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

Tony S.K. Mok, Yi Long Wu, Iveta Kudaba, Dariusz M. Kowalski, Byoung Chul Cho, Hande Z. Turna, Gilberto Castro, Vichien Srimuninnimit, Konstantin K. Laktionov, Igor Bondarenko, Kaoru Kubota, Gregory M. Lubiniecki, Jin Zhang, Debra Kush, Gilberto Lopes, Gonzalo Gomez Aubin, Luis Fein, Diego Kaen, Ruben Kowalyszyn, Guillermo LerzoGaston Martinengo, Matias Molina, Eduardo Richardet, Pablo Picon, Mirta Varela, Juan Jose Zarba, Sergio Jobim de Azevedo, Carlos Henrique Barrios, Carlos Beato, Carlos Alexandre Sydow Cerny, Pedro Rafael Martins De Marchi, Gustavo Fernandes, Fabio Andre Franke, Helano Freitas, Gustavo Girotto, Valeria Lopes, Lucas Santos, Marcos Andre Costa, Andrea Kazumi Shimada, Oren Smaletz, Joao Paulo Holanda Soares, Ana Paula Victorino, Carlos Ferreira, Marchela Koleva, Krassimir Koynov, Rumyana Micheva, Tsvetan Deliverski, Zhasmina Milanova, Boyan Doganov, Susanna Cheng, Flavia De Angelis, Giovanna Speranza, Rosalyn Anne Juergens, Doran Ksienski, David Fenton, Osvaldo Aren, Christian Caglevic, Hector Galindo, Felipe Rey, Jianhua Chang, Gongyan Chen, Xi Chen, Xuenong Ouyang, Ying Cheng, Zhenyu Ding, Mei Hou, Yun Fan, Jifeng Feng, Jianxing He, Yong He, Yi Hu, Wei Li, Xiaoqing Liu, Zhe Liu, Shun Lu, Shukui Qin, Qiyou Tang, Buhai Wang, Kai Wang, Li Zhang, Xin Zhang, Jun Zhao, Jie Wang, Caicun Zhou, Jianying Zhou, Qing Zhou, Yilong Wu, Andres Cardona, Ricardo Duarte, Luis Gomez Wolff, Angela Zambrano, Marcela Vallejo, Libor Havel, Vitezslav Kolek, Petr Kolman, Leona Koubkova, Lubos Petruzelka, Patrice Popelkova, Jaromir Roubec, Jaroslav Vanasek, Tomas Vlasek, Jana Jaal, Gerli Kuusk, Oscar Avendano, Hugo Castro, Karla Lopez, Mario Sandoval, Chung Man James Ho, Sing Hung Lo, Ibolya Laczo, Bela Piko, Gyula Ostoros, Keisuke Aoe, Yasuhito Fujisaka, Tomonori Hirashima, Atsushi Horiike, Yukio Hosomi, Katsuyuki Hotta, Masao Ichiki, Fumio Imamura, Yasuo Iwamoto, Kazuo Kasahara, Nobuyuki Katakami, Terufumi Kato, Shuji Murakami, Tomoya Kawaguchi, Kazuma Kishi, Kaoru Kubota, Takayasu Kurata, Yoshitaro Torii, Yasuharu Nakahara, Takashi Nishimura, Tatsuo Ohira, Hideo Saka, Toshiyuki Sawa, Nobuhiko Seki, Shunichi Sugawara, Kazuhisa Takahashi, Nagio Takigawa, Hiroshi Tanaka, Kazuhiko Yamada, Takuma Yokoyama, Toshihide Yokoyama, Hiroshige Yoshioka, Iveta Kudaba, Gunta Purkalne, Zinaida Stara, Alvydas Cesas, Saulius Cicenas, Marius Zemaitis, Soon Hin How, Chong Kin Liam, Choo Khoon Ong, Lye Mun Tho, Oscar Arrieta Rodriguez, Flor de The Bustamante Valles, Carlos Hernandez Hernandez, Luis Mas, Luis Vera, Jorge Salas, Hermes Tejada, Regina Edusma-Dy, Christina Galvez, Guia Elena Imelda Ladrera, Jerry Tan Chun Bing, Jacek Jassem, Ewa Kalinka-Warzocha, Boguslawa Karaszewska, Andrzej Kazarnowicz, Dariusz Kowalski, Krzysztof Lesniewski Kmak, Rodryg Ramlau, Antonio Araujo, Fernando Barata, Nuno Gil, Venceslau Hespanhol, Aurelia Alexandru, Mircea Dediu, Nelly Cherciu, Daniel Ciurescu, Doina Ganea, Lucian Miron, Daniela Sirbu, Maria Turdean, Sergey Emelyanov, Nina Karaseva, Lyudmila Kuzina, Sergey Lazarev, Igor Lifirenko, Larisa Bolotina, Oleg Lipatov, Elena Ovchinnikova, Marina Matrosova, Anna Alyasova, Artem Poltoratsky, Pavel Taranov, Oleg Zarubenkov, Graham Cohen, Lydia Dreosti, Freddy Seolwane, Jacqueline Hall, Gregory Hart, Christa Jordaan, Sayeuri Buddu, Michiel Botha, Gregory Landers, Bernardo Rappaport, Paul Ruff, Lucinda Shepherd, Waldemar Szpak, Myung Ju Ahn, Byoung Chul Cho, Joo Hang Kim, Per Bergstrom, Ronny Ohman, Hakan Griph, Daniel Betticher, Adrian Ochsenbein, Alfred Zippelius, Gee Chen Chan, Chao Hua Chiu, Te Chun Hsia, Wu Chou Su, Chih Hsin Yang, Touch Ativitavas, Pongwut Danchaivijitr, Vichien Srimuninnimit, Kasan Seetalarom, Aumkhae Sookprasert, Virote Sriuranpong, Ozden Altundag, Filiz Cay Senler, Mustafa Erman, Tuncay Goksel, Erdem Goker, Ozgur Ozyilkan, Mesut Seker, Mahmut Gumus, Hande Turna, Fulden Yumuk, Grigory Adamchuk, Igor Bondarenko, Oleksandr Ivashchuk, Olga Ponomarova, Andrii Rusyn, Sergii Shevnya, Yaroslav Shparyk, Ivan Sinielnikov, Orest Andrusenko, Dmytro Trukhyn, Grygoriy Ursol, Ihor Vynnychenko, Tien Quang Nguyen, Xuan Dung Pham, Gilberto Castro, Kaoru Kubota

研究成果: Article

257 引文 斯高帕斯(Scopus)

摘要

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 (≥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 (≥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 (≥50% hazard ratio 0·69, 95% CI 0·56–0·85, p=0·0003; ≥20% 0·77, 0·64–0·92, p=0·0020, and ≥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.

原文English
頁(從 - 到)1819-1830
頁數12
期刊The Lancet
393
發行號10183
DOIs
出版狀態Published - 2019 五月 4

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Mok, T. S. K., Wu, Y. L., Kudaba, I., Kowalski, D. M., Cho, B. C., Turna, H. Z., Castro, G., Srimuninnimit, V., Laktionov, K. K., Bondarenko, I., Kubota, K., Lubiniecki, G. M., Zhang, J., Kush, D., Lopes, G., Gomez Aubin, G., Fein, L., Kaen, D., Kowalyszyn, R., ... Kubota, K. (2019). 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. The Lancet, 393(10183), 1819-1830. https://doi.org/10.1016/S0140-6736(18)32409-7