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.

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.

Informations de copyright

© IGCS and ESGO 2022. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: CM: funded research, EU, FWF, AstraZeneca, and Roche; honoraria/expenses, Roche, Novartis, Amgen, Merck, Pharmamar, AstraZeneca, Tesaro, and GSK; consulting/advisory board, Roche, Novartis, Amgen, Merck, AstraZeneca, Pfizer, Pharmamar, Cerulean, Vertex, GSK, Seagen, and Eisai. AT: funded research, AstraZeneca, Roche, MSD, and RUSSCO; honoraria/expenses, AstraZeneca, Roche, MSD, Eisai, Biocad, and RUSSCO; consulting/advisory board, AstraZeneca, Pfizer, MSD, Eisai, Tesaro, and Biocad. SP: honoraria, MSD, Eisai, GSK, AstraZeneca, Clovis, Pfizer, Pharmamar, and Roche. LG: institutional grants from AstraZeneca, Pfizer, Merck Sharp & Dohme, Karyopharm, Tesaro, IMV, Alkermes, Clovis, ImmunoGen Inc, Roche, Mersana, Esperas, Novocure GmbH, and OncoQuest Pharmaceuticals; advisory boards, AstraZeneca, GSK, Eisai, Eisai-Merck, and Alkermes. DK: clinical trials, Roche, Lilly Oncology, Clovis, MSD, Abbvie, Takeda, Novartis, Pfizer, Array BioPharma Inc, Servier, Nektar Therapeutics, Merck Healthcare KGaA, and GlaxoSmithKline; consultancy, Roche, Boehringer Ingelheim, Pfizer, MSD, BMS, Novartis, AstraZeneca, Raffo-tecnofarma, Varifarma, and Bayer. MJR: consulting/advisory board, MSD, AstraZeneca, GSK, Pharmamar, and Roche. SF: consulting/advisory board, Akesobio; honoraria/expenses, Amgen. MM-M: consulting/advisory board, Roche, Eli-Lilly, BMS, AstraZeneca, Teva, Amgen, Bayer, and Pfizer. RB: travel expenses, Clovis Oncology, Roche, and MSD. CV: study funding for present publication from MSD; institutional grant, MSD; consulting fees, Janssen-Cilag, Roche, GSK, Atheneum Partners, Astellas Pharma, MSD, BMS, and Leo-Pharma; payment or honoraria for presentations, Janssen Cilag, Leo Pharma, and Bayer; payment or honoraria for advisory boards, Janssen Cilag, Leo Pharma, MSD, GSK, and AstraZeneca; support for travel, Roche and Pfizer. KH: funded research, MSD, Ono, Takeda, Daiichi-Sankyo, and Eisai; honoraria, Takeda, Chugai, Kyowa-Kirin, Genmab, AstraZeneca, and MSD; consulting/advisory board, MSD, Eisai, and Takeda. EB: funded research, EU, DLR, AstraZeneca, Roche Diagnostics, and Bayer; honoraria/expenses, Roche, Merck, AstraZeneca, Tesaro, GSK, Clovis, Roche Diagnostics, Molecular Health, and Eisai; consulting/advisory board, Roche, Eisai, Merck, AstraZeneca, GSK, and Clovis. JM: employee of Eisai Inc, Woodcliff Lake, New Jersey, USA. JJL: employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, New Jersey, USA and stockholder in Merck & Co. VM: study support (all funding to institution)/consultant/advisory board membership, Merck, Eisai, Karyopharm, AstraZeneca, Clovis, Moreo, Takeda, Zymeworks, and Genentech; supported in part by the NIH/NCI Cancer Center Support grant P30 CA008748.