Phase 3 Randomized Study of Sacituzumab Tirumotecan and Pembrolizumab Versus Pembrolizumab in Mismatch Repair Proficient Endometrial Carcinoma

The primary objective of this study is to compare the efficacy of **sacituzumab tirumotecan** in combination with **pembrolizumab** versus pembrolizumab alone as a first-line maintenance treatment in participants with mismatch repair proficient (pMMR) primary advanced or recurrent **endometrial carcinoma**. This comparison will focus on progression-free survival (PFS) as assessed by blinded independent central review (BICR) using RECIST 1.1 criteria, and overall survival (OS). The clinical relevance of this objective lies in determining the potential benefits of adding sacituzumab tirumotecan to pembrolizumab, which could lead to improved treatment outcomes for patients with this specific type of endometrial cancer.

Secondary objectives include:

• Evaluating maintenance treatment with sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab alone with respect to PFS2, as assessed by the investigator, in participants with pMMR primary advanced or recurrent endometrial carcinoma.
• Assessing the safety and tolerability of maintenance treatment with sacituzumab tirumotecan plus pembrolizumab in the same patient population.
• Comparing the maintenance treatment with respect to mean change from baseline in health-related quality of life (HRQoL) using the EORTC QLQ-C30 and EORTC QLQ-EN24 in participants with pMMR primary advanced or recurrent endometrial carcinoma.

The clinical trial involves a total of **797 participants** diagnosed with **proficient mismatch repair (pMMR) endometrial carcinoma**. The study population is exclusively female, with participants falling within the age categories of 18 to 64 years. The trial does not include any vulnerable populations. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of primary advanced or recurrent endometrial carcinoma, with radiographically evaluable disease. The trial excludes individuals who have received prior systemic therapy for endometrial carcinoma, except under certain conditions specified in the protocol. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection process ensures that participants have measurable or non-measurable Stage III or IV disease, as assessed by the investigator, aligning with the study's objective to evaluate the efficacy of maintenance treatment with sacituzumab tirumotecan plus pembrolizumab compared to pembrolizumab alone.

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy and safety of **sacituzumab tirumotecan** in combination with **pembrolizumab** versus pembrolizumab alone as a first-line maintenance treatment in participants with mismatch repair proficient endometrial cancer. The trial aims to compare progression-free survival (PFS) and overall survival (OS) between the two treatment groups. The study is expected to commence recruitment on July 1, 2025, and conclude by July 16, 2029, with an estimated duration of four years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of primary advanced or recurrent endometrial carcinoma and radiographically evaluable disease. Following the screening, participants will be randomized to receive either the combination therapy or pembrolizumab alone. The trial will include regular follow-up visits to monitor treatment response and adverse events, with assessments conducted per the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1). The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement in the trial is approximately one year, contingent upon individual response to treatment and the occurrence of any adverse events. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The primary endpoints of the trial are progression-free survival and overall survival, while secondary endpoints include progression-free survival 2, the number of participants experiencing adverse events, and changes in quality of life scores as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Pembrolizumab**, marketed as Keytruda, is a biological agent used in this study. It is provided as a 25 mg/mL concentrate for solution for infusion. The route of administration is via **intravenous infusion**. Pembrolizumab is administered as a maintenance treatment, and its role in the trial is as a comparator to assess its efficacy and safety when used alone versus in combination with other agents. The dosing schedule and participant compliance are monitored according to the study protocol.

**Sacituzumab tirumotecan**, also known by its sponsor product code MK-2870, is another biological agent used in this trial. It is provided in the form of a powder for solution for injection. The administration route is categorized as "other use," and it is used in combination with pembrolizumab to evaluate its efficacy in comparison to pembrolizumab alone. The dosing regimen and compliance are closely monitored to ensure adherence to the study protocol.

Several auxiliary treatments are included in the study, such as **docetaxel**, **paclitaxel**, and **carboplatin**. These are chemical agents provided in various pharmaceutical forms, primarily for "other use" routes of administration. These agents are used to support the primary treatment regimen and are not the focus of the efficacy comparison in this trial. The administration and dosing of these auxiliary treatments are managed according to the study's guidelines to ensure participant safety and data integrity.

Additional chemical agents, such as **cimetidine**, are also included in the study as auxiliary treatments. These agents are provided in specific pharmaceutical forms and are administered through "other use" routes. Their role is to support the primary treatment regimen, and their administration is carefully controlled to maintain the study's integrity and participant safety.

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)**. These endpoints will be evaluated to compare the maintenance treatment of sacituzumab tirumotecan plus pembrolizumab versus pembrolizumab alone in participants with proficient mismatch repair (pMMR) primary advanced or recurrent endometrial carcinoma. The assessment of PFS will be conducted per RECIST 1.1 criteria as evaluated by a blinded independent central review (BICR).

Secondary endpoints will include **Progression-Free Survival 2 (PFS2)** as assessed by the investigator, the number of participants experiencing one or more adverse events (AEs), and the number of participants who discontinue the study intervention due to an AE. Additionally, changes from baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) will be measured, focusing on Global Health Status, Quality of Life, Physical Functioning, Role Functioning, and Endometrial Cancer Symptom Score (QLQ-EN24).