First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial
Christian Marth, Richard G. Moore, Mariusz Bidziński, Sandro Pignata, Ali̇ Ayhan, María Jesús Rubio, Mario Beiner, Marcia Hall, Christof Vulsteke, Elena Ioana Braicu, Kenzo Sonoda, Xiaohua Wu, Sophia Frentzas, André Mattar, Stéphanie Lheureux, Xiaojun Chen, Kosei Hasegawa, Manuel Magallanes-Maciel, Chel Hun Choi, Mariia Shalkova, Diego Kaen, Peng‐Hui Wang, Regina Berger, Chinyere E. Okpara, Jodi A. McKenzie, Lili Yao, Robert Orlowski, Vivek Khemka, Lucy Gilbert, Vicky Makker, on behalf of the ENGOT-en9/LEAP-001 Investigators, Diego Kaen, Gonzalo Gómez Abuin, Liliana Zamora, Margarita Sonia Alfie, Ignacio Casarini, Michelle Harrison, Sumitra Ananda, Catherine Shannon, Sophia Frentzas, Michael J. Friedlander, Tarek Meniawy, Bo Gao, Sally Baron‐Hay, Connie I. Diakos, Christian Marth, Stephan Polterauer, Edgar Petru, Marlies De Bock, Christof Vulsteke, Jean‐François Baurain, Toon Van Gorp, Sevilay Altıntaş, João Paulo da Silveira Nogueira Lima, André Mattar, Ruffo de Freitas Junior, RO de Sant'ana, Andréia Cristina de Melo, Fábio Franke, Graziela Zibetti Dal Molin, Fernanda Damian, João Daniel Guedes, Susan Ellard, Anna V. Tinker, Vanessa Samouëlian, Suzanne Fortin, Paul Bessette, Michael Kolinsky, Nidhi Kumar Tyagi, Josée-Lyne Ethier, Lucy Gilbert, Stéphanie Lheureux, Helen Mackay, Charles Henry Lim, Xiaohua Wu, Lingya Pan, Ruifang An, Xiaojun Chen, Hong Zheng, Yumei Wu, Jianqing Zhu, Shuzhong Yao, Xuemei Jia, Yi Huang, Weiguo Lv, Yu Zhang, Qi Zhou, Cailing Ma, Radoslav Chekerov, Paweł Mach, Ralf Witteler, Frederik Marmè, Karen Cadoo, Jacob Korach, Talia Levy, Mario Beiner, Amnon Amit, Paolo Scollo, Emanuele Naglieri, Sandro Pignata
Abstract
PURPOSE Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101 ) that evaluated len + pembro versus chemotherapy in first-line aEC. METHODS Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m 2 plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis–tested hazard ratio [HR], 1.1). RESULTS Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients. CONCLUSION First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.