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Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4.

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.

Collaborators (243)

Adamchuk G, Ahn MJ, Alexandru A, Altundag O, Alyasova A, Andrusenko O, Aoe K, Araujo A, Aren O, Arrieta Rodriguez O, Ativitavas T, Avendano O, Barata F, Barrios CH, Beato C, Bergstrom P, Betticher D, Bolotina L, Bondarenko I, Botha M, Buddu S, Caglevic C, Cardona A, Castro G Jr, Castro H, Cay Senler F, Cerny CAS, Cesas A, Chan GC, Chang J, Chen G, Chen X, Cheng S, Cheng Y, Cherciu N, Chiu CH, Cho BC, Cicenas S, Ciurescu D, Cohen G, Costa MA, Danchaivijitr P, De Angelis F, de Azevedo SJ, Dediu M, Deliverski T, De Marchi PRM, de The Bustamante Valles F, Ding Z, Doganov B, Dreosti L, Duarte R, Edusma-Dy R, Emelyanov S, Erman M, Fan Y, Fein L, Feng J, Fenton D, Fernandes G, Ferreira C, Franke FA, Freitas H, Fujisaka Y, Galindo H, Galvez C, Ganea D, Gil N, Girotto G, Goker E, Goksel T, Gomez Aubin G, Gomez Wolff L, Griph H, Gumus M, Hall J, Hart G, Havel L, He J, He Y, Hernandez Hernandez C, Hespanhol V, Hirashima T, Ho CMJ, Horiike A, Hosomi Y, Hotta K, Hou M, How SH, Hsia TC, Hu Y, Ichiki M, Imamura F, Ivashchuk O, Iwamoto Y, Jaal J, Jassem J, Jordaan C, Juergens RA, Kaen D, Kalinka-Warzocha E, Karaseva N, Karaszewska B, Kazarnowicz A, Kasahara K, Katakami N, Kato T, Kawaguchi T, Kim JH, Kishi K, Kolek V, Koleva M, Kolman P, Koubkova L, Kowalyszyn R, Kowalski D, Koynov K, Ksienski D, Kubota K, Kudaba I, Kurata T, Kuusk G, Kuzina L, Laczo I, Ladrera GEI, Laktionov K, Landers G, Lazarev S, Lerzo G, Lesniewski Kmak K, Li W, Liam CK, Lifirenko I, Lipatov O, Liu X, Liu Z, Lo SH, Lopes V, Lopez K, Lu S, Martinengo G, Mas L, Matrosova M, Micheva R, Milanova Z, Miron L, Mok T, Molina M, Murakami S, Nakahara Y, Nguyen TQ, Nishimura T, Ochsenbein A, Ohira T, Ohman R, Ong CK, Ostoros G, Ouyang X, Ovchinnikova E, Ozyilkan O, Petruzelka L, Pham XD, Picon P, Piko B, Poltoratsky A, Ponomarova O, Popelkova P, Purkalne G, Qin S, Ramlau R, Rappaport B, Rey F, Richardet E, Roubec J, Ruff P, Rusyn A, Saka H, Salas J, Sandoval M, Santos L, Sawa T, Seetalarom K, Seker M, Seki N, Seolwane F, Shepherd L, Shevnya S, Shimada AK, Shparyk Y, Sinielnikov I, Sirbu D, Smaletz O, Soares JPH, Sookprasert A, Speranza G, Srimuninnimit V, Sriuranpong V, Stara Z, Su WC, Sugawara S, Szpak W, Takahashi K, Takigawa N, Tanaka H, Tan Chun Bing J, Tang Q, Taranov P, Tejada H, Tho LM, Torii Y, Trukhyn D, Turdean M, Turna H, Ursol G, Vanasek J, Varela M, Vallejo M, Vera L, Victorino AP, Vlasek T, Vynnychenko I, Wang B, Wang J, Wang K, Wu Y, Yamada K, Yang CH, Yokoyama T, Yokoyama T, Yoshioka H, Yumuk F, Zambrano A, Zarba JJ, Zarubenkov O, Zemaitis M, Zhang L, Zhang L, Zhang X, Zhao J, Zhou C, Zhou J, Zhou Q, Zippelius A.

Author information

1
Department of Clinical Oncology, State Key Laboratory of South China, Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China. Electronic address: tony@clo.cuhk.edu.hk.
2
Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guandong, China.
3
Department of Internal Diseases, Riga East Clinical University-Latvian Oncology Center, Riga, Latvia.
4
Department of Lung Cancer and Chest Tumours, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
5
Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea.
6
Department of Internal Medicine, Division of Medical Oncology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey.
7
Department of Medical Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
8
Division of Medical Oncology, Department of Medicine, Siriraj Hospital, Bangkok, Thailand.
9
Department of Thoracic and Abdominal Oncology, N N Blokhin Russian Cancer Research Center, Moscow, Russia.
10
Oncology and Medical Radiology Department, Dnipropetrovsk Medical Academy, Dnipro, Ukraine.
11
Department of Pulmonary Medicine and Oncology, Nippon Medical School Hospital, Tokyo, Japan.
12
Global Clinical Development, Merck & Co, Kenilworth, NJ, USA.
13
Biostatistics and Research Design Statistics, Merck & Co, Kenilworth, NJ, USA.
14
Department of Medical Oncology, Sylvester Comprehensive Cancer Center at the University of Miami, Miami, FL, USA.

Abstract

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.

Comment in

PMID:
30955977
DOI:
10.1016/S0140-6736(18)32409-7
[Indexed for MEDLINE]

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