First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial
Authors: Marth Christian , Moore Richard G. , Bidziński Mariusz , Pignata Sandro , Ayhan Ali , Rubio M. Jesús , Beiner Mario , Hall Marcia , Vulsteke Christof , Braicu Elena Ioana , Sonoda Kenzo , Wu Xiaohua , Frentzas Sophia , Mattar André , Lheureux Stephanie , Chen Xiaojun , Hasegawa Kosei , Magallanes-Maciel Manuel , Choi Chel Hun , Shalkova Mariia , Kaen Diego , Wang Peng-Hui , Berger Regina , Okpara Chinyere E. , McKenzie Jodi , Yao Lili , Orlowski Robert , Khemka Vivek , Gilbert Lucy , Makker Vicky ,   on behalf of the ENGOT-en9/LEAP-001 Investigators, Kaen Diego Lucas , Gomez Abuin Gonzalo , Zamora Liliana Beatriz , Alfie Margarita Sonia , Casarini Ignacio Alfredo , Harrison Michelle , Ananda Sumitra , Shannon Catherine Margaret , Frentzas Sophia , Friedlander Michael , Meniawy Tarek , Gao Bo , Baron-Hay Sally , Diakos Connie , Marth Christian , Polterauer Stephan , Petru Edgar , De Bock Marlies , Vulsteke Christof , Baurain Jean-Francois , Van Gorp Toon , Altintas Sevilay , Lima Joao Paulo da Silveira Nogueira , Mattar Andre , de Freitas Junior Ruffo , Santana Rosane O. , de Melo Andreia Cristina , Franke Fabio Andre , Zibetti Dal Molin Graziela , Damian Fernanda Bronzon , Guedes João Daniel Cardoso , Ellard Susan , Tinker Anna , Samouëlian Vanessa , Fortin Suzanne , Bessette Paul , Kolinsky Michael , Kumar Tyagi Nidhi , Ethier Josee-Lyne , Gilbert Lucy , Lheureux Stephanie , MacKay Helen , Lim Charles , Wu Xiaohua , Pan Lingya , An Ruifang , Chen Xiaojun , Zheng Hong , Wu Yumei , Zhu Jianqing , Yao Shuzhong , Jia Xuemei , Huang Yi , Lv Weiguo , Zhang Yu , Zhou Qi , Ma Cailing , Chekerov Radoslav , Mach Pawel , Witteler Ralf , Marmè Frederik , Cadoo Karen , Korach Jacob , Levy Talia , Beiner Mario , Amnon Amit , Scollo Paolo , Naglieri Emanuele , Pignata Sandro , Zamagni Claudio , Salutari Vanda , Usami Tomoka , Nakamura Kazuto , Matsumoto Koji , Yamagami Wataru , Kobayashi Yoichi , Takano Masashi , Kato Hidenori , Sonoda Kenzo , Kikuchi Akira , Katsumata Noriyuki , Kamiura Shoji , Horie Koji , Hasegawa Kosei , Tsunoda Takuya , Suzuki Nao , Yunokawa Mayu , Nishio Shin , Kudaka Wataru , Guerrero Cabrera Fernando Felix , Gonzalez Mendoza Rene Lazaro , Magallanes Maciel Manuel Ernesto , Villalobos Valencia Ricardo , Escobar Penagos Jose , Lopez Chuken Yamil Alonso , Mackowiak-Matejczyk Beata , Tarnawski Rafal , Kalinka Ewa , Bidzinski Mariusz , Bednarek Wieslawa , Danska-Bidzinska Anna , Koralewski Piotr , Roszak Andrzej , Kedrova Anna , Musaeva Natalia , Urmancheeva Adiliya Fettekhovna , Vasiliev Aleksandr Gennadievich , Safina Sufia Zievna , Lisyanskaya Alla Sergeevna , Rykov Ivan V. , Rumyantsev Alexey Alexandrovich , Belonogov Aleksandr , Makarycheva Yulia , Kim Yong Man , Choi Chel Hun , Kim Yong Beom , Kim Hee Seung , Kim Sang Wun , Quindos Varela Maria , Casado Herraez Antonio , Diaz Redondo Tamara , Rubio Perez Maria Jesus , Romeo Marin Margarita , Romero Noguera Ignacio , Taus Garcia Alvaro , Lin Wu-Chou , Chou Hung-Hsueh , Cheng Wen-Fang , Lu Chien-Hsing , Wang Peng-Hui , Simsek Tayup , Kose Fatih , Ayhan Ali , Vardar Mehmet Ali , Ozerkan Kemal , Hughes Andrew , Stillie Alison , Eminowicz Gemma , Khalique Saira , Shalkova Mariia , Sukhina Olena , Piatnytska Tetiana , Averina Hanna , Kulyaba Yaroslav , Kryzhanivska Anna , Bondarenko Igor , Svintsitsky Valentyn , Krasnohrud Yuliia , Voitko Nataliia , Buscema Joseph , Ghamande Sharad , Lewin Sharyn , Graham Deena M. , Makker Vicky , Bell Maria , Santin Alessandro , Lee Christine , Blank Stephanie , Konecny Gottfried E. , Corr Bradley , Van Le Linda , Moore Richard G. , Scalici Jennifer , Anderson Charles , Braly Patricia , Fehniger Julia , Westhoff Gina , Bollinger Lauren 
Published: November 2024

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.