ENGOT-en11/GOG-3053/KEYNOTE-B21: A phase 3 study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed high-risk endometrial cancer (570)

Objectives: Pembrolizumab, a selective humanized anti-PD-1 monoclonal antibody, has demonstrated activity in patients with previously treated mismatch repair (MMR) deficient (dMMR; 57.1% objective response rate [ORR] as monotherapy and 63.6% ORR as combination therapy with lenvatinib) and MMR proficient (pMMR; 36.2% ORR as combination therapy with lenvatinib) endometrial cancer. ENGOT-en11/GOG-3O53/KEYNOTE-B21 (NCT04634877) is a phase III, randomized, double-blind study of pembrolizumab or placebo in combination with adjuvant chemotherapy with/without radiotherapy in patients with endometrial cancer. Methods: Eligible patients are ≥18 years old with newly diagnosed, histologically confirmed high-risk (stage I/II non-endometrioid or with p53 abnormality and any histology, stage III/IVA), previously untreated endometrial cancer following surgery with curative intent with no evidence of disease postoperatively or on imaging. Approximately 990 patients are randomized to receive pembrolizumab 200 mg or placebo every three weeks (Q3W) for six cycles plus chemotherapy (carboplatin AUC of 5 or 6 plus paclitaxel 175 mg/m2 Q3W or carboplatin AUC of 2 or 2.7 plus paclitaxel 60 mg/m2 QW) in stage I. Patients receive pembrolizumab 400 mg or placebo Q6W for six cycles in stage II per their treatment assignment. At the investigator’s discretion, radiotherapy (external beam radiotherapy [EBRT] and/or brachytherapy) ± radiosensitizing cisplatin 50 mg/m2 (days 1 and 29) may be administered after completion of chemotherapy. Randomization is stratified by MMR status (pMMR vs dMMR) and, within pMMR, by planned radiation therapy (cisplatin-EBRT vs EBRT vs no EBRT), histology (endometrioid vs non-endometrioid), and International Federation of Gynecology and Obstetrics (FIGO) surgical stage (I/II vs III/IVA). Dual primary endpoints are disease- free survival (DFS; per investigator assessment) and overall survival (OS), both estimated by the Kaplan-Meier method, with a stratified log-rank test to assess treatment differences and a Cox proportional hazard model with Efron’s method of tie handling to assess the magnitude of treatment differences. Secondary endpoints include DFS (per blinded independent central review), DFS (per investigator assessment) and OS by biomarker status (PD-L1 and tumor mutational burden), safety (per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0), and quality of life (per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] and Endometrial Cancer Module [EORTC QLQ-EN24]). Enrolment began December 2020 and is ongoing; a total of 221 sites in 28 countries are planned.

目的：帕博利珠单抗是一种选择性人源化抗PD - 1单克隆抗体，在既往接受过治疗的错配修复缺陷（dMMR；单药治疗客观缓解率[ORR]为57.1%，与仑伐替尼联合治疗ORR为63.6%）和错配修复正常（pMMR；与仑伐替尼联合治疗ORR为36.2%）的子宫内膜癌患者中已显示出活性。ENGOT - en11 / GOG - 3O53 / KEYNOTE - B21（NCT04634877）是一项针对子宫内膜癌患者的Ⅲ期、随机、双盲研究，比较帕博利珠单抗或安慰剂联合辅助化疗（±放疗）的疗效。 方法：符合条件的患者年龄≥18岁，新诊断为经组织学证实的高危子宫内膜癌（Ⅰ/Ⅱ期非子宫内膜样癌或伴有p53异常且任何组织学类型，Ⅲ/ⅣA期），手术后有治愈意图且术后或影像学无疾病证据，既往未接受过治疗。大约990名患者被随机分配在Ⅰ期接受每3周（Q3W）一次的帕博利珠单抗200 mg或安慰剂，共6个周期，同时联合化疗（卡铂AUC为5或6加紫杉醇175 mg/m² Q3W，或卡铂AUC为2或2.7加紫杉醇60 mg/m²每周一次[QW]）。Ⅱ期患者根据治疗分配接受每6周（Q6W）一次的帕博利珠单抗400 mg或安慰剂，共6个周期。根据研究者的判断，在化疗完成后可给予放疗（外照射放疗[EBRT]和/或近距离放疗）±放疗增敏剂顺铂50 mg/m²（第1天和第29天）。随机分组根据错配修复状态（pMMR与dMMR）分层，在pMMR中，再根据计划的放疗（顺铂 - EBRT与EBRT与无EBRT）、组织学（子宫内膜样与非子宫内膜样）以及国际妇产科联合会（FIGO）手术分期（Ⅰ/Ⅱ期与Ⅲ/ⅣA期）进一步分层。双重主要终点是无病生存期（DFS；根据研究者评估）和总生存期（OS），两者均采用Kaplan - Meier方法估计，采用分层对数秩检验评估治疗差异，并采用Cox比例风险模型及Efron处理并列的方法评估治疗差异的大小。次要终点包括DFS（根据盲态独立中心审查）、按生物标志物状态（PD - L1和肿瘤突变负荷）划分的DFS（根据研究者评估）和OS、安全性（根据美国国家癌症研究所不良事件通用术语标准第5.0版）以及生活质量（根据欧洲癌症研究与治疗组织生活质量问卷 - 核心30[EORTC QLQ - C30]和子宫内膜癌模块[EORTC QLQ - EN24]）。招募于2020年12月开始，目前正在进行中；计划在28个国家共设221个研究中心。