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

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Investigational drug late phase More information Active drug More information Moderate burden on patient More information

Trial Details

Sponsor: AstraZeneca (industry)

Phase: 3

Start date: March 27, 2025

Planned enrollment: 600

Trial ID: NCT06989112
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More trial details at ClinicalTrials.gov More info

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chevron Show for: Rilvegostomig (AZD2936)

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Goal: To determine whether first-line trastuzumab deruxtecan (T-DXd) combined with rilvegostomig or with pembrolizumab improves progression-free survival versus standard carboplatin/paclitaxel plus pembrolizumab in patients with HER2-expressing, pMMR primary advanced or recurrent endometrial cancer.

Patients: Adults with histologically confirmed epithelial endometrial carcinoma (all histologies except sarcomas; carcinosarcomas allowed) that is HER2 IHC 3+ or 2+ and mismatch repair proficient by central testing. Eligible disease settings include primary Stage III with measurable disease, primary Stage IV regardless of measurability, or first recurrence regardless of measurability. Patients must be systemic therapy–naïve in the advanced/recurrent setting; prior adjuvant/neoadjuvant chemotherapy is allowed if relapse occurred ≥6 months after completion. ECOG 0–1, adequate organ function, LVEF ≥50%, and provision of adequate non-irradiated FFPE tissue for central HER2/MMR/PD-L1 testing are required. Key exclusions include prior ADCs or immune checkpoint inhibitors, significant cardiac disease, history or suspicion of ILD/pneumonitis, clinically significant pulmonary comorbidity, uncontrolled autoimmune disease, uncontrolled infections including active TB or hepatitis, and uncontrolled CNS disease.

Design: Multicenter, open-label, sponsor-blinded, randomized, controlled Phase III trial. Approximately 600 participants randomized to one of three arms; efficacy assessed by blinded independent central review for the primary endpoint. First-line treatment setting with stratification by biomarker-defined subgroups through central testing.

Treatments: Arm A: T-DXd IV every 3 weeks plus rilvegostomig IV every 3 weeks until progression or discontinuation. Arm B: T-DXd IV every 3 weeks plus pembrolizumab IV every 3 weeks until progression or discontinuation. Arm C (control): Carboplatin plus paclitaxel and pembrolizumab every 3 weeks for 6 cycles, then pembrolizumab maintenance every 6 weeks to complete up to 20 cycles total; at investigator discretion, combination may continue up to 10 cycles; docetaxel may replace paclitaxel after hypersensitivity. Trastuzumab deruxtecan is an anti-HER2 antibody–drug conjugate delivering a topoisomerase I inhibitor (DXd) with bystander effect; it has demonstrated substantial antitumor activity across HER2-expressing tumors and is associated with risks including interstitial lung disease/pneumonitis and cytopenias. Rilvegostomig is an investigational bispecific IgG1 antibody targeting PD-1 and TIGIT with Fc-silencing mutations to limit effector functions; in a Phase I NSCLC study it showed acceptable tolerability, dose-proportional exposure, approximately 90% dual receptor occupancy at ≥210 mg, and preliminary antitumor activity in heavily pretreated patients, supporting Phase III evaluation. Pembrolizumab plus carboplatin/paclitaxel represents an established first-line chemoimmunotherapy backbone in endometrial cancer.

Outcomes: Primary: Progression-free survival by blinded independent central review per RECIST 1.1. Key secondary endpoints include overall survival; investigator-assessed PFS; PFS2; objective response rate and duration of response by BICR and investigator; safety and tolerability (AEs, SAEs, AESIs, labs, vitals, ECG, echocardiography/MUGA); pharmacokinetics of T-DXd, total anti-HER2 antibody, DXd, and rilvegostomig; immunogenicity (ADAs); patient-reported tolerability (symptomatic AEs and overall side-effect bother); and exploratory assessment of PFS and OS by MMR status and by HER2 expression to evaluate diagnostic utility. Follow-up for PFS up to approximately 45 months and for OS up to approximately 70 months.

Burden on patient: Moderate. Requirements include central confirmation of HER2 and MMR status on adequate FFPE tissue, which may necessitate a diagnostic or archival sample meeting quality criteria. Treatment visits are every 3 weeks for combination therapy and involve IV infusions, routine labs, vitals, ECGs, and echocardiography/MUGA to monitor LVEF, plus periodic imaging per RECIST; the control arm includes multi-drug chemotherapy for 6–10 cycles with associated clinic time and infusion-related logistics. Experimental arms include pharmacokinetic and immunogenicity blood draws at predefined time points, adding to visit duration. Safety monitoring for T-DXd includes vigilance for ILD/pneumonitis with potential additional imaging or pulmonology evaluation if symptomatic. Overall visit frequency and imaging schedule are similar to standard-of-care chemoimmunotherapy, but added PK/ADA sampling and cardiac monitoring increase time and procedural burden compared with routine care.

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East Melbourne, 3002, Australia

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Nedlands, 6009, Australia

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South Brisbane, 4101, Australia

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Wein, 1130, Austria

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Vienna, 1090, Austria

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Innsbruck, 6020, Austria

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Brussels, 1200, Belgium

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Charleroi, 6060, Belgium

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Teresina, 64049-200, Brazil

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Barretos, 14784-057, Brazil

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Belo Horizonte, 30130 100, Brazil

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Goiânia, 74000-000, Brazil

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Londrina, 86015-520, Brazil

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Halifax, Nova Scotia, B3H 2Y9, Canada

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London, Ontario, N6A 4L6, Canada

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Yibin, 610500, China

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Xuzhou, 221009, China

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Xi'an, 710061, China

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Wuhan, 430022, China

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Wuhan, 430000, China

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Ürümqi, 830000, China

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Tianjin, 300060, China

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Taiyuan, 030001, China

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Shenyang, 110042, China

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Shenyang, 110004, China

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Shantou, China

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Shanghai, 201318, China

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Nanning, 530021, China

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Nanchang, 330006, China

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Lanzhou, 730030, China

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Kunming, 650118, China

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Jining, 272029, China

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Jinan, 250117, China

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Hefei, 230001, China

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Harbin, 150049, China

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Hangzhou, 310022, China

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Haikou, 570311, China

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Chongqing, 400030, China

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Chengdu, 610072, China

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Changsha, 410013, China

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Changchun, 130021, China

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Beijing, 100142, China

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Aalborg, 9100, Denmark

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Herlev, 2730, Denmark

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København Ø, 2100, Denmark

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Odense, 5000, Denmark

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Helsinki, 00290, Finland

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Oulu, 90029, Finland

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Tampere, 33520, Finland

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Turku, 20520, Finland

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Paris, 75015, France

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Besançon, 25030, France

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Bordeaux, 33076, France

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Caen, 14076, France

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Clermont-Ferrand, 63000, France

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Lyon, 69373, France

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Montpellier, 34298, France

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Nice, 06100, France

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Plérin, 22190, France

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Poitiers, 86021, France

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Saint-Herblain, 44805, France

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Toulouse, 31059, France

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Leipzig, 04103, Germany

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Marburg, 35043, Germany

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Münster, 48149, Germany

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Dresden, 01307, Germany

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Saarbrücken, 66113, Germany

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Dessau, 06847, Germany

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Chemnitz, 09116, Germany

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Berlin, 13353, Germany

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Hamburg, 20246, Germany

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Kassel, 34125, Germany

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Mannheim, 68167, Germany

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Essen, 45147, Germany

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Debrecen, 4032, Hungary

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Budapest, 1122, Hungary

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Budapest, 1088, Hungary

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Monza, 20900, Italy

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Milan, 20159, Italy

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Milan, 20141, Italy

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Florence, 50134, Italy

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Catania, 95100, Italy

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Turin, 10128, Italy

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Torino, 10128, Italy

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Rome, 00168, Italy

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Roma, 00144, Italy

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Reggio Emilia, 422122, Italy

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Napoli, 80131, Italy

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Milan, 20162, Italy

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Sendai, 980-8574, Japan

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Hidaka-shi, 350-1298, Japan

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Isehara-shi, 259-1193, Japan

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Kashiwa, 227-8577, Japan

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Kashiwa-shi, 277-8567, Japan

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Kobe, 650-0047, Japan

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Kōtoku, 135-8550, Japan

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Kurume-shi, 830-0011, Japan

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Matsuyama, 791-0280, Japan

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Morioka, 028-3695, Japan

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Nagoya, 464-8681, Japan

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Nakagami-gun, 903-0215, Japan

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Niigata, 951-8520, Japan

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Osaka, 541-8567, Japan

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Ota-shi, 373-8550, Japan

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Sapporo, 060-8648, Japan

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Akashi-shi, 673-8558, Japan

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Shinjuku-ku, 160-8582, Japan

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Sunto-gun, 411-8777, Japan

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Tokyo, 104-0045, Japan

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Amsterdam, 1066CX, Netherlands

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Leiden, 2333 ZA, Netherlands

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Nijmegen, 6525 GA, Netherlands

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Rotterdam, 3015 GD, Netherlands

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Stavanger, 4011, Norway

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Oslo, 0379, Norway

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Lodz, 93-338, Poland

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Szczecin, 70-111, Poland

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Siedlce, 08-110, Poland

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Poznan, 60-569, Poland

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Gdansk, 80-214, Poland

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Bialystok, 15-027, Poland

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Suwon, 16499, South Korea

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Goyang-si, 10408, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 05505, South Korea

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Seoul, 06351, South Korea

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Córdoba, 14004, Spain

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A Coruña, 15009, Spain

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Donostia / San Sebastian, 20014, Spain

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El Palmar, 30120, Spain

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L'Hospitalet de Llobregat, 08908, Spain

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Madrid, 28034, Spain

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Madrid, 28041, Spain

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Palma de Mallorca, 07010, Spain

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Valencia, 46006, Spain

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Valencia, 46009, Spain

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Zaragoza, 50009, Spain

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Uppsala, 751 85, Sweden

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Stockholm, 17164, Sweden

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Lund, 22185, Sweden

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Linköping, 581 85, Sweden

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Zurich, 8091, Switzerland

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Liestal, CH- 4410, Switzerland

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Frauenfeld, 8501, Switzerland

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Tainan City, 704, Taiwan

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Kaohsiung City, 81362, Taiwan

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Changhua, 500, Taiwan

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New Taipei City, 220, Taiwan

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Taipei, 10449, Taiwan

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Taichung, 40705, Taiwan

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Taunton, TA1 5DA, United Kingdom

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Bath, BA1 3NG, United Kingdom

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Cambridge, CB2 0QQ, United Kingdom

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Leeds, LS9 7TF, United Kingdom

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London, EC1A 7BE, United Kingdom

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Manchester, M20 4BX, United Kingdom

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Northwood, HA6 2RN, United Kingdom

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Tucson, Arizona, 85704, United States

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Little Rock, Arkansas, 72205, United States

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La Jolla, California, 92037, United States

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Sylmar, California, 91342, United States

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Palo Alto, California, 94304, United States

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Fort Myers, Florida, 33908, United States

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West Palm Beach, Florida, 33401, United States

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Tampa, Florida, 33612, United States

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St. Petersburg, Florida, 33705, United States

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Miami Beach, Florida, 33140, United States

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Augusta, Georgia, 30912, United States

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Honolulu, Hawaii, 96813, United States

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Niles, Illinois, 60714, United States

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Evanston, Illinois, 60201, United States

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Shreveport, Louisiana, 71103, United States

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Baltimore, Maryland, 21201, United States

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Worcester, Massachusetts, 01655, United States

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Boston, Massachusetts, 02111, United States

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Detroit, Michigan, 48201, United States

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Ann Arbor, Michigan, 48109, United States

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Minneapolis, Minnesota, 55455, United States

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Rochester, Minnesota, 55905, United States

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Jackson, Mississippi, 39216, United States

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St Louis, Missouri, 63141, United States

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Las Vegas, Nevada, 89169, United States

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Hackensack, New Jersey, 07601, United States

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Albuquerque, New Mexico, 87109, United States

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New York, New York, 10075, United States

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New York, New York, 10065, United States

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New York, New York, 10016, United States

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Winston-Salem, North Carolina, 27103, United States

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Charlotte, North Carolina, 28204, United States

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Cincinnati, Ohio, 45220, United States

No email / No phone

Status: Not yet recruiting

Research Site

Tulsa, Oklahoma, 74134, United States

No email / No phone

Status: Withdrawn

Research Site

Eugene, Oregon, 97401, United States

No email / No phone

Status: Not yet recruiting

Research Site

Philadelphia, Pennsylvania, 19111, United States

No email / No phone

Status: Not yet recruiting

Research Site

Pittsburgh, Pennsylvania, 15224, United States

No email / No phone

Status: Not yet recruiting

Research Site

Abington, Pennsylvania, 19001, United States

No email / No phone

Status: Withdrawn

Research Site

Hershey, Pennsylvania, 17033, United States

No email / No phone

Status: Withdrawn

Research Site

Providence, Rhode Island, 02905, United States

No email / No phone

Status: Not yet recruiting

Research Site

Charleston, South Carolina, 29425, United States

No email / No phone

Status: Not yet recruiting

Research Site

Sioux Falls, South Dakota, 57105, United States

No email / No phone

Status: Not yet recruiting

Research Site

Irving, Texas, 75063, United States

No email / No phone

Status: Not yet recruiting

Research Site

Fredericksburg, Texas, 78624, United States

No email / No phone

Status: Not yet recruiting

Research Site

Austin, Texas, 78758, United States

No email / No phone

Status: Not yet recruiting

Research Site

Houston, Texas, 77030, United States

No email / No phone

Status: Not yet recruiting

Research Site

Saint Johnsbury, Vermont, 05819, United States

No email / No phone

Status: Not yet recruiting

Research Site

Charlottesville, Virginia, 22908, United States

No email / No phone

Status: Not yet recruiting

Research Site

Seattle, Washington, 98133, United States

No email / No phone

Status: Withdrawn

Research Site

Madison, Wisconsin, 53705, United States

No email / No phone

Status: Not yet recruiting

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