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)

Abstract

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. 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.