Clinical trial NCT06989112: 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
Official title: DESTINY-Endometrial01: An Open-Label, Sponsor-Blinded, Randomized, Controlled, Multicenter, Phase III Study of Trastuzumab Deruxtecan (T-DXd) Plus Rilvegostomig or Pembrolizumab vs Chemotherapy Plus Pembrolizumab as First-Line Therapy of HER2-Expressing (IHC 3+/2+), Mismatch Repair Proficient (pMMR), Primary Advanced or Recurrent Endometrial Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Endometrial Cancer
Keywords: Endometrial Cancer
Uterine Cancer
Endometrial Carcinoma
Human epidermal growth factor receptor 2 (HER2)
PMMR
Trastuzumab deruxtecan
T-DXd
DS-8201a
Anti-HER2-Antibody Drug Conjugate(ADC)
DESTINY-Endometrial01
Programmed Cell Death-1 (PD1, PD-1)
Immune checkpoint inhibitor
TIGIT
Pembrolizumab
Carboplatin
Paclitaxel
Rilvegostomig
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo Co., Ltd.
name: Gynecologic Oncology Group (GOG) Foundation Inc.
name: European Network for Gynaecological Oncological Trial groups(ENGOT)
First posted: 2025-05-25
Enrollment: 600
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants with HER2-expressing (IHC 3+/2+), pMMR, primary advanced (Stage III/IV) or recurrent EC will be randomly assigned to treatment with trastuzumab deruxtecan (T-DXd) plus rilvegostomig (Arm A), T-DXd plus pembrolizumab (Arm B), or chemotherapy (carboplatin plus paclitaxel) plus pembrolizumab (Arm C).
Primary purpose: TREATMENT

Brief summary: DESTINY-Endometrial01 will investigate 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.


Eligibility criteria: * Key Inclusion Criteria:

  * Participants must be ≥ 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).
  * 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.
  * Endometrial cancer with HER2 IHC expression of 3+ or 2+ as assessed by prospective central testing.
  * Endometrial cancer that is determined pMMR by prospective central IHC testing.
  * 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.
  * 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.
  * Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
  * Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before randomization.
  * Adequate organ and bone marrow function within 14 days before randomization.
* Key Exclusion Criteria:

  * History of organ transplant
  * 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.
  * Spinal cord compression or clinically active central nervous system metastases
  * 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
  * 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.
  * 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).
  * Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
  * 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.
  * 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.

Primary outcomes:
measure: Progression-free survival (PFS), as assessed by BICR
timeFrame: Until progression or death due to any cause (assessed up to approximately 45 months).
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Until the date of death due to any cause (assessed up to approximately 70 months).
measure: Progression Free Survival (PFS) as assessed by the investigator
timeFrame: Until progression or death due to any cause (assessed up to approximately 70 months).
measure: Time from randomization to second progression or death (PFS2)
timeFrame: Until the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death (assessed up to approximately 70 months).
measure: Objective response rate (ORR), as assessed by BICR and investigator
timeFrame: Until progression or the starting of subsequent anticancer therapy (assessed up to approximately 45 months).
measure: Duration of response (DoR), as assessed by BICR and investigator
timeFrame: Until progression or death due to any cause (assessed up to approximately 45 months).
measure: Safety and tolerability
timeFrame: Safety is assessed until the 90 days (+7) after the last dose (assessed up to approximately 70 months).
measure: Pharmacokinetics of T-DXd, total anti-HER2 antibody, DXd and rilvegostomig
timeFrame: Up to safety follow-up period (assessed up to approximately 45 months).
measure: Immunogenicity of T- DXd and rilvegostomig
timeFrame: Up to safety follow-up period (assessed up to approximately 45 months).
measure: Patient-reported tolerability
timeFrame: Up to progression as assessed by BICR (assessed up to approximately 45 months).
measure: Progression-free survival (PFS) according to MMR status to determine the clinical utility of a MMR diagnostic test
timeFrame: Through completion of study, assessed up to approximately 70 months.
measure: Overall survival (OS) according to MMR status to determine the clinical utility of a MMR diagnostic test
timeFrame: Through completion of study, assessed up to approximately 70 months.
measure: Progression-free survival (PFS) according to HER2 expression to determine the clinical utility of a HER2 diagnostic test
timeFrame: Through completion of study, assessed up to approximately 70 months.
measure: Overall survival (OS) according to HER2 expression to determine the clinical utility of a HER2 diagnostic test
timeFrame: Through completion of study, assessed up to approximately 70 months.
Other outcomes:
Locations:
city: Tucson
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state: Arizona
city: Little Rock
country: United States
facility: Research Site
state: Arkansas
city: La Jolla
country: United States
facility: Research Site
state: California
city: Palo Alto
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facility: Research Site
state: California
city: Sylmar
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city: Worcester
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city: Ann Arbor
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city: Detroit
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city: Saint Louis
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city: Las Vegas
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city: Albuquerque
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state: New York
city: New York
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state: New York
city: New York
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state: New York
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city: Tulsa
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city: Pittsburgh
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city: Providence
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state: South Dakota
city: Conroe
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state: Texas
city: Fredericksburg
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state: Texas
city: Irving
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state: Texas
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state: Vermont
city: Charlottesville
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state: Virginia
city: Seattle
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state: Washington
city: Madison
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state: Wisconsin
city: Blacktown
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city: East Melbourne
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facility: Research Site
city: Nedlands
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city: South Brisbane
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facility: Research Site
city: Anderlecht
country: Belgium
facility: Research Site
city: Bruxelles
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facility: Research Site
city: Charleroi
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facility: Research Site
city: Gent
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city: Leuven
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city: Liège
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facility: Research Site
city: Barretos
country: Brazil
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city: Belo Horizonte
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city: Goiânia
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city: Londrina
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city: Porto Alegre
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city: Porto Alegre
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city: Rio de Janeiro
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city: Salvador
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city: Sao Paulo
country: Brazil
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city: São Paulo
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city: São Paulo
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city: Teresina
country: Brazil
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city: Calgary
country: Canada
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state: Alberta
city: Edmonton
country: Canada
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state: Alberta
city: Halifax
country: Canada
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state: Nova Scotia
city: London
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state: Ontario
city: Toronto
country: Canada
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state: Ontario
city: Toronto
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state: Ontario
city: Montreal
country: Canada
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state: Quebec
city: Montréal
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state: Quebec
city: Montréal
country: Canada
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state: Quebec
city: Québec
country: Canada
facility: Research Site
state: Quebec
city: Beijing
country: China
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city: Changchun
country: China
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city: Changsha
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city: Chengdu
country: China
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city: Chengdu
country: China
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city: Chongqing
country: China
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city: Fuzhou
country: China
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city: Fuzhou
country: China
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city: Guangzhou
country: China
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city: Guangzhou
country: China
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city: Guangzhou
country: China
facility: Research Site
city: Haikou City
country: China
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city: Hangzhou
country: China
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city: Hefei
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Jinan
country: China
facility: Research Site
city: Jining
country: China
facility: Research Site
city: Kunming
country: China
facility: Research Site
city: Lanzhou
country: China
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city: Nanchang
country: China
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city: Nanning
country: China
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city: Shanghai
country: China
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city: Shanghai
country: China
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city: Shantou
country: China
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city: Shenyang
country: China
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country: China
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country: China
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country: China
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country: China
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country: China
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country: China
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country: China
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country: China
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country: China
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city: Aalborg
country: Denmark
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city: Herlev
country: Denmark
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city: København Ø
country: Denmark
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city: Odense
country: Denmark
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city: Helsinki
country: Finland
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city: Oulu
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city: Tampere
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city: Berlin
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city: Chemnitz
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city: Dessau-Roßlau
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city: Dresden
country: Germany
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city: Essen
country: Germany
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city: Hamburg
country: Germany
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city: Kassel
country: Germany
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city: Leipzig
country: Germany
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city: Mannheim
country: Germany
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city: Marburg
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city: Münster
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city: Saarbrücken
country: Germany
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city: Budapest
country: Hungary
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city: Budapest
country: Hungary
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city: Debrecen
country: Hungary
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city: Catania
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city: Milano
country: Italy
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city: Milan
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city: Milan
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city: Monza
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city: Napoli
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facility: Research Site
city: Reggio Emilia
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city: Roma
country: Italy
facility: Research Site
city: Rome
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facility: Research Site
city: Torino
country: Italy
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city: Turin
country: Italy
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city: Akashi-shi
country: Japan
facility: Research Site
city: Hidaka-shi
country: Japan
facility: Research Site
city: Isehara-shi
country: Japan
facility: Research Site
city: Kashiwa-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Matsuyama-shi
country: Japan
facility: Research Site
city: Morioka-shi
country: Japan
facility: Research Site
city: Nakagami-gun
country: Japan
facility: Research Site
city: Niigata-shi
country: Japan
facility: Research Site
city: Ota-shi
country: Japan
facility: Research Site
city: Sapporo-shi
country: Japan
facility: Research Site
city: Sendai-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon-si
country: Korea, Republic of
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Leiden
country: Netherlands
facility: Research Site
city: Nijmegen
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Stavanger
country: Norway
facility: Research Site
city: Białystok
country: Poland
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Siedlce
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
city: El Palmar
country: Spain
facility: Research Site
city: L'Hospitalet de Llobregat
country: Spain
facility: Research Site
city: La Coruna
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Palma de Mallorca
country: Spain
facility: Research Site
city: San Sebastian
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Zaragoza
country: Spain
facility: Research Site
city: Linköping
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
city: Frauenfeld
country: Switzerland
facility: Research Site
city: Liestal
country: Switzerland
facility: Research Site
city: Zurich
country: Switzerland
facility: Research Site
city: Changhua
country: Taiwan
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: New Taipei
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Bath
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Northwood
country: United Kingdom
facility: Research Site
Study officials:
References: