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ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer
T. Van Gorp, D. Cibula, W. Lv, F. Backes, F. Ortaç, K. Hasegawa, K. Lindemann, A. Savarese, A. Laenen, YM. Kim, L. Bodnar, MP. Barretina-Ginesta, L. Gilbert, B. Pothuri, X. Chen, MB. Flores, T. Levy, N. Colombo, C. Papadimitriou, T. Buchanan, LC....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, klinické zkoušky, fáze III, randomizované kontrolované studie, multicentrická studie
- MeSH
- adjuvantní chemoterapie metody MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- humanizované monoklonální protilátky * aplikace a dávkování terapeutické užití škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory endometria * patologie farmakoterapie terapie MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Ankara University School of Medicine Ankara Turkey
Aretaieio University Hospital National and Kapodistrian University of Athens Athens Greece
Belgian and Luxembourg Gynaecological Oncology Group Leuven Belgium
Central and Eastern European Gynecologic Oncology Group Prague Czech Republic
Centre Catherine de Sienne Hôpital Privé du Confluent Nantes France
Department of Gynecological Oncology Oslo University Hospital Oslo Norway
Department of Gynecology and Obstetrics University Hospital Muenster Muenster Germany
Department of Medicine and Surgery University of Milan Bicocca Milan Italy
Department of Obstetrics and Gynecology LSU Health Shreveport Shreveport USA
Department of Oncology Obstetrics and Gynecology Hospital of Fudan University Shanghai China
Division of Gynecologic Oncology McGill University Health Centre Montreal Canada
Division of Gynecologic Oncology Ohio State University and James Cancer Hospital Columbus USA
Faculty of Medicine Institute of Clinical Medicine University of Oslo Oslo Norway
Gerald Bronfman Department of Oncology McGill University Health Centre Montreal Canada
German Gynecological Oncology Group Wiesbaden Germany
GOG Foundation Philadelphia USA
Gynecologic Oncology Program European Institute of Oncology IRCCS Milan Italy
Hellenic Cooperative Oncology Group Athens Greece
Instituto Oncológico Fundación Arturo López Pérez Santiago Chile
IRCCS Regina Elena National Cancer Institute Rome Italy
Jefferson Health Asplundh Cancer Pavilion Willow Grove USA
Leuven Biostatistics and Statistical Bioinformatics Center KU Leuven Leuven Belgium
Mario Negri Gynecologic Oncology Milan Italy
Mount Sinai Medical Center Miami Beach USA
Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies Rome Italy
National Cancer Research Institute London UK
National Investigators Group for the Study of Ovarian and Breast Cancers Paris France
Nordic Society of Gynaecological Oncology Clinical Trial Unit Copenhagen Denmark
Polish Group of Gynaecological Oncology Warsaw Poland
Shanghai Gynecologic Oncology Group Shanghai China
Spanish Ovarian Cancer Research Group Madrid Spain
Turkish Society of Gynecologic Oncology Istanbul Turkey
University College London Hospitals and University College London London UK
University Hospital Schleswig Holstein Lubeck Germany
Willis Knighton Physician Network Shreveport USA
Women's Health Research Unit Research Institute McGill University Health Centre Montreal Canada
Citace poskytuje Crossref.org
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- $a Van Gorp, T $u Division of Gynaecological Oncology, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium; Belgian and Luxembourg Gynaecological Oncology Group (BGOG), Leuven, Belgium. Electronic address: toon.vangorp@uzleuven.be
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- $a BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
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