ENGOT-EN9/LEAP-001: A phase III, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer

Abstract

Background: While early stage endometrial cancer (EC) is associated with a favorable prognosis, prognosis for advanced or recurrent EC is poor. Paclitaxel and carboplatin chemotherapy (CT) is often used as first‐line treatment for these patients; however, there exists an imperative need for more effective and tolerable therapies. In KEYNOTE‐146, combination therapy with the PD‐1 inhibitor pembrolizumab (pembro) and the tyrosine kinase inhibitor lenvatinib resulted in an ORR of 39% in patients with EC (Makker et al. ASCO 2018). Based on these promising data, the ENGOT‐EN9/ LEAP‐001 study was initiated to assess this combination therapy in women with recurrent or advanced EC. Trial design: The ENGOT‐EN9/LEAP‐001 study (NCT03884101) is a phase 3, randomized, open‐label, active‐controlled trial comparing combination therapy with pembro and lenvatinib to paclitaxel and carboplatin CT in patients with newly diagnosed stage III‐IV or recurrent EC (NCT03884101). Approximately 720 patients not previously treated with systemic chemotherapy (except as part of a chemoradiation regimen), antiangiogenic agents, PD‐1 or PD‐L1 inhibitors, or other T‐cell receptor‐ targeted agents will be randomized 1:1 to pembro (200 mg Q3W) plus lenvatinib (20 mg daily) or paclitaxel and carboplatin CT (pac 175 mg/m2 plus carb AUC 6 Q3W). Patients will first be stratified by proficient vs deficient mismatch repair status (pMMR vs dMMR), and pMMR patients will be further stratified by ECOG performance status (0 vs 1), measurable disease (yes vs no), and prior chemoradiation (yes vs no). Treatment will continue until disease progression, initiation of new anticancer treatment, unacceptable adverse events, or withdrawal of consent for up to 35 cycles for pembro or 7 cycles of paclitaxel and carboplatin CT. Primary endpoints are PFS per RECIST v1.1, assessed by blinded independent central review, and OS. Secondary endpoints are ORR, health‐related quality of life, safety and tolerability, and pharmacokinetics of lenvatinib. Exploratory endpoints include duration of response, disease control rate, and clinical benefit rate. Enrollment is ongoing.