Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study
Authors: Kawazoe Akihito , Xu Rui-Hua , García-Alfonso Pilar , Passhak Maria , Teng Hao-Wei , Shergill Ardaman , Gumus Mahmut , Qvortrup Camilla , Stintzing Sebastian , Towns Kathryn , Kim Tae Won , Shiu Kai Keen , Cundom Juan , Ananda Sumitra , Lebedinets Andrey , Fu Rong , Jain Rishi , Adelberg David , Heinemann Volker , Yoshino Takayuki , Elez Elena ,   the LEAP-017 Investigators, Cundom Juan , Slutsky Ezequiel , Grasselli Julieta , Fein Luis , Bella Quero Luciana , Joubert Warren , Gibbs Peter , Price Timothy , Burge Matthew , Ananda Sumitra , Khattak Muhammad , Colwell Bruce , Couture Felix , Meyers Brandon , Towns Kathryn , Sawyer Michael , Sideris Lucas , Xu Ruihua , Wang Wei , Pan Hongming , Pfeiffer Per , Jensen Lars Henrik , Qvortrup Camilla , Stintzing Sebastian , Arnold Dirk , Lorenzen Sylvie , Kubicka Stefan , Depenbusch Reinhard , Passhak Maria , Geva Ravit , Hubert Ayala , Shacham-Shmueli Einat , Kornev Gleb , Kawazoe Akihito , Masuishi Toshiki , Takashima Atsuo , Hara Hiroki , Kawakami Hisato , Machida Nozomu , Yamazaki Kentaro , Yasui Hisateru , Tsuji Akihito , Esaki Taito , Yamaguchi Kensei , Kim Tae-You , Ahn Joong Bae , Lee Myung Ah , Kim Tae Won , Park Joon Oh , Lee Soohyeon , Orlova Rashida , Sarzhevskiy Vladislav , Sekacheva Marina , Tjulandin Sergey , Shirokova Oksana , Iskhakova Alsu , Lebedinets Andrey , Jimenez Fonseca Paula , Rivera Herrero Fernando , Elez Fernandez Elena , Garcia Alfonso Pilar , Gomez Reina Maria Jose , Yeh Kun-Huei , Teng Hao-Wei , Yang Tsai Sheng , Wang Hwei-Ming , Yeh Yu-Min , Ozguroglu Mustafa , Gumus Mahmut , Yalcin Suayib , Erdogan Bulent , Demirci Umut , Gursoy Pinar , Harputluoglu Hakan , Demir Atakan , Shiu Kai-Keen , Brown Ewan , Ross Paul , Smyth Elizabeth , Chau Ian , Saunders Mark , Vaccaro Gina , McCune Steven , Wadlow Raymond , Khan Gazala , Bashir Babar , Koontz Michael , Martin Ludmila , Shergill Ardaman , Cobb Patrick , Kochenderfer Mark 
Published: June 2024

PURPOSE Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. METHODS In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov ( NCT04776148 ), and has completed recruitment. RESULTS Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. CONCLUSION In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.