학술논문
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial
Document Type
Academic Journal
Author
Mok, Tony S K; Wu, Yi-Long; Kudaba, Iveta; Kowalski, Dariusz M; Cho, Byoung Chul; Turna, Hande Z; Castro, Gilberto, Jr; Srimuninnimit, Vichien; Laktionov, Konstantin K; Bondarenko, Igor; Kubota, Kaoru; Lubiniecki, Gregory M; Zhang, Jin; Kush, Debra; Lopes, Gilberto; Adamchuk, Grigory; Ahn, Myung-Ju; Alexandru, Aurelia; Altundag, Ozden; Alyasova, Anna; Andrusenko, Orest; Aoe, Keisuke; Araujo, Antonio; Aren, Osvaldo; Arrieta Rodriguez, Oscar; Ativitavas, Touch; Avendano, Oscar; Barata, Fernando; Barrios, Carlos Henrique; Beato, Carlos; Bergstrom, Per; Betticher, Daniel; Bolotina, Larisa; Botha, Michiel; Buddu, Sayeuri; Caglevic, Christian; Cardona, Andres; Castro, Hugo; Cay Senler, Filiz; Cerny, Carlos Alexandre Sydow; Cesas, Alvydas; Chan, Gee-Chen; Chang, Jianhua; Chen, Gongyan; Chen, Xi; Cheng, Susanna; Cheng, Ying; Cherciu, Nelly; Chiu, Chao-Hua; Cicenas, Saulius; Ciurescu, Daniel; Cohen, Graham; Costa, Marcos Andre; Danchaivijitr, Pongwut; De Angelis, Flavia; de Azevedo, Sergio Jobim; Dediu, Mircea; Deliverski, Tsvetan; De Marchi, Pedro Rafael Martins; de The Bustamante Valles, Flor; Ding, Zhenyu; Doganov, Boyan; Dreosti, Lydia; Duarte, Ricardo; Edusma-Dy, Regina; Emelyanov, Sergey; Erman, Mustafa; Fan, Yun; Fein, Luis; Feng, Jifeng; Fenton, David; Fernandes, Gustavo; Ferreira, Carlos; Franke, Fabio Andre; Freitas, Helano; Fujisaka, Yasuhito; Galindo, Hector; Galvez, Christina; Ganea, Doina; Gil, Nuno; Girotto, Gustavo; Goker, Erdem; Goksel, Tuncay; Gomez Aubin, Gonzalo; Gomez Wolff, Luis; Griph, Hakan; Gumus, Mahmut; Hall, Jacqueline; Hart, Gregory; Havel, Libor; He, Jianxing; He, Yong; Hernandez Hernandez, Carlos; Hespanhol, Venceslau; Hirashima, Tomonori; Ho, Chung Man James; Horiike, Atsushi; Hosomi, Yukio; Hotta, Katsuyuki; Hou, Mei; How, Soon Hin; Hsia, Te-Chun; Hu, Yi; Ichiki, Masao; Imamura, Fumio; Ivashchuk, Oleksandr; Iwamoto, Yasuo; Jaal, Jana; Jassem, Jacek; Jordaan, Christa; Juergens, Rosalyn Anne; Kaen, Diego; Kalinka-Warzocha, Ewa; Karaseva, Nina; Karaszewska, Boguslawa; Kazarnowicz, Andrzej; Kasahara, Kazuo; Katakami, Nobuyuki; Kato, Terufumi; Kawaguchi, Tomoya; Kim, Joo Hang; Kishi, Kazuma; Kolek, Vitezslav; Koleva, Marchela; Kolman, Petr; Koubkova, Leona; Kowalyszyn, Ruben; Kowalski, Dariusz; Koynov, Krassimir; Ksienski, Doran; Kurata, Takayasu; Kuusk, Gerli; Kuzina, Lyudmila; Laczo, Ibolya; Ladrera, Guia Elena Imelda; Laktionov, Konstantin; Landers, Gregory; Lazarev, Sergey; Lerzo, Guillermo; Lesniewski Kmak, Krzysztof; Li, Wei; Liam, Chong Kin; Lifirenko, Igor; Lipatov, Oleg; Liu, Xiaoqing; Liu, Zhe; Lo, Sing Hung; Lopes, Valeria; Lopez, Karla; Lu, Shun; Martinengo, Gaston; Mas, Luis; Matrosova, Marina; Micheva, Rumyana; Milanova, Zhasmina; Miron, Lucian; Mok, Tony; Molina, Matias; Murakami, Shuji; Nakahara, Yasuharu; Nguyen, Tien Quang; Nishimura, Takashi; Ochsenbein, Adrian; Ohira, Tatsuo; Ohman, Ronny; Ong, Choo Khoon; Ostoros, Gyula; Ouyang, Xuenong; Ovchinnikova, Elena; Ozyilkan, Ozgur; Petruzelka, Lubos; Pham, Xuan Dung; Picon, Pablo; Piko, Bela; Poltoratsky, Artem; Ponomarova, Olga; Popelkova, Patrice; Purkalne, Gunta; Qin, Shukui; Ramlau, Rodryg; Rappaport, Bernardo; Rey, Felipe; Richardet, Eduardo; Roubec, Jaromir; Ruff, Paul; Rusyn, Andrii; Saka, Hideo; Salas, Jorge; Sandoval, Mario; Santos, Lucas; Sawa, Toshiyuki; Seetalarom, Kasan; Seker, Mesut; Seki, Nobuhiko; Seolwane, Freddy; Shepherd, Lucinda; Shevnya, Sergii; Shimada, Andrea Kazumi; Shparyk, Yaroslav; Sinielnikov, Ivan; Sirbu, Daniela; Smaletz, Oren; Soares, Joao Paulo Holanda; Sookprasert, Aumkhae; Speranza, Giovanna; Sriuranpong, Virote; Stara, Zinaida; Su, Wu-Chou; Sugawara, Shunichi; Szpak, Waldemar; Takahashi, Kazuhisa; Takigawa, Nagio; Tanaka, Hiroshi; Tan Chun Bing, Jerry; Tang, Qiyou; Taranov, Pavel; Tejada, Hermes; Tho, Lye Mun; Torii, Yoshitaro; Trukhyn, Dmytro; Turdean, Maria; Turna, Hande; Ursol, Grygoriy; Vanasek, Jaroslav; Varela, Mirta; Vallejo, Marcela; Vera, Luis; Victorino, Ana-Paula; Vlasek, Tomas; Vynnychenko, Ihor; Wang, Buhai; Wang, Jie; Wang, Kai; Wu, Yilong; Yamada, Kazuhiko; Yang, Chih-Hsin; Yokoyama, Takuma; Yokoyama, Toshihide; Yoshioka, Hiroshige; Yumuk, Fulden; Zambrano, Angela; Zarba, Juan Jose; Zarubenkov, Oleg; Zemaitis, Marius; Zhang, Li; Zhang, Xin; Zhao, Jun; Zhou, Caicun; Zhou, Jianying; Zhou, Qing; Zippelius, Alfred
Source
The Lancet. May 4, 2019, Vol. 393 Issue 10183, 1819
Subject
Language
English
ISSN
0140-6736
Abstract
Summary Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults ([greater than or equal to]18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS ([greater than or equal to]50% vs 1--49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0*0122, p=0*0120, and p=0*0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57--69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12*8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations ([greater than or equal to]50% hazard ratio 0*69, 95% CI 0*56--0*85, p=0*0003; [greater than or equal to]20% 0*77, 0*64--0*92, p=0*0020, and [greater than or equal to]1% 0*81, 0*71--0*93, p=0*0018). The median surival values by TPS population were 20*0 months (95% CI 15*4--24*9) for pembrolizumab versus 12*2 months (10*4--14*2) for chemotherapy, 17*7 months (15*3--22*1) versus 13*0 months (11*6--15*3), and 16*7 months (13*9--19*7) versus 12*1 months (11*3--13*3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.