Phase 3 Randomized Study of Sacituzumab Tirumotecan and Pembrolizumab Versus Physician's Choice in Triple-Negative Breast Cancer Post-Neoadjuvant Therapy

The primary objective of this Phase 3, randomized, open-label study is to compare the efficacy of **MK-2870** in combination with **pembrolizumab** versus the treatment of physician's choice (TPC), which includes pembrolizumab or pembrolizumab plus capecitabine, in participants with triple-negative breast cancer (TNBC) who have received neoadjuvant therapy and did not achieve a pathological complete response (pCR) at surgery. The primary endpoint is invasive disease-free survival (iDFS) as assessed by investigators. This is clinically relevant as it aims to improve outcomes in TNBC, a subtype of breast cancer with limited treatment options and a high risk of recurrence.

Secondary objectives include: - Comparing MK-2870 plus pembrolizumab to TPC with respect to overall survival (OS). - Evaluating MK-2870 plus pembrolizumab and TPC with respect to distant recurrence-free survival (DRFS) per investigator assessment. - Assessing the mean change from baseline in health-related quality of life (QoL) using the EORTC QLQ-C30 in all participants. - Evaluating the safety and tolerability of MK-2870 plus pembrolizumab.

The clinical trial involves a total of **714 participants** diagnosed with **triple negative breast cancer**. 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 inclusion criteria, such as having centrally confirmed triple negative breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial does not involve a vulnerable population. Participants are required to have completed neoadjuvant treatment based on the KEYNOTE-522 regimen, followed by surgery, and must have adequately recovered from surgery. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraception guidelines if capable of producing sperm or if they are females of childbearing potential. The trial excludes individuals with evidence of locoregional or distant relapse and requires participants to have no pathologic complete response at surgery. The study does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is a **Phase 3**, randomized, open-label study designed to evaluate the efficacy and safety of adjuvant MK-2870 in combination with **pembrolizumab** compared to the treatment of physician's choice in participants with **triple-negative breast cancer** (TNBC) who have received neoadjuvant therapy and did not achieve a pathological complete response at surgery. The trial aims to assess the **invasive disease-free survival** (iDFS) as the primary endpoint, with secondary endpoints including overall survival, distant recurrence-free survival, and changes in quality of life scores. The study is expected to commence recruitment on June 15, 2024, and conclude by December 14, 2037.

Participants will be randomly assigned to receive either MK-2870 plus pembrolizumab or the treatment of physician's choice, which may include pembrolizumab or pembrolizumab plus **capecitabine**. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed TNBC, recovery from previous therapies, and adequate surgical excision. Follow-up visits will be scheduled to monitor treatment response, adverse events, and adherence to the study protocol. The end-of-study visit will assess the final outcomes and collect data for analysis.

The expected duration of participant involvement is up to 24 months, with conditions for early termination including the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. Participants must adhere to specific contraceptive measures and agree to refrain from sperm donation during the study period. The trial will be conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is administered via **intravenous infusion**. The dosage is set at a maximum of 400 mg per day, with a total maximum dose of 2000 mg over the treatment period. The treatment duration is up to 24 months. Pembrolizumab is a biological product, specifically a protein of other origin, and is not formulated for pediatric use.

Another experimental medication used in the trial is **MK-2870** (sacituzumab tirumotecan), provided as a **powder for solution for injection**. This medication is also administered through **intravenous infusion**. The dosing regimen allows for a maximum daily dose of 4 mg/kg, with a total maximum dose of 48 mg/kg over the course of the study. The treatment period is similarly capped at 24 months. Sacituzumab tirumotecan is a biological product, classified as a protein of other origin, and is not intended for pediatric patients.

In addition to the experimental treatments, the study includes the use of **CAPECITABINE**, a chemical compound administered orally. The maximum daily dose is 2500 mg/m², with a total maximum dose of 280,000 mg/m² over the treatment period, which is also limited to 24 months. Capecitabine is not a pediatric formulation.

Other non-experimental treatments include **H2-receptor antagonists**, **buclizine hydrochloride, paracetamol, codeine phosphate**, and **dexamethasone acetate**. These are chemical compounds used as auxiliary treatments in the study. The administration routes for these substances are categorized as "other use," and they are not formulated for pediatric use. The maximum daily and total doses for these auxiliary treatments are not specified, and their treatment period is consistent with the 24-month duration of the trial.

Efficacy in this clinical trial will be assessed primarily through the measurement of **Invasive Disease-Free Survival (iDFS)**, as determined by investigator assessment. This endpoint will provide insights into the effectiveness of the treatment in preventing the recurrence of invasive disease in participants with triple-negative breast cancer (TNBC) who did not achieve a pathological complete response (pCR) after neoadjuvant therapy and surgery. Secondary endpoints include **Overall Survival (OS)**, **Distant Recurrence-Free Survival (DRFS)**, and changes from baseline in various scores from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), such as Global Health Status, Quality of Life, Physical Functioning, Role Functioning, and Fatigue scores. Additionally, the number of participants experiencing adverse events (AEs) and those discontinuing the study intervention due to AEs will be recorded.

The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, with the primary focus on the duration of the study, which is estimated to conclude by December 14, 2037. The trial will employ validated scales and questionnaires to ensure the accuracy and reliability of the data collected. The study will compare the efficacy of MK-2870 in combination with pembrolizumab against the treatment of physician's choice, which may include pembrolizumab alone or in combination with capecitabine. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimens in the specified patient population.