The DESTINY-Endometrial01 is a global, randomized (treatment assignment for the individual patient is by chance) Phase 3 study investigating a new treatment option for patients with advanced or recurrent endometrial cancer whose tumor cells overexpress HER2 and have a pMMR status. Two new combination therapies with the drug Trastuzumab deruxtecan (T-DXd with Rilvegostomig or Pembrolizumab) are compared with the current standard therapy of chemotherapy and immunotherapy. The aim is to find out whether the new treatments can prevent disease progression for longer.

What is being investigated in this study?

Endometrial carcinomas are among the most common cancers of the uterus.

For patients with advanced or recurrent disease at initial diagnosis, standard treatment often consists of a combination of chemotherapy and immunotherapy. Nevertheless, many patients experience disease progression over time, which is why new therapeutic approaches are needed.

The study targets patients whose tumors express human epidermal growth factor receptor 2 (HER2). HER2 is a protein on the surface of tumor cells that can transmit growth signals to the cancer cell. Some endometrial carcinomas show an increased presence of HER2, which can be used as a target for directed therapies.

In addition, the tumors must have a so-called pMMR status (proficient Mismatch Repair). This means that this repair system for genetic errors is fundamentally functional. These tumors often respond less well to immunotherapies than tumors with a defective repair system (dMMR), which is why new treatment strategies are being investigated.

This study uses, among other things, Trastuzumab deruxtecan (T-DXd). This is a so-called antibody-drug conjugate (ADC). The antibody specifically recognizes HER2 on the surface of tumor cells and then introduces a cell toxin into the cancer cell to destroy it.

In this study, T-DXd is combined either with Pembrolizumab, an immunotherapy, or with Rilvegostomig. Rilvegostomig is a new immunotherapeutic agent designed to simultaneously influence various mechanisms of the immune system to strengthen the body’s defense against the tumor.

What is the aim of the study?

The primary objective of the study is to investigate whether the combination of Trastuzumab deruxtecan with Rilvegostomig or Pembrolizumab can prevent disease progression for longer than the current standard treatment of chemotherapy and Pembrolizumab.

Furthermore, the study will investigate whether the new treatment strategies affect overall survival and how well the therapies are tolerated. Quality of life and patient-reported symptoms during treatment will also be examined.

What is the study procedure?

Patients participating in the study will be randomly assigned to one of three treatment arms:

Arm 1:
Trastuzumab deruxtecan + Rilvegostomig as an infusion every three weeks.

Arm 2:
Trastuzumab deruxtecan + Pembrolizumab as an infusion every three weeks.

Arm 3:
Current standard therapy consisting of chemotherapy with Carboplatin and Paclitaxel + Pembrolizumab for 6 treatment cycles. Subsequently, Pembrolizumab will be continued as maintenance therapy for up to 14 cycles.

Treatment will be continued in all study arms until disease progression, unacceptable side effects occur, or other reasons for discontinuing therapy arise.

Throughout the study, regular examinations will take place to monitor the effect of the treatment, possible side effects, and the general health status of the patients.

Are there risks?

You will be informed about possible risks or side effects associated with participation by your doctor during an informational consultation.

Eligibility criteria:

Women aged 18 years and older can participate in this study with:

• confirmed diagnosis of epithelial endometrial carcinoma. All histological types are permissible, with the exception of sarcomas (carcinosarcomas are permissible).
• advanced endometrial carcinoma (Stage III/IV) at initial diagnosis or first recurrence of endometrial carcinoma
• centrally confirmed positive HER2 status (IHC 3+ or 2+)
• confirmed pMMR status (functional MMR repair mechanism)
• No prior systemic therapy for the disease is allowed, with the exception of: adjuvant/neoadjuvant chemotherapy or chemoradiotherapy (for recurrences, recurrence or progression of the disease must have occurred ≥ 6 months after the last chemotherapy dose), treatment with Trastuzumab in the adjuvant/neoadjuvant setting and previous radiation therapy are permitted
• Previous treatment with ADCs or immune checkpoint inhibitors, including (but not limited to) anti-PD-1/PD-L1/PD-L2 and anti-CTLA-4 antibodies, as well as therapeutic cancer vaccines, is not permitted.

In addition, there are other criteria that must be met for participation in the study. Further information can be obtained from your treating physicians.

Further information on the study and centers where participation is possible can be found on the study homepage: https://www.astrazenecaclinicaltrials.com/study/D781DC00001/

This study is conducted by: