioning, fatigue, and diarrhea scores. The number of participants experiencing one or more adverse events (AEs) and those discontinuing study treatment due to an AE will also be recorded.