Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Randomized Controlled Trial, Clinical Trial, Phase III, Multicenter Study
PubMed
39288779
DOI
10.1016/s0140-6736(24)01808-7
PII: S0140-6736(24)01808-7
Knihovny.cz E-resources
- MeSH
- Adenocarcinoma drug therapy mortality radiotherapy MeSH
- Carcinoma, Adenosquamous drug therapy mortality radiotherapy MeSH
- Chemoradiotherapy * methods MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Antibodies, Monoclonal, Humanized * adverse effects therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Uterine Cervical Neoplasms * drug therapy mortality radiotherapy MeSH
- Antineoplastic Agents, Immunological therapeutic use adverse effects MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Aged MeSH
- Carcinoma, Squamous Cell drug therapy mortality radiotherapy MeSH
- Neoplasm Staging MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
- Names of Substances
- Antibodies, Monoclonal, Humanized * MeSH
- pembrolizumab MeSH Browser
- Antineoplastic Agents, Immunological MeSH
BACKGROUND: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. METHODS: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
Clinical Therapeutics Alexandra Hospital Athens Greece
Department of Obstetrics and Gynecology Ehime University Hospital Toon Ehime Japan
Department of Obstetrics and Gynecology MacKay Memorial Hospital Taipei Taiwan
Department of Oncology University of Ostrava North Moravia Czech Republic
Department of Oncology Xiangya Hospital Central South University Hunan China
Department of Radiation Oncology University Hospitals Leuven Leuven Belgium
Gynelogic Oncology University of Virginia School of Medicine Charlottesville VA USA
Meir Medical Center Sackler School of Medicine Tel Aviv University Kfar Saba Israel
Oncología Clínica Instituto Nacional de Cancerologia Bogota Colombia
Oncologia Clínica Liga Norte Riograndense Contra o Cancer Natal Rio Grande do Norte Brazil
Oncología Médica Instituto Peruano de Oncología y Radioterapia Lima Perú
Oncología Médica Integra Cancer Institute Edificio Integra Medical Center Guatemala City Guatemala
Turkish Society of Gynecologic Oncology Başkent University Ankara Turkiye
Yonsei Cancer Center and Severance Hospital Yonsei University College of Medicine Seoul South Korea
References provided by Crossref.org
ClinicalTrials.gov
NCT04221945
