DESTINY-Endometrial01: A Phase III Study of Trastuzumab Deruxtecan Plus Rilvegostomig or Pembrolizumab as First-Line Treatment of HER2-Expressing (IHC 3+/2+), Mismatch Repair Proficient (pMMR) Endometrial Cancer

Prior treatment

• Active or prior documented autoimmune or inflammatory disorders requiring chronic systemic treatment with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs.
• Lung criteria:
  • Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, etc.).
  • Any autoimmune, connective tissue or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of screening.
  • Prior pneumonectomy (complete).
• History of myocardial infarction or unstable angina within 6 months before randomization, or symptomatic congestive heart failure (NYHA Class II to IV), clinically significant arrhythmia, uncontrolled hypertension, cardiomyopathy of any etiology or history of myocarditis.

Other illness

• Any severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or would jeopardize compliance with the protocol.
• Active or ongoing serious chronic gastrointestinal conditions associated with diarrhea, primary immunodeficiency, or non-infectious skin disease requiring systemic treatment.
• History of (non-infectious) ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
• History of organ transplant or allogeneic stem cell transplant.
• Evidence of any of the following infections:
  • Active tuberculosis
  • HIV infection that is not well controlled.
  • Active hepatitis B or C infection.

Other

• Spinal cord compression or clinically active central nervous system metastases. Participants with clinically inactive brain metastases may be included in the study.

• ≥ 18 years of age at the time of screening. Other age restrictions may apply as per local regulations.
• Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies are allowed except for sarcomas (carcinosarcomas are allowed).
• Participant must have primary advanced disease (Stage III/IV) or recurrent endometrial cancer and meet at least one of the following criteria:
  • Primary Stage III (per FIGO 2023) disease with measurable disease at baseline per RECIST 1.1 based on the investigator's assessment.
  • Primary Stage IV (per FIGO 2023) disease regardless of presence of measurable disease at baseline.
  • Recurrent disease regardless of presence of measurable disease at baseline.
• Endometrial cancer with HER2 IHC expression of 3+ or 2+ by prospective central testing.
• Endometrial cancer that is determined pMMR by prospective central testing.
• Provision of an adequate FFPE tumor tissue sample for central HER2, MMR, and PD-L1 IHC testing.
• Prior therapy:
  • No prior chemotherapy for the treatment of EC, except for one prior line of adjuvant/ neoadjuvant chemotherapy with curative intent (chemotherapy or chemoradiation) if completed ≥ 6 months prior to signature of the main ICF. Prior trastuzumab in the adjuvant/neoadjuvant setting is allowed.
  • No prior exposure to antibody-drug conjugates or immune checkpoint inhibitors
  • Participants may have received prior radiation therapy for the treatment of endometrial cancer. Adequate treatment washout period is required
  • Participants may have received prior hormonal therapy for the treatment of endometrial cancer. Adequate treatment washout period is required
• ECOG 0-1.
• Left ventricular ejection fraction ≥ 50% within 28 days before randomization.
• Adequate organ and bone marrow function within 14 days before randomization.
• The participant is not considered a candidate for curative therapy in the judgment of the investigator.