Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III, Randomized LEAP-015 Study
Abstract
PURPOSE The phase III randomized open-label LEAP-015 study (ClinicalTrials.gov identifier: NCT04662710 ) evaluated first-line lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy for advanced metastatic gastroesophageal adenocarcinoma. METHODS Eligible participants 18 years and older with untreated human epidermal growth factor receptor 2–negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma were randomly assigned 1:1 to induction with oral lenvatinib 8 mg once daily plus pembrolizumab 400 mg intravenously once every 6 weeks (×2) and investigators’ choice of capecitabine and oxaliplatin once every 3 weeks (×4) or fluorouracil, leucovorin, and oxaliplatin once every 2 weeks (×6) and consolidation with lenvatinib plus pembrolizumab, or chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 combined positive score (CPS) ≥1 and all participants. Secondary end points included objective response rate (ORR) and duration of response. RESULTS Of 880 participants randomly assigned, 443 received lenvatinib plus pembrolizumab and 437 received chemotherapy. The median follow-ups were 32.2 months (range, 19.0-41.7) in participants with PD-L1 CPS ≥1 and 31.8 months (19.0-41.7) in all participants. At interim analysis, PFS was statistically significant with lenvatinib plus pembrolizumab versus chemotherapy in participants with PD-L1 CPS ≥1 (median, 7.3 v 6.9 months; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.9]; P = .0012) and all participants (median, 7.2 v 7.0 months; HR, 0.78 [95% CI, 0.66 to 0.92]; P = .0019). The ORR was 59.5% versus 45.4% in participants with PD-L1 CPS ≥1 and 58.0% versus 43.9% in all participants, P < .0001 for both. At final analysis, OS was not statistically significant in participants with PD-L1 CPS ≥1 (median, 12.6 v 12.9 months; HR, 0.84 [95% CI, 0.71 to 1.00]; P = .0244; P value boundary = .0204). Grade ≥3 drug-related adverse event rates were 65% versus 49%. CONCLUSION Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis although the clinical significance of this difference seems to be limited. No significant improvement occurred in OS in participants with PD-L1 CPS ≥1.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (165)
Manuel González Fernández
Hemato Oncólogo, IMAT-Oncomedica, Montería, Colombia
Felipe Reyes-Cosmelli
Fundación Arturo López Pérez, Santiago, Chile
Yovany Rodriguez Peña
Clinica Colsanitas SA SEDE Clinica Universitaria, Bogotá, Colombia
Lucjan Wyrwicz
Department of Oncology and Radiotherapy, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Deirdre J. Cohen
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
Josep Tabernero
Vall d’Hebron Hospital Campus, Barcelona
Shu-Kui Qin
Nanjing Jinling Hospital, Nanjing, China
Jianming Xu
State Key Laboratory of Soil Pollution Control and Safety,
Li Wen Liang
Merck & Co, Inc, Rahway, NJ
Sonal Bordia
Merck & Co, Inc, Rahway, NJ
Pooja Bhagia
Merck & Co, Inc, Rahway, NJ
Ezequiel Heman Slutsky
Juan Cundom
Andrea Gabriela Soria
Hospital Privado Centro Medico de Cordoba, Cordoba, Argentina
Marcela Alejandro Carballido
Juan Manuel O'Connor
Instituto Alexander Fleming, Buenos Aires, Argentina
Julieta Grasseli
Matthew Burge
Daniel Paul Brungs
Muhammad Adnan Khattak
One Clinical Research, Hollywood Private Hospital and Edith Cowan University, Perth, Western Australia, Australia
Karen Paula Jozefa Geboes
Eric Van Cutsem
University Hospitals Gasthuisberg, Leuven, Belgium
Jeroen Dekervel
University Hospitals Gasthuisberg, Leuven, Belgium
Lionel D. Hondt
Frederic Lemay
Rosalyn Anne Juergens
Felipe Reyes
Gonzalo Pizarro Brito
Maria Alejandra Ojeda
Herman Adolfo Araya
Patricio Eduardo Yanez
Jianwei Yang
Frontiers Science Center for High Energy Material, Advanced Technology Research Institute (Jinan), Key Laboratory of Cluster Science, Ministry of Education, Beijing Key Laboratory of Photoelectronic/Electrophotonic Conversion Materials, School of Interdisciplinary Science, School of Chemistry and Chemical Engineering
Xi Chen
Yuxian Bai
Hongming Pan
Department of Medical Oncology, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, China
Nong Xu
The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
Yueyin Pan
Qinghong Guo
Baorui Liu
Feng Ye
Xin Wang
Qi Li
Yong Tang
Ensem Therapeutics, Inc., 200 Boston Ave., Medford, Massachusetts 02155, United States
Huiting Xu
Haichuan Su
Tangdu Hospital, Air Force Medical University, Shaanxi Provincial Clinical Research Center for Oncology Diseases, Xi'an, China
Ying Cheng
Institute of Biomedical Research, Yunnan University
Xianli Yin
Hunan Cancer Hospital, Hunan, China
Qun Zhao
State Key Laboratory of Medical Proteomics, National Chromatographic Research & Analysis Center, Chinese Academy of Sciences Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences
Ning Li
Jun You
The First Affiliated Hostpital of Xiamen University, Xiamen, China
Yi Ba
Jinsheng We
Lin Shen
Jin Li
Wangjun Liao
Zhen Li
Lei Yang
Yovany Eduardo Rodriguez Pena
Ivan Jose Bustillo
Carlos Jose Narvaez
Manuel Enrique Gonzalez Fernandez
Raimundo Manneh
Andres Fernando Arenas Arias
Luis Corrales
Centro de Investigacion y Manejo del Cancer (CIMCA), San José, Costa Rica
Andres Wiernik Rodriguez
Thomas Aparicio
Gastroenterology and Digestive Oncology Department, CHU Saint Louis, APHP, Université de Paris, Paris, France
Yuan Touchefeu
Helene Boussion-Desloges
Laurent Mineur
Oncologue Radiotherapeute Unité Fonctionnelle Cancérologie Digestive, Avignon, France
Christophe Tournigand
AP-HP, Hôpital Henri Mondor, Service d'oncologie médicale, Créteil, France
François Ghiringhelli
Marie Pierre Galais
Eric Terrebonne
Thomas Walter
Mathieu Baconnier
Sylvie Lorenzen
Eray Goekkurt
Annika Kurreck
Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Cancer Immunology, Berlin, Germany
Arne Kandulski
Thorsten Goetze
Florian Lordick
From Bielefeld University, Medical School and University Medical Center Ostwestfalen-Lippe, Campus Hospital Lippe, Detmold, Germany (J.H.); the Department of Radiation Oncology, Medical University of Graz, Graz, Austria (T.B.); the Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany (C.S.); the Institute of Surgical Pathology, University Medical Center Freiburg, Germany (P.B.); the Department of Surgery, University Medical Center Schleswig-Holstein–Campus Lübeck, Lübeck, Germany (B.K., T.K.); Comprehensive Cancer Center Augsburg, Faculty of Medicine, University of Augsburg, Augsburg, Germany (R.C.); the Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany (S.U.); the Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg–Eppendorf, Hamburg, Germany (J.R.I.); the Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute and San Raffaele Vita-Salute Universi...
Mynor Aguilar
Medi-K Cayala Treatment Center, Cayala/Universidad Francisco Marroquin, Guatemala City, Guatemala
Karla Alejandra Lopez
Rixci Augusto Lenin Ramirez Fallas
Pier Anyelo Ramos Elias
Juan Pablo Moreira
Wing Lok Wendy Chan
Ashely Cheng
Winnie Yeo
The Chinese University of Hong Kong, Hong Kong, Hong Kong
Maeve Lowery
Adrian Murphy
Sharon Pelles Avraham
Ayala Hubert
Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Irit Ben-Aharon
Division of Oncology, Rambam Health Care Center, Haifa, Israel
Valeriya Semenisty
Gali Perl
Wael Hozaeel
Armando Santoro
IRCCS Humanitas Research Hospital, Milan
Elena Aurelia Mazza
Ferdinando De Vita
Division of Medical Oncology, Department of Precision Medicine, University of Campania “L Vanvitelli”, Naples, NA, Italy
Guiseppe Aprile
Giovanni Gerardo Cardellino
Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
Filippo Pietrantonio
Pierfrancesco Tassone
Kohei Shitara
Hirokazu Shoji
Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo
Yukiya Narita
Aichi Cancer Center Hospital, Nagoya, Japan
Hiroki Hara
Saitama Cancer Center, Ina, Japan
Kensei Yamaguchi
Naotoshi Sugimoto
Osaka International Cancer Institute, Osaka, Japan
Nozomu Machida
Tomohiro Nishina
Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan
Akihito Tsuji
Department of Clinical Oncology, Kagawa University Faculty of Medicine, Kita-Gun, Japan
Yasuhiro Choda
Hiroshima City Hospital, Hiroshima, Japan
Kenji Amagai
Masahiro Tsuda
Shogen Boku
Boguslawa Karaszewska
Department of Oncology, Regional Polyclinical Hospital in Konin, Konin, Poland
Kamil Stanislaw Kuc
Jacek Mackiewicz
Cancer Genetic Laboratory, Greater Poland Cancer Centre, Poznan, Poland
Lucjan Stanislaw Wyrwicz
Lukasz Hajac
Neuroendocrine Cancer Unit, Lower Silesian Oncology Center, Wrocław, Poland
Alexy Alexandrovich Tryakin
Dmitry Aleksandrovich Nosov
Rashida Orlova
Saint Petersburg State University, Saint Petersburg, Russian Federation
Alexey Mikhailovich Karachun
Michael Osipov
Mikhail Valerievich Kopp
Natalia Vladimirovna Fadeeva
Nikolay Viktorovich Kislov
Sun Young Rha
Seung Tae Kim
Min-Hee Ryu
Asan Medical Center, Seoul, South Korea
Do-Youn Oh
Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, and the Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
Keun-Wook Lee
Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
Hei-Cheul Jeung
Jonggwon Choi
Konyang University Hospital, Seo-Gu, Daejeon, South Korea
Sang Cheul Oh
Paula Jimenez Fonseca
Fernando Rivera Herrero
Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
Pilar Aitana Calvo Ferrandiz
Daniel Acosta Eyzaguirre
Medical Oncology Department, Vall d’Hebron University Hospital, VHIO, Barcelona, Spain
Kun-Huei Yeh
National Taiwan University Hospital; National Taiwan University College of Medicine, Taipei, Taiwan
Jen-Shi Chen
Chang Gung Memorial Hospital at Linkou and Chang Gung University, Tao-Yuan, Taiwan
Li-Yuan Bai
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
Chia-Jui Yen
Bulent Erdogan
Pinar Gursoy
Mustafa Özgüroğlu
Suayib Yalcin
Umut Demirci
Memorial Ankara Hospital, Ankara, Turkey
Mehmet Bilici
Department of Internal Medicine, Division of Medical Oncology, Atatürk University Faculty of Medicine, Erzurum, Turkey
Ilhan Hacibekiroglu
Hugo Ford
Kai-Keen Shiu
Martin Scott-Brown
University Hospital Coventry and Warwickshire, Coventry, United Kingdom
Russell Petty
Wasat Mansoor
Christie NHS Foundation Trust, Manchester, United Kingdom
Zev A. Wainberg
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles
Marcus Noel
Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
Peter Enzinger
2Dana-Farber Cancer Institute, Boston, United States
Sreenivasa Chandana
START Midwest, Grand Rapids, MI
Geoffrey Ku
Memorial Sloan Kettering Cancer Center, New York
Dierdre Cohen
Vincent Lam