Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

<jats:sec><jats:title>Background</jats:title><jats:p>Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy.</jats:p></jats:sec><jats:sec><jats:title>Primary Objective</jats:title><jats:p>To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease.</jats:p></jats:sec><jats:sec><jats:title>Study Hypothesis</jats:title><jats:p>Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers).</jats:p></jats:sec><jats:sec><jats:title>Trial Design</jats:title><jats:p>Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no).</jats:p></jats:sec><jats:sec><jats:title>Major Inclusion/Exclusion Criteria</jats:title><jats:p>Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded.</jats:p></jats:sec><jats:sec><jats:title>Primary Endpoints</jats:title><jats:p>Progression-free and overall survival (dual primary endpoints).</jats:p></jats:sec><jats:sec><jats:title>Sample Size</jats:title><jats:p>About 875 patients.</jats:p></jats:sec><jats:sec><jats:title>Estimated Dates for Completing Accrual and Presenting Results</jats:title><jats:p>Enrollment is expected to take approximately 24 months, with presentation of results in 2022.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials.gov,<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT03884101">NCT03884101</jats:ext-link>.</jats:p></jats:sec>