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Study of Trastuzumab Deruxtecan, Rilvegostomig, and Pembrolizumab for Advanced or Recurrent Endometrial Cancer in HER2-Positive Patients

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study is focused on endometrial cancer, specifically HER2-expressing, mismatch repair proficient (pMMR) type that is either primary advanced or recurrent. The treatments being tested include trastuzumab deruxtecan (T-DXd) combined with either rilvegostomig or pembrolizumab, compared against standard chemotherapy (carboplatin plus paclitaxel) combined with pembrolizumab. The purpose of this research is to determine if these new combination treatments are more effective than the standard therapy for patients with this specific type of endometrial cancer.

Endometrial cancer is a cancer that begins in the lining of the uterus (the endometrium). In this study, participants will be randomly assigned to receive one of three treatment combinations. Some will receive trastuzumab deruxtecan with rilvegostomig, others will receive trastuzumab deruxtecan with pembrolizumab, and a third group will receive the standard chemotherapy with pembrolizumab. Trastuzumab deruxtecan is a medication that targets cancer cells with high levels of a protein called HER2. Pembrolizumab and rilvegostomig are types of immunotherapy medications that help the immune system recognize and attack cancer cells.

Throughout the study, participants will undergo regular evaluations to monitor how their cancer responds to treatment and to check for any side effects. These evaluations will include imaging tests to measure tumors and laboratory tests to assess organ function and overall health. The study will track how long participants remain without their cancer getting worse and their overall survival time.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Study Randomization

    After qualifying for the study, you will be randomly assigned to one of three treatment groups:

    Group A: Trastuzumab deruxtecan plus rilvegostomig

    Group B: Trastuzumab deruxtecan plus pembrolizumab

    Group C: Chemotherapy (carboplatin and paclitaxel) plus pembrolizumab

  2. Step 2

    Initial Assessments

    Before starting treatment, several tests will be performed:

    A heart function test (to measure your left ventricular ejection fraction) to ensure your heart function is at least 50%

    Blood tests to check your organ function and bone marrow

    Imaging scans to measure your cancer

  3. Step 3

    Treatment Administration

    Depending on your assigned group, you will receive:

    Group A: Trastuzumab deruxtecan (an antibody-drug conjugate that targets HER2 proteins) given by intravenous (IV) infusion, along with rilvegostomig given by IV infusion

    Group B: Trastuzumab deruxtecan given by IV infusion, along with pembrolizumab (an immunotherapy drug) given by IV infusion

    Group C: Carboplatin and paclitaxel (traditional chemotherapy drugs) given by IV infusion, along with pembrolizumab given by IV infusion

    All treatments will be administered as solutions for infusion (given through a vein)

  4. Step 4

    Regular Monitoring

    Throughout the treatment period, you will have:

    Regular imaging scans to assess how your cancer is responding to treatment

    Blood tests to monitor your health and organ function

    Heart function tests to monitor for any heart-related side effects

    Regular assessments of any side effects or symptoms you may experience

    You may be asked to complete questionnaires about how you're feeling and your quality of life

  5. Step 5

    Treatment Duration

    You will continue receiving treatment until one of the following occurs:

    Your disease progresses (gets worse) as determined by imaging scans

    You experience unacceptable side effects

    You decide to withdraw from the study

    The study reaches its end date (anticipated to be September 2025)

  6. Step 6

    Follow-up After Treatment

    After your treatment ends, you will continue to be monitored:

    Regular follow-up visits to assess your health status

    Imaging scans to monitor your cancer status

    Tracking of any additional treatments you receive after study treatment

    Long-term monitoring for survival information may continue until the study ends in February 2031

Who can join the trial?

12 criteria

  • You must be at least 18 years old at screening time.
  • You must have adequate organ and bone marrow function within 14 days before being randomly assigned to a treatment group.
  • You must have a confirmed diagnosis of epithelial endometrial carcinoma (a type of uterine cancer). All types are allowed except for sarcomas (carcinosarcomas are allowed).
  • You must have either primary advanced disease (Stage III/IV) or first recurrent endometrial cancer after surgery or diagnostic biopsy.
  • Your cancer must show HER2 expression (a protein found on some cancer cells) at levels of 3+ or 2+ as determined by central testing.
  • Your cancer must be pMMR (proficient mismatch repair, meaning certain DNA repair mechanisms in your cancer cells are working normally) as determined by central testing.
  • You must be able to provide an adequate tumor tissue sample for testing that has not been previously treated with radiation.
  • You must not have received any previous first-line systemic anticancer therapy for your current condition. If you received prior chemotherapy for cure, your disease must have returned at least 6 months after your last dose.
  • You must not have been previously treated with ADCs (antibody-drug conjugates) or immune checkpoint inhibitors (medications that help your immune system fight cancer).
  • You may have received prior radiation therapy, but an adequate washout period is required.
  • You must have good physical functioning ability, with an ECOG performance status of 0-1 (able to perform daily activities with little or no assistance).
  • Your heart function must be adequate with a left ventricular ejection fraction (pumping ability of your heart) of at least 50% within 28 days before randomization.

Who cannot join the trial?

14 criteria

  • Previous treatment with any anti-cancer therapy for advanced or recurrent endometrial cancer.
  • Having a tumor that does not express HER2 (a protein that promotes cell growth) at the required levels (IHC 3+ or IHC 2+).
  • Having a tumor with deficient mismatch repair (dMMR) status (a specific feature related to how DNA is repaired in cells).
  • History of another cancer within the last 3 years, except for certain types of skin cancer or cancer that has been successfully treated.
  • Having active or untreated brain metastases (cancer that has spread to the brain).
  • History of interstitial lung disease (a group of disorders that cause scarring of lung tissue) or pneumonitis (inflammation of lung tissue).
  • Significant heart problems, including heart failure or recent heart attack.
  • Active autoimmune disease requiring systemic treatment (diseases where the immune system attacks the body's own tissues).
  • Current use of immunosuppressive medications (drugs that reduce immune system activity).
  • Active infection requiring therapy, including hepatitis B, hepatitis C, or HIV.
  • Prior organ transplantation.
  • Pregnancy or breastfeeding.
  • Unable to swallow oral medications or conditions that might affect drug absorption.
  • Known allergies to any of the study medications or their components.
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Investigated drugs

  • Trastuzumab Deruxtecan (T-DXd)

    is a medication that targets cancer cells with a protein called HER2 on their surface. It works by attaching to these HER2 proteins and delivering a cancer-killing drug directly into the cancer cells.

  • Rilvegostomig

    is a medication that helps boost the body's immune system to fight cancer cells. It works by helping the immune system recognize and attack cancer cells more effectively.

  • Pembrolizumab

    is an immunotherapy medication that helps the body's immune system detect and fight cancer cells. It works by blocking a protein called PD-1, which normally prevents the immune system from attacking cancer cells.

  • Carboplatin

    is a chemotherapy medication that works by interfering with the DNA in cancer cells, preventing them from growing and multiplying.

  • Paclitaxel

    is a chemotherapy medication that works by stopping cancer cells from dividing and growing. It disrupts the structural framework inside cancer cells that allows them to divide.

What is already known about the treatment

  • Trastuzumab Deruxtecan (T-DXd)

    An antibody-drug conjugate administered via intravenous infusion that combines the HER2-targeting abilities of trastuzumab with a potent topoisomerase I inhibitor payload. Currently being investigated in Phase III clinical trials for HER2-expressing endometrial cancer, this medication works by binding to HER2 receptors on cancer cells and delivering a cytotoxic agent directly to them, causing cell death. This targeted approach allows for precision treatment while potentially minimizing damage to healthy tissues.

  • Rilvegostomig

    An investigational immunotherapy medication administered intravenously that is being studied in combination with Trastuzumab Deruxtecan for HER2-expressing endometrial cancer. It is designed to enhance the immune system's ability to recognize and attack cancer cells by targeting specific immune pathways. This medication represents a novel approach in cancer treatment by potentially amplifying the body's natural defenses against tumors.

  • Pembrolizumab

    An immunotherapy medication administered through intravenous infusion that belongs to the class of PD-1 inhibitors, which helps the immune system detect and fight cancer cells. Approved for multiple cancer types and currently being studied in combination therapies for endometrial cancer, it works by blocking a protein called PD-1 on T cells, allowing them to recognize and attack cancer cells more effectively. This medication has shown significant promise in various cancer treatments by essentially removing the "invisibility cloak" that cancer cells use to hide from immune detection.

  • Carboplatin

    A platinum-based chemotherapy medication administered intravenously that is commonly used in combination with other agents to treat various cancers, including endometrial cancer. It works by binding to DNA in cancer cells, interfering with their ability to repair damage and ultimately leading to cell death. This well-established treatment is often used as part of standard chemotherapy regimens due to its proven efficacy against rapidly dividing cells, though it may affect both cancerous and normal cells.

  • Paclitaxel

    A chemotherapy medication given through intravenous infusion that belongs to the taxane family and is frequently used in combination with carboplatin for treating endometrial and other cancers. It works by stabilizing microtubules in cancer cells, preventing them from dividing properly and ultimately causing cell death. This medication has been a cornerstone of cancer treatment for decades, demonstrating effectiveness against various tumor types while requiring careful management of side effects.

Investigated diseases

  • Endometrial Cancer

    Endometrial cancer is a malignancy that develops in the lining of the uterus (endometrium). It typically begins with abnormal cell growth in the endometrial tissue, which can eventually form a tumor. The disease often develops slowly, starting as endometrial hyperplasia before potentially progressing to cancer. As it advances, endometrial cancer can spread locally within the pelvis, and in later stages may metastasize to distant organs such as the lungs or liver. In recurrent cases, the cancer returns after a period of remission, either in the same location or elsewhere in the body.

  • HER2-Expressing Endometrial Cancer

    This subtype of endometrial cancer is characterized by overexpression of the HER2 protein on cancer cell surfaces. HER2 (Human Epidermal Growth Factor Receptor 2) is a protein that promotes cell growth, and when overexpressed, can lead to more aggressive cancer behavior. In pathology, this is identified as either strongly positive (IHC 3+) or moderately positive (IHC 2+) using immunohistochemistry testing. HER2-expressing endometrial cancers may have distinct growth patterns and cellular characteristics compared to non-HER2 expressing types.

  • Mismatch Repair Proficient (pMMR) Endometrial Cancer

    This refers to endometrial cancer that has functioning DNA mismatch repair proteins. Mismatch repair is a cellular process that corrects errors during DNA replication. In pMMR endometrial cancer, this repair system works normally, as opposed to deficient mismatch repair (dMMR) tumors. pMMR endometrial cancers typically have fewer mutations overall compared to dMMR tumors. This molecular classification helps define the biological behavior of the tumor and its progression pattern.

Trial detailsLast updated 4 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2023-508056-19-00Protocol codeDESTINYEndometrial01Estimated enrolment568 patientsSponsorAstraZeneca AB

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