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

Abstract

Background: 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.

Primary objective: 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.

Study hypothesis: 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).

Trial design: 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).

Major inclusion/exclusion criteria: 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.

Primary endpoints: Progression-free and overall survival (dual primary endpoints).

Sample size: About 875 patients.

Estimated dates for completing accrual and presenting results: Enrollment is expected to take approximately 24 months, with presentation of results in 2022.

Trial registration: ClinicalTrials.gov, NCT03884101.

Keywords: endometrial neoplasms; uterine cancer.

Figure 1

ENGOT-en9/LEAP-001 study design. ^aTreat until disease progression or unacceptable toxicity. Pembrolizumab must be stopped after 35 cycles, but lenvatinib may continue after stopping pembrolizumab. ^bStudy will be fully enrolled when 612 patients with mismatch repair-proficient (pMMR) tumors and ~263 patients with mismatch repair-deficient (dMMR) tumors are recruited. ^cA lower starting dose of paclitaxel (135 mg/m²) and carboplatin (AUC 5 mg/mL/min) may be administered to patients at risk of developing toxicities due to previous pelvic/spine radiation. An AUC of 5 mg/mL/min dose of carboplatin may be administered in accordance with local practice. ^dPatients may receive up to seven cycles of paclitaxel/carboplatin; however, chemotherapy treatment beyond seven cycles may be permitted (with the sponsors’ approval) for patients who continue to derive clinical benefit. AUC, area under the curve (unit, mg/mL/min); ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PS, performance status; QD, once daily; Q3W, every 3 weeks.