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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Oct 2025 → ongoing

Decision date (initial)

2025-07-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Therapy

To demonstrate the efficacy of first-line T-DXd + rilvegostomig (Arm A) and/or T-DXd+ pembrolizumab (Arm B) when compared to chemotherapy (carboplatin + paclitaxel) + pembrolizumab (Arm C), by assessment of progression free survival (PFS), as assessed by BICR, in participants with HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent EC.

Secondary objectives 12

1. To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of overall survival (OS).
2. To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of PFS as assessed by the investigator.
3. To assess the efficacy of Arm A and/or Arm B compared to Arm C in terms of time from randomization to second progression or death (PFS2).
4. To assess the efficacy of Arm A and/or Arm B relative to Arm C in terms of the confirmed objective response rate (ORR) according to BICR and investigator assessment.
5. To assess the efficacy of Arm A and/or ArmB compared to Arm C in terms of duration of response (DoR) according to BICR and investigator assessment.
6. To assess the efficacy of Arm A compared to Arm B in terms of PFS, as assessed by BICR.
7. To assess the efficacy of Arm A compared to Arm B in terms of OS.
8. To assess the safety and tolerability of Arm A and/or Arm B compared to Arm C.
9. To assess the PK of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig in serum.
10. To investigate the immunogenicity of T- DXd and rilvegostomig.
11. To describe patient-reported tolerability of Arm A and/or Arm B compared to Arm C.
12. To collect and assess tissue samples for development of regulated companion diagnostics for the detection of HER2 expression and MMR status.

Conditions and MedDRA coding

HER2-Expressing (IHC 3+/IHC 2+), Mismatch Repair Proficient (pMMR), Primary Advanced or Recurrent Endometrial Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Participants must be ≥ 18 years of age at the time of screening. Other age restrictions may apply as per local regulations.
2. Histologically confirmed diagnosis of epithelial endometrial carcinoma. All histologies are allowed except for sarcomas (carcinosarcomas are allowed).
3. Following surgery or diagnostic biopsy, participant must have primary advanced disease (Stage III/IV) or first 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 disease (per FIGO 2023) regardless of presence of measurable disease at baseline. - First recurrent disease regardless of presence of measurable disease at baseline.
4. Endometrial cancer with HER2 IHC expression of 3+ or 2+ as assessed by prospective central testing.
5. Endometrial cancer that is determined pMMR by prospective central IHC testing.
6. Provision of adequate FFPE tumor tissue sample of a tumor lesion that was not previously irradiated for central HER2, MMR, and PD-L1 IHC testing and valid central test results for randomization/ stratification.
7. Prior therapy: - Naïve to first-line systemic anticancer therapy. Participants may have received one prior line of adjuvant/neoadjuvant chemotherapy with curative intent (chemotherapy or chemoradiation) if disease recurrence or progression occurred ≥ 6 months after last dose of chemotherapy. Prior trastuzumab in the adjuvant/neoadjuvant setting is allowed. - No prior exposure to ADCs or immune checkpoint inhibitors including (but not limited to) anti-PD-1/PD-L1/PD-L2 and anti-CTLA-4 antibodies and therapeutic anticancer vaccines. - Participants may have received prior radiation therapy for the treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy. Adequate treatment washout period is required.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
9. Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before randomization.
10. Adequate organ and bone marrow function within 14 days before randomization.

Exclusion criteria 9

1. History of organ transplant.
2. Uncontrolled intercurrent illness, including, but not limited to ongoing or active known infection, serious chronic gastrointestinal conditions associated with diarrhea and active non-infectious skin disease requiring systemic treatment.
3. Spinal cord compression or clinically active central nervous system metastases.
4. Participants with a medical history of myocardial infarction (MI) within 6 months before randomization, or symptomatic congestive heart failure (CHF) (NYHA Class II to IV), clinically significant arrhythmia, or cardiomyopathy of any etiology. Participants with troponin levels above ULN at screening (as defined by the manufacturer), should have a cardiologic consultation before enrollment to rule out MI
5. 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.
6. 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, pleural effusion 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).
7. Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
8. Active primary immunodeficiency/ active infectious disease(s) including: - Tuberculosis (TB) - HIV infection that is not well controlled. - Chronic or active hepatitis B, chronic or active hepatitis C; however, participants who have chronic hepatitis B and are receiving suppressive antiviral therapy are allowed to be enrolled if alanine aminotransferase (ALT) is normal and viral load is controlled.
9. Any concurrent anticancer treatment without an adequate washout period prior to the first dose of study intervention. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., HRT) is allowed.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression free survival (PFS) as assessed by BICR defined as time from randomization until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.

Secondary endpoints 10

1. Overall survival (OS) defined as the time from randomization until the date of death due to any cause.
2. PFS as assessed by investigator (has the same attributes as estimand of PFS by BICR, except tumor assessment is by the investigator).
3. PFS2 defined as the time from randomization to the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death.
4. ORR as assessed by BICR is defined as the proportion of participants who have a complete response (CR) or partial response (PR), as determined and confirmed by BICR per RECIST 1.1. ORR as assessed and confirmed by the investigator has the same attributes as estimand of ORR by BICR except tumor assessment per the investigator.
5. DoR as assessed by BICR will be defined as the time from the date of first documented response of confirmed responders until date of documented progression per RECIST 1.1 as assessed by BICR or death due to any cause. DoR as assessed by the investigator has the same attributes as estimand of DoR by BICR except tumor assessment per the investigator.
6. Safety and tolerability (evaluated in terms of AEs/serious AEs (SAEs), AESI, vital signs, clinical safety laboratory assessments, ECG and ECHO/MUGA scan results).
7. Serum concentration of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig.
8. Presence of ADAs for T-DXd and rilvegostomig.
9. Patient-reported tolerability.
10. Assessment of MMR and HER2 expression in tissue samples and their impact to clinical endpoints, addressing clinical utility of the tests.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 4

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

13 EU/EEA countries · 82 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 107 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications