Phase III Evaluation of Trastuzumab Deruxtecan with Rilvegostomig or Pembrolizumab versus Chemotherapy and Pembrolizumab in HER2-Expressing pMMR Endometrial Cancer

The primary objective of this study is to demonstrate the efficacy of first-line **trastuzumab deruxtecan** (T-DXd) combined with either **rilvegostomig** (Arm A) or **pembrolizumab** (Arm B) compared to chemotherapy (carboplatin + paclitaxel) combined with pembrolizumab (Arm C). This will be assessed by evaluating progression-free survival (PFS) as determined by blinded independent central review (BICR) in participants with HER2-expressing (IHC 3+/2+), mismatch repair proficient (pMMR), primary advanced (Stage III/IV) or recurrent endometrial cancer. The clinical relevance of this objective lies in potentially improving first-line treatment options for this specific patient population, which could lead to better management of the disease and improved patient outcomes.

Secondary objectives include: - Assessing the efficacy of Arm A and/or Arm B compared to Arm C in terms of overall survival (OS). - Evaluating efficacy in terms of PFS as assessed by the investigator. - Assessing efficacy in terms of time from randomization to second progression or death (PFS2). - Evaluating efficacy in terms of confirmed objective response rate (ORR) according to BICR and investigator assessment. - Assessing efficacy in terms of duration of response (DoR) according to BICR and investigator assessment. - Comparing the efficacy of Arm A to Arm B in terms of PFS and OS. - Evaluating the safety and tolerability of Arm A and/or Arm B compared to Arm C. - Assessing the pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody, DXd, and rilvegostomig in serum. - Investigating the immunogenicity of T-DXd and rilvegostomig. - Describing patient-reported tolerability of Arm A and/or Arm B compared to Arm C. - Collecting and assessing tissue samples for the development of regulated companion diagnostics for the detection of HER2 expression and MMR status.

The clinical trial involves a total of **381 participants** diagnosed with **HER2-expressing (IHC 3+/2+), mismatch repair proficient (pMMR), primary advanced or recurrent endometrial cancer**. The study population is exclusively female, with participants aged 18 years and older, reflecting the inclusion of adult women. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of epithelial endometrial carcinoma, excluding sarcomas, and the presence of primary advanced disease (Stage III/IV) or first recurrent endometrial cancer. All participants must have adequate organ and bone marrow function, an Eastern Cooperative Oncology Group performance status of 0-1, and a left ventricular ejection fraction of at least 50%. Prior to randomization, participants must provide a tumor tissue sample for central testing. The trial excludes individuals with prior exposure to antibody-drug conjugates or immune checkpoint inhibitors, although prior radiation therapy and certain chemotherapy treatments are permitted with an adequate washout period. The trial does not include male participants, and the population is considered vulnerable, necessitating careful ethical considerations in the study design and execution.

The clinical trial is designed as a **randomized**, **controlled**, and sponsor-blinded study to evaluate the efficacy of **trastuzumab deruxtecan** combined with either **rilvegostomig** or **pembrolizumab** compared to chemotherapy (carboplatin and paclitaxel) plus pembrolizumab in patients with HER2-expressing, mismatch repair proficient, primary advanced or recurrent **endometrial cancer**. The trial is a Phase III study, with the primary objective of assessing progression-free survival (PFS) as evaluated by blinded independent central review (BICR). Secondary endpoints include overall survival (OS), PFS as assessed by the investigator, and objective response rate (ORR) among others. The trial is expected to commence recruitment on September 30, 2025, and conclude by February 24, 2031.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, organ function, and histological diagnosis. The inclusion criteria specify that participants must have HER2 IHC expression of 3+ or 2+ and be mismatch repair proficient. Following the screening, eligible participants will be randomized into one of the treatment arms. The trial will include regular follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST 1.1 criteria. The end-of-study visit will occur after the final treatment cycle or upon early termination.

The expected duration of participant involvement will vary depending on individual response to treatment and disease progression, with the maximum treatment period set at 9999999 days. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will ensure rigorous monitoring of safety and efficacy, with data collected on adverse events, laboratory assessments, and imaging studies to evaluate treatment impact. The study aims to provide valuable insights into the therapeutic potential of the investigational combinations in this patient population.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Trastuzumab deruxtecan** (DS-8201a) is an experimental medication used in this study. It is an antibody-drug conjugate formulated as a **solution for infusion**. The administration route is **intravenous use**, and the dosage is expressed in **mg/kg**. The frequency of administration is determined by the study protocol, and the maximum treatment period is set to an extensive duration, allowing for long-term administration as needed.

Another experimental treatment in the trial is **Rilvegostomig** (AZD2936), a bispecific IgG1 monoclonal antibody targeting PDCD1 and TIGIT. It is also provided as a **solution for infusion** and administered via **intravenous use**. The dosage is measured in **mg**, with the administration schedule and compliance monitored according to the study's guidelines.

**Pembrolizumab** is included as a non-experimental treatment in the study. It is a **solution for infusion** administered intravenously. The dosage is specified in **mg**, and the treatment duration is aligned with the study's requirements. Pembrolizumab serves as a comparator treatment in combination with chemotherapy agents.

The chemotherapy regimen includes **Carboplatin** and **Paclitaxel**, both of which are non-experimental treatments. **Carboplatin** is provided as a **concentrate for solution for infusion** and administered intravenously. The dosage is expressed in **mg/ml**, and the treatment period is extensive. **Paclitaxel** is also a **concentrate for solution for infusion**, administered via **intravenous use**, with the dosage in **mg/m²**. Both agents are used in combination with Pembrolizumab in the comparator arm of the study.

Additional non-experimental treatments include **Docetaxel**, **Mycophenolate mofetil**, and **Infliximab**. **Docetaxel** is a **concentrate for solution for infusion** administered intravenously, with dosage in **mg/ml**. **Mycophenolate mofetil** is provided in a **capsule, hard** form for **oral use**, with dosage in **mg**. **Infliximab** is a **powder for concentrate for solution for infusion**, administered intravenously, with dosage in **mg**. These treatments are used as comparators or auxiliary agents, depending on the study arm.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression Free Survival (PFS)**, as evaluated by Blinded Independent Central Review (BICR). PFS is defined as the time from randomization until disease progression, as per RECIST 1.1 criteria, or death from any cause. Secondary endpoints include Overall Survival (OS), which is the time from randomization until death from any cause, and PFS as assessed by the investigator, which shares the same attributes as PFS by BICR but with tumor assessment conducted by the investigator. Additional secondary endpoints include PFS2, Overall Response Rate (ORR), Duration of Response (DoR), safety and tolerability, serum concentrations of T-DXd, total anti-HER2 antibody, DXd, and rilvegostomig, presence of anti-drug antibodies (ADAs) for T-DXd and rilvegostomig, patient-reported tolerability, and the assessment of MMR and HER2 expression in tissue samples.

The trial will utilize validated scales and laboratory tests to measure these endpoints. The schedule for measuring and collecting data will be aligned with the trial protocol, ensuring consistent and accurate data collection throughout the study duration. The analysis of these efficacy parameters will be conducted using appropriate statistical methods to determine the efficacy of the investigational treatments compared to the control group. The trial aims to demonstrate the efficacy of first-line T-DXd combined with rilvegostomig or pembrolizumab compared to chemotherapy plus pembrolizumab in participants with HER2-expressing, mismatch repair proficient, primary advanced or recurrent endometrial cancer.