Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15)

NCT05173987Active, Not RecruitingPHASE3INTERVENTIONAL

Summary

The purpose of this study is to assess the safety and efficacy of treatment with pembrolizumab (MK-3475) compared to a combination of carboplatin and paclitaxel in women with mismatch repair deficient (dMMR) advanced or recurrent endometrial carcinoma who have not previously been treated with prior systemic chemotherapy. The primary study hypotheses are that pembrolizumab is superior to the combination of carboplatin and paclitaxel with respect to Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR) and Overall Survival (OS).

Key Facts

Lead Sponsor

Merck Sharp & Dohme LLC

Enrollment

280

Start Date

2022-02-03

Completion Date

2027-05-27

Study Type

INTERVENTIONAL

Official Title

A Phase 3 Randomized, Open-label, Active-comparator Controlled Clinical Study of Pembrolizumab Versus Platinum Doublet Chemotherapy in Participants With Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma in the First-line Setting (KEYNOTE-C93/GOG-3064/ENGOT-en15)

Interventions

pembrolizumabcarboplatinpaclitaxeldocetaxelcisplatin

Conditions

Endometrial Neoplasms

Eligibility

Age Range

18 Years+

Sex

FEMALE

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

* Has a histologically confirmed diagnosis of inoperable, Stage III or IV or recurrent Endometrial Carcinoma (EC) or carcinosarcoma (mixed Mullerian tumor) that is centrally confirmed as dMMR.
* Has radiographically evaluable disease, either measurable or non-measurable per RECIST 1.1, as assessed by the investigator. Note: primary Stage IVB that has undergone surgical resection is allowed regardless of presence of measurable or evaluable disease.
* Has received no prior systemic therapy for EC except for the following:

  1. May have received 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of curative-intent resection if the recurrence occurred ≥6 months after the last dose of chemotherapy.
  2. May have received prior radiation with or without radiosensitizing chemotherapy if \>2 weeks before the start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
  3. May have received prior hormonal therapy for treatment of EC, provided that it was discontinued ≥1 week prior to randomization.
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization.
* Is not pregnant or breastfeeding and agrees to not donate eggs and use a highly effective contraceptive method for 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy if a woman of childbearing potential (WOCBP).
* Has a negative highly sensitive pregnancy test (urine or serum) within 24 hours for urine or 72 hours for serum before the first dose of study intervention if a WOCBP.
* Provides an archival tumor tissue sample or newly obtained (core, incisional, or excisional) biopsy of a tumor lesion not previously irradiated for verification of dMMR status and histology.
* If Hepatitis B surface antigen (HBsAg) positive, has received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load prior to randomization.
* If has a history of Hepatitis C virus (HCV) infection, has undetectable HCV viral load at screening.

Exclusion Criteria:

* Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas and neuroendocrine tumors are not allowed.
* Has EC of any histology that is proficient mismatch repair (pMMR).
* Is a candidate for curative-intent surgery or curative-intent radiotherapy.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], Tumor necrosis factor receptor superfamily, member 4 \[OX 40\], tumor necrosis factor receptor superfamily member 9 \[CD137\]).
* Has received prior systemic anticancer therapy including investigational agents for any advanced or metastatic EC. (Note: Prior chemotherapy administered as adjuvant therapy, neoadjuvant therapy, and/or concurrently with radiation is permitted.
* Has had a major operation and has not recovered adequately from the procedure and/or any complications from the operation before starting study intervention.
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
* Is currently participating in or has participated in a study of an investigational agent for EC, has participated in a study of an investigational agent for non-EC within 4 weeks before the first dose of study intervention, or has used an investigational device within 4 weeks before the first dose of study intervention.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) that have undergone potentially curative therapy are not excluded.
* Has known active CNS metastases and/or carcinomatous meningitis.
* Has a known intolerance to any study intervention and/or any of its excipients.
* Has an active autoimmune disease that has required systemic treatment in past 2 years.
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection, requiring systemic therapy.
* Has a known history of human immunodeficiency virus (HIV) infection.
* Has had an allogenic tissue/solid organ transplant.

Outcome Measures

Primary Outcomes

Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by BICR will be reported for participants.

Time frame: Up to approximately 45 months

Overall Survival

OS is defined as the time from randomization to death due to any cause. The OS will be reported for all participants.

Time frame: Up to approximately 59 months

Secondary Outcomes

Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

ORR is defined as the percentage of participants who have a best response of confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.

Time frame: Up to approximately 45 months

Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

DCR is defined, per RECIST 1.1, as the percentage of participants who have achieved Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or demonstrated Stable Disease (SD) for at least 24 weeks. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD.) The DCR as assessed by BICR will be presented.

Time frame: Up to approximately 45 months

Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

DOR is defined as the time from first documented evidence of CR or PR until the first documented date of disease progression (PD) or death due to any cause, whichever occurs first, for participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.

Time frame: Up to approximately 45 months

Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator

PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by investigator will be reported for participants.

Time frame: Up to approximately 45 months

Progression-Free Survival 2 (PFS2) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator

PFS2 is defined as the time from randomization to subsequent disease progression (PD) per RECIST 1.1 after initiation of a new anticancer therapy, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS2 per RECIST 1.1 as assessed by investigator will be reported for participants.

Time frame: Up to approximately 45 months

Number of Participants Who Experience at Least One Adverse Event (AE)

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience an AE will be reported.

Time frame: Up to approximately 27 months

Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinue study treatment due to an AE will be reported.

Time frame: Up to approximately 24 months

Change From Baseline in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) (Item 29) And Quality of Life (QoL) (Item 30) Combined Score

The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score will be presented.

Time frame: Baseline and up to approximately 25 months

Change From Baseline in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Combined Score

The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score will be presented. A higher score indicates a better quality of life.

Time frame: Baseline and up to approximately 25 months

Locations

HonorHealth-USOR HonorHealth ( Site 8000), Phoenix, United States

Moores Cancer Center ( Site 0037), La Jolla, United States

Kaiser Permanente Riverside Medical Center ( Site 0045), Riverside, United States

Yale-New Haven Hospital-Smilow Cancer Hospital at Yale-New Haven ( Site 0013), New Haven, United States

Mount Sinai Cancer Center ( Site 0018), Miami Beach, United States

Sarasota Memorial Hospital ( Site 0005), Sarasota, United States

Northside Hospital ( Site 0017), Atlanta, United States

Southeastern Regional Medical Center ( Site 0046), Newnan, United States

Midwestern Regional Medical Center,Inc. DBA CTCA, Chicago ( Site 0003), Zion, United States

St. Vincent Hospital and Health Care Center, Inc ( Site 0006), Indianapolis, United States

Baptist Health Lexington ( Site 0042), Lexington, United States

Maryland Oncology Hematology, P.A.-USOR Maryland Oncology Hematology, P.A. ( Site 8002), Rockville, United States

University of Massachusetts Medical School-Division of Gynecologic Oncology ( Site 0008), Worcester, United States

Karmanos Cancer Institute ( Site 0029), Detroit, United States

St. Dominic's Hospital ( Site 0024), Jackson, United States

John Theurer Cancer Center at Hackensack University Medical Center ( Site 0026), Hackensack, United States

The Blavatnik Family- Chelsea Medical Center at Mount Sinai ( Site 0023), New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone ( Site 0016), New York, United States

Icahn School of Medicine at Mount Sinai ( Site 0052), New York, United States

Memorial Sloan Kettering Cancer Center ( Site 0009), New York, United States

FirstHealth Clinical Trials ( Site 0050), Pinehurst, United States

Sanford Medical Center ( Site 0054), Bismarck, United States

Sanford Fargo Medical Center-Roger Maris Cancer Center ( Site 0055), Fargo, United States

University of Cincinnati Medical Center-University of Cincinnati Cancer Center ( Site 0039), Cincinnati, United States

The James Cancer Hospital and Solove Research Institute at The Ohio State University Comprehensive C, Columbus, United States

Providence Portland Medical Center ( Site 0031), Portland, United States

Sidney Kimmel Cancer Center - Jefferson Health ( Site 0053), Philadelphia, United States

University of Pittsburgh Medical Center Magee-Womens Hospital ( Site 0034), Pittsburgh, United States

AHN West Penn Hospital ( Site 0011), Pittsburgh, United States

Asplundh Cancer Pavilion ( Site 0014), Willow Grove, United States

Sanford Cancer Center-Gynecologic Oncology ( Site 0002), Sioux Falls, United States

Texas Oncology - Austin-USOR Texas Oncology - Austin ( Site 8003), Austin, United States

Texas Oncology - Dallas-USOR Texas Oncology - Dallas (Sammons) ( Site 8005), Dallas, United States

Texas Oncology - Tyler-USOR Texas Oncology - Northeast Texas ( Site 8004), Tyler, United States

VCU Health Adult Outpatient Pavillion ( Site 0022), Richmond, United States

Northern Cancer Institute ( Site 0206), St Leonards, Australia

Westmead Hospital-Department of Gynaecological Oncology ( Site 0201), Westmead, Australia

Royal Brisbane and Women's Hospital-Medical Oncology Clinical Trials Unit, Cancer Care Services ( Si, Brisbane, Australia

Monash Health ( Site 0202), Clayton, Australia

Peter MacCallum Cancer Centre-Parkville Cancer Clinical Trials Unit (PCCTU) ( Site 0207), Melbourne, Australia

Epworth Freemasons ( Site 0203), Melbourne, Australia

St. John of God Subiaco Hospital-Oncology Clinical Trials Unit ( Site 0204), Subiaco, Australia

Institut Jules Bordet-Medicine Oncology ( Site 0321), Brussels, Belgium

Grand Hôpital de Charleroi-Oncology & Hematology ( Site 0323), Charleroi, Belgium

Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman ( Site 0320), Liège, Belgium

Liga Norte Riograndense Contra o Câncer-Centro de Pesquisa Clínica ( Site 3005), Natal, Brazil

ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO ( Site 3001), São Paulo, Brazil

A. C. Camargo Cancer Center-CAPEC ( Site 3003), São Paulo, Brazil

Cross Cancer Institute ( Site 0513), Edmonton, Canada

BC Cancer Kelowna ( Site 0517), Kelowna, Canada

BC Cancer Vancouver-Clinical Trials Unit ( Site 0518), Vancouver, Canada

Sunnybrook Health Sciences - Odette Cancer Centre ( Site 0509), Toronto, Canada

Princess Margaret Cancer Centre ( Site 0510), Toronto, Canada

Centre Hospitalier de l'Université de Montréal ( Site 0519), Montreal, Canada

Jewish General Hospital ( Site 0504), Montreal, Canada

McGill University Health Centre ( Site 0505), Montreal, Canada

Saskatoon Cancer Center-Clinical Research Department ( Site 0520), Saskatoon, Canada

FALP-UIDO ( Site 0602), Santiago, Chile

Pontificia Universidad Catolica de Chile-Centro del Cáncer ( Site 0604), Santiago, Chile

Bradfordhill-Clinical Area ( Site 0603), Santiago, Chile

Anhui Provincial Hospital-Obstetrics and Gynecology ( Site 0730), Hefei, China

Beijing Obstetric and Gynecology Hospital ( Site 0740), Beijing, China

Peking University First Hospital ( Site 0723), Beijing, China

Beijing Cancer hospital ( Site 0715), Beijing, China

Southwest Hospital of Third Military Medical University ( Site 0719), Chongqing, China

2nd Affiliated Hospital Chongqing Medical Universi ( Site 0745), Chongqing, China

Fuling Central Hospital ( Site 0733), Fulingqu, China

Fujian Provincial Cancer Hospital ( Site 0720), Fuzhou, China

SUN YAT-SEN UNIVERSITY CANCER CENTRE ( Site 0710), Guangzhou, China

Cancer Hospital of Shantou University Medical College ( Site 0732), Shantou, China

Affiliated Hospital of Guangdong Medical College ( Site 0731), Zhanjiang, China

Guangxi Medical University Affiliated Tumor Hospital-Gynecological oncology ( Site 0704), Nanning, China

Hainan General Hospital ( Site 0703), Haikou, China

Harbin Medical University Cancer Hospital ( Site 0711), Harbin, China

Henan Cancer Hospital ( Site 0713), Zhengzhou, China

Wuhan Union Hospital-Medical Oncology ( Site 0716), Wuhan, China

Xiangya Hospital Central South University-Gynecology ( Site 0708), Changsha, China

Hunan Cancer Hospital ( Site 0709), Changsha, China

Jiangsu Province Hospital-Oncology Department ( Site 0707), Nanjing, China

The First Affiliated Hospital of Nanchang University ( Site 0729), Nanchang, China

The First Hospital of Jilin University ( Site 0705), Changchun, China

Shaanxi Provincial Cancer Hospital ( Site 0714), Xi'an, China

Binzhou Medical University Hospital-Oncology department ( Site 0735), Binzhou, China

Obstetrics & Gynecology Hospital of Fudan University ( Site 0702), Shanghai, China

Shanghai First Maternity and Infant Hospital-Gynecology department ( Site 0717), Shanghai, China

West China Second University Hospital Sichuan University ( Site 0701), Chengdu, China

Tianjin Medical University Cancer Institute and Hospital ( Site 0706), Tianjin, China

Yunnan Province Cancer Hospital-Gynecology Department ( Site 0721), Kunming, China

The Affiliated Women's Hospital of Zhejiang University-Obstetrics and Gynecology ( Site 0726), Hangzhou, China

Zhejiang Cancer Hospital-Oncology ( Site 0700), Hangzhou, China

The First Affiliated Hospital of Wenzhou Medical University-Gynecology ( Site 0725), Wenzhou, China

Fakultní nemocnice Brno Bohunice-Gynekologicko-porodnicka klinika ( Site 0404), Brno, Czechia

Fakultni nemocnice Ostrava-Gynekologicko-porodnicka klinika ( Site 0403), Ostrava, Czechia

Nemocnice AGEL Novy Jicin a.s.-Oddeleni radioterapie a onkologie ( Site 0406), Nový Jiín, Czechia

Fakultni nemocnice Olomouc-Onkologicka klinika ( Site 0402), Olomouc, Czechia

Vseobecna fakultni nemocnice v Praze-Gynekologicko-porodnicka klinika 1.LF a VFN ( Site 0405), Prague, Czechia

Fakultni nemocnice Bulovka-Gynekologicko-porodnicka klinika ( Site 0401), Prague, Czechia

Nemocnice Tomase Bati ve Zline-Onkologické oddělení ( Site 0407), Zlín, Czechia

Fakultni nemocnice Kralovske Vinohrady-Gynekologicko-porodnická klinika ( Site 0408), Prague, Czechia

Rigshospitalet ( Site 0903), Copenhagen, Denmark

Herlev and Gentofte Hospital ( Site 0902), Copenhagen, Denmark

Aalborg Universitetshospital, Syd ( Site 0905), Aalborg, Denmark

Roskilde Sygehus-Oncology department ( Site 0904), Roskilde, Denmark

Kuopion Yliopistollinen Sairaala ( Site 1002), Kuopio, Finland

Tampereen yliopistollinen sairaala-Gynecology and Obstetrics ( Site 1001), Tampere, Finland

Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus) ( Site 1003), Helsinki, Finland

Universitaetsklinikum Ulm ( Site 1106), Ulm, Germany

Universitätsklinikum Bonn-Gynaecological oncology ( Site 1105), Bonn, Germany

Universitaetsklinikum Carl Gustav Carus Dresden-Klinik und Poliklinik für Frauenheilkunde und Gebur, Dresden, Germany

Charité Campus Virchow-Klinikum ( Site 1103), Berlin, Germany

Országos Onkológiai Intézet-Ngyógyászat ( Site 1201), Budapest, Hungary

Bon Secours Cork Hospital ( Site 1305), Cork, Ireland

St. James's Hospital-Cancer clinical trials office ( Site 1301), Dublin, Ireland

Soroka Medical Center ( Site 1403), Beersheba, Israel

Rambam Health Care Campus-Gyneco-oncology unit ( Site 1402), Haifa, Israel

Edith Wolfson Medical Center-Obstetrics & Gynecology ( Site 1405), Holon, Israel

Shaare Zedek Medical Center ( Site 1404), Jerusalem, Israel

Sheba Medical Center ( Site 1401), Ramat Gan, Israel

Istituto Nazionale Tumori IRCCS Fondazione Pascale-S.C. Oncologia Sperimentale Uro-Genitale ( Site 1, Naples, Italy

IRCCS - AOU di Bologna-SSD Oncologia medica Addarii ( Site 1503), Bologna, Italy

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-Oncologia Medica ( Site 1513), Meldola, Italy

Fondazione Policlinico Universitario Agostino Gemelli-Ginecologia Oncologica ( Site 1502), Rome, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori-Struttura Complessa Chirurgia Ginecologica ( Site 150, Milan, Italy

Ospedale Mauriziano-SCDU ONCOLOGIA MEDICA ( Site 1514), Turin, Italy

Istituto Nazionale Tumori Regina Elena-Oncologia Medica 1 ( Site 1504), Rome, Italy

Azienda Ospedaliera Universitaria Careggi-SOD ONCOLOGIA MEDICA ( Site 1509), Florence, Italy

AULSS8 Berica-Ospedale S.Bortolo-ONCOLOGIA CLINICA ( Site 1510), Vicenza, Italy

Istituto Europeo di Oncologia IRCCS-Divisione di Ginecologia Oncologica ( Site 1506), Milan, Italy

National Cancer Center Hospital East ( Site 1604), Kashiwa, Japan

National Hospital Organization Shikoku Cancer Center ( Site 1611), Matsuyama, Japan

Ehime University Hospital ( Site 1614), Tōon, Japan

Kurume University Hospital ( Site 1612), Kurume, Japan

Gunma Prefectural Cancer Center-Gynecology ( Site 1603), Ōta, Japan

Hokkaido University Hospital ( Site 1601), Sapporo, Japan

Tsukuba University Hospital ( Site 1618), Tsukuba, Japan

Iwate Medical University Hospital ( Site 1602), Shiwa-gun Yahaba-cho, Japan

Niigata University Medical & Dental Hospital ( Site 1613), Chuo-ku, Niigata, Japan

Saitama Medical University International Medical Center ( Site 1605), Hidaka-shi, Japan

Shizuoka Cancer Center ( Site 1609), Nagaizumi-cho,Sunto-gun, Japan

National Cancer Center Hospital ( Site 1607), Chuo-ku, Japan

Japanese Foundation for Cancer Research ( Site 1616), Koto, Japan

The Jikei University Hospital ( Site 1615), Minato-ku, Japan

Keio university hospital ( Site 1606), Shinjyuku-ku, Japan

National Hospital Organization Kyushu Cancer Center ( Site 1608), Fukuoka, Japan

Osaka International Cancer Institute ( Site 1617), Osaka, Japan

Radboudumc-Medical Oncology ( Site 1703), Nijmegen, Netherlands

Maastricht UMC+ ( Site 1709), Maastricht, Netherlands

Catharina Ziekenhuis-Oncology ( Site 1704), Eindhoven, Netherlands

Amsterdam UMC, locatie AMC ( Site 1706), Amsterdam, Netherlands

Leids Universitair Medisch Centrum-Medical Oncology ( Site 1702), Leiden, Netherlands

Erasmus Medisch Centrum-Medical Oncology ( Site 1701), Rotterdam, Netherlands

University Medical Center Groningen ( Site 1707), Groningen, Netherlands

Universitair Medisch Centrum Utrecht-Medical Oncology ( Site 1705), Utrecht, Netherlands

Auckland City Hospital-Cancer & Blood Research ( Site 1801), Auckland, New Zealand

Oslo universitetssykehus, Radiumhospitalet ( Site 1901), Oslo, Norway

Szpital Kliniczny im. Heliodora Święcickiego Uniwersytetu Me-Oddzial Ginekologii Onkologicznej ( Sit, Poznan, Poland

Centrum Onkologii Ziemi Lubelskiej ( Site 2006), Lublin, Poland

Mazowiecki Szpital Wojewódzki w Siedlcach-Siedleckie Centrum Onkologii ( Site 2007), Siedlce, Poland

Szpital Kliniczny im. Księżnej Anny Mazowieckiej ( Site 2009), Warsaw, Poland

Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Klinika Ginekologii Onkologicznej ( Sit, Warsaw, Poland

Bialostockie Centrum Onkologii-Oddzial Onkologii Ginekologicznej ( Site 2003), Bialystok, Poland

Narodowy Instytut Onkologii - Oddzial w Gliwicach-III Klinika Radioterapii i Chemioterapii ( Site 20, Gliwice, Poland

Swietokrzyskie Centrum Onkologii, Samodzielny Publiczny Zaklad Opieki Zdrowotnej ( Site 2010), Kielce, Poland

Moscow City Oncology Hospital #62 ( Site 2204), Krasnogorsk, Russia

Yaroslavl Regional Cancer Hospital-Oncology ( Site 2202), Yaroslavl, Russia

Seoul National University Hospital ( Site 2302), Seoul, South Korea

Severance Hospital, Yonsei University Health System-Gynecologic cancer center ( Site 2301), Seoul, South Korea

Asan Medical Center-Division of Gynecologic Oncology, Dept. of Obstetrics & Gynecology ( Site 2303), Seoul, South Korea

Gangnam Severance Hospital ( Site 2304), Seoul, South Korea

Institut Català d'Oncologia - L'Hospitalet-Medical Oncology ( Site 2406), Hospitalet, Spain

CHUAC-Complejo Hospitalario Universitario A Coruña ( Site 2405), A Coruña, Spain

Hospital Universitario Ramón y Cajal-Medical Oncology ( Site 2402), Madrid, Spain

COMPLEJO HOSPITALARIO DE NAVARRA ( Site 2407), Pamplona, Spain

Fundación Instituto Valenciano de Oncología-Oncologico ( Site 2404), Valencia, Spain

Hospital Universitari Vall d'Hebron ( Site 2403), Barcelona, Spain

HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO ( Site 2401), Seville, Spain

Skånes Universitetssjukhus Lund-Department of Hematology ( Site 2504), Lund, Sweden

Karolinska Universitetssjukhuset Solna ( Site 2502), Solna, Sweden

Norrlands universitetssjukhus-Cancercentrum ( Site 2503), Umeå, Sweden

Taichung Veterans General Hospital ( Site 2602), Taichung, Taiwan

NATIONAL CHENG-KUNG UNI. HOSP. ( Site 2604), Tainan, Taiwan

National Taiwan University Hospital ( Site 2603), Taipei, Taiwan

Mackay Memorial Hospital ( Site 2601), Taipei, Taiwan

Taipei Veterans General Hospital ( Site 2605), Taipei, Taiwan

Istanbul Universitesi Cerrahpasa ( Site 2702), Fatih, Turkey (Türkiye)

Hacettepe Universite Hastaneleri-oncology hospital ( Site 2704), Ankara, Turkey (Türkiye)

Ankara Bilkent Şehir Hastanesi-Medical Oncology ( Site 2706), Ankara, Turkey (Türkiye)

Akdeniz Universitesi Hastanesi ( Site 2701), Antalya, Turkey (Türkiye)

Istanbul University Capa Campus-department of obstetrics and gynaecology ( Site 2705), Istanbul, Turkey (Türkiye)

T.C. Saglik Bakanligi Turkiye Kamu Hastaneleri Kurumu - Bakirkoy Dr. Sadi Konuk Egitim ve Arastirma, Istanbul, Turkey (Türkiye)

St Bartholomew's Hospital ( Site 2804), London, United Kingdom

The Christie ( Site 2807), Manchester, United Kingdom

The Beatson West of Scotland Cancer Centre ( Site 2805), Glasgow, United Kingdom

ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 2806), London, United Kingdom

Hammersmith Hospital-Medical Oncology ( Site 2808), London, United Kingdom

Linked Diseases

Endometrial Neoplasms

Endometrial Neoplasms — a type of gynecological cancer.

Linked Papers

2025-09-18

Molecular Characterization and Clinical Implications of Endometrial Cancer

The classification of endometrial cancer (EC) has diverged from traditional histologic features based on microscopic appearance to objective molecular characterization. Molecular characterization of EC is pivotal to inform prognosis and to guide therapeutic recommendations. First described by the Cancer Genome Atlas, molecular profiling was later revised by the Proactive Molecular Risk Classifier for Endometrial Cancer and TransPORTEC algorithms to create clinically applicable and relatively easy-to-implement molecular classification systems. Since 2020, the World Health Organization recommended molecular classification of EC into four distinct prognostic subtypes: ECs with polymerase ε (POLE) pathogenic mutations assessed by gene sequencing, mismatch repair deficiency determined by immunohistochemistry or microsatellite instability assay, and p53 abnormalities determined by immunohistochemistry or next-generation sequencing. The final molecular subtype without any of these defining features is called “no specific molecular profile” (NSMP). This is further stratified by estrogen receptor (ER) immunohistochemistry status. Patients with cancers identified as POLE pathogenic mutations have the best prognosis with almost no recurrence or death events, followed by those with strong ER-positive NSMP cancers. Mismatch repair deficiency ECs have intermediate prognosis, whereas p53 abnormalities and ER-negative NSMP have the worst prognosis. Other molecular and pathologic biomarkers of interest include tumor mutational burden, human epidermal growth factor receptor 2, L1 cell adhesion molecule, β-catenin (CTNNB1), and lymph vascular space invasion, which may have prognostic and predictive implications. The current guidelines will continue to evolve; however, at minimum, it is recommended that all patients undergo testing for mismatch repair, p53, and ER, and POLE testing may be prioritized in select circumstances. Molecular classification provides the critical framework to deliver effective, personalized, high-quality care and informs clinical trial design. Molecular assessment ensures consistent diagnosis and provides prognostic information and predictive data to guide appropriate management.

Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15)