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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1819-1830 |
| Number of pages | 12 |
| Journal | The Lancet |
| Volume | 393 |
| Issue number | 10183 |
| DOIs | |
| State | Published - May 4 2019 |
ASJC Scopus subject areas
- Medicine(all)
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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. / Mok, Tony S.K.; Wu, Yi Long; Kudaba, Iveta; Kowalski, Dariusz M.; Cho, Byoung Chul; Turna, Hande Z.; Castro, Gilberto; Srimuninnimit, Vichien; Laktionov, Konstantin K.; Bondarenko, Igor; Kubota, Kaoru; Lubiniecki, Gregory M.; Zhang, Jin; Kush, Debra; Lopes, Gilberto; Gomez Aubin, Gonzalo; Fein, Luis; Kaen, Diego; Kowalyszyn, Ruben; Lerzo, Guillermo; Martinengo, Gaston; Molina, Matias; Richardet, Eduardo; Picon, Pablo; Varela, Mirta; Zarba, Juan Jose; de Azevedo, Sergio Jobim; Barrios, Carlos Henrique; Beato, Carlos; Cerny, Carlos Alexandre Sydow; De Marchi, Pedro Rafael Martins; Fernandes, Gustavo; Franke, Fabio Andre; Freitas, Helano; Girotto, Gustavo; Lopes, Valeria; Santos, Lucas; Costa, Marcos Andre; Shimada, Andrea Kazumi; Smaletz, Oren; Soares, Joao Paulo Holanda; Victorino, Ana Paula; Ferreira, Carlos; Koleva, Marchela; Koynov, Krassimir; Micheva, Rumyana; Deliverski, Tsvetan; Milanova, Zhasmina; Doganov, Boyan; Cheng, Susanna; De Angelis, Flavia; Speranza, Giovanna; Juergens, Rosalyn Anne; Ksienski, Doran; Fenton, David; Aren, Osvaldo; Caglevic, Christian; Galindo, Hector; Rey, Felipe; Chang, Jianhua; Chen, Gongyan; Chen, Xi; Ouyang, Xuenong; Cheng, Ying; Ding, Zhenyu; Hou, Mei; Fan, Yun; Feng, Jifeng; He, Jianxing; He, Yong; Hu, Yi; Li, Wei; Liu, Xiaoqing; Liu, Zhe; Lu, Shun; Qin, Shukui; Tang, Qiyou; Wang, Buhai; Wang, Kai; Zhang, Li; Zhang, Xin; Zhao, Jun; Wang, Jie; Zhou, Caicun; Zhou, Jianying; Zhou, Qing; Cardona, Andres; Duarte, Ricardo; Gomez Wolff, Luis; Zambrano, Angela; Vallejo, Marcela; Havel, Libor; Kolek, Vitezslav; Kolman, Petr; Koubkova, Leona; Petruzelka, Lubos; Popelkova, Patrice; Roubec, Jaromir; Vanasek, Jaroslav; Vlasek, Tomas; Jaal, Jana; Kuusk, Gerli; Avendano, Oscar; Castro, Hugo; Lopez, Karla; Sandoval, Mario; Ho, Chung Man James; Lo, Sing Hung; Laczo, Ibolya; Piko, Bela; Ostoros, Gyula; Aoe, Keisuke; Fujisaka, Yasuhito; Hirashima, Tomonori; Horiike, Atsushi; Hosomi, Yukio; Hotta, Katsuyuki; Ichiki, Masao; Imamura, Fumio; Iwamoto, Yasuo; Kasahara, Kazuo; Katakami, Nobuyuki; Kato, Terufumi; Murakami, Shuji; Kawaguchi, Tomoya; Kishi, Kazuma; Kurata, Takayasu; Torii, Yoshitaro; Nakahara, Yasuharu; Nishimura, Takashi; Ohira, Tatsuo; Saka, Hideo; Sawa, Toshiyuki; Seki, Nobuhiko; Sugawara, Shunichi; Takahashi, Kazuhisa; Takigawa, Nagio; Tanaka, Hiroshi; Yamada, Kazuhiko; Yokoyama, Takuma; Yokoyama, Toshihide; Yoshioka, Hiroshige; Purkalne, Gunta; Stara, Zinaida; Cesas, Alvydas; Cicenas, Saulius; Zemaitis, Marius; How, Soon Hin; Liam, Chong Kin; Ong, Choo Khoon; Tho, Lye Mun; Arrieta Rodriguez, Oscar; de The Bustamante Valles, Flor; Hernandez Hernandez, Carlos; Mas, Luis; Vera, Luis; Salas, Jorge; Tejada, Hermes; Edusma-Dy, Regina; Galvez, Christina; Ladrera, Guia Elena Imelda; Tan Chun Bing, Jerry; Jassem, Jacek; Kalinka-Warzocha, Ewa; Karaszewska, Boguslawa; Kazarnowicz, Andrzej; Lesniewski Kmak, Krzysztof; Ramlau, Rodryg; Araujo, Antonio; Barata, Fernando; Gil, Nuno; Hespanhol, Venceslau; Alexandru, Aurelia; Dediu, Mircea; Cherciu, Nelly; Ciurescu, Daniel; Ganea, Doina; Miron, Lucian; Sirbu, Daniela; Turdean, Maria; Emelyanov, Sergey; Karaseva, Nina; Kuzina, Lyudmila; Lazarev, Sergey; Lifirenko, Igor; Bolotina, Larisa; Lipatov, Oleg; Ovchinnikova, Elena; Matrosova, Marina; Alyasova, Anna; Poltoratsky, Artem; Taranov, Pavel; Zarubenkov, Oleg; Cohen, Graham; Dreosti, Lydia; Seolwane, Freddy; Hall, Jacqueline; Hart, Gregory; Jordaan, Christa; Buddu, Sayeuri; Botha, Michiel; Landers, Gregory; Rappaport, Bernardo; Ruff, Paul; Shepherd, Lucinda; Szpak, Waldemar; Ahn, Myung Ju; Kim, Joo Hang; Bergstrom, Per; Ohman, Ronny; Griph, Hakan; Betticher, Daniel; Ochsenbein, Adrian; Zippelius, Alfred; Chan, Gee Chen; Chiu, Chao Hua; Hsia, Te Chun; Su, Wu Chou; Yang, Chih Hsin; Ativitavas, Touch; Danchaivijitr, Pongwut; Seetalarom, Kasan; Sookprasert, Aumkhae; Sriuranpong, Virote; Altundag, Ozden; Cay Senler, Filiz; Erman, Mustafa; Goksel, Tuncay; Goker, Erdem; Ozyilkan, Ozgur; Seker, Mesut; Gumus, Mahmut; Yumuk, Fulden; Adamchuk, Grigory; Ivashchuk, Oleksandr; Ponomarova, Olga; Rusyn, Andrii; Shevnya, Sergii; Shparyk, Yaroslav; Sinielnikov, Ivan; Andrusenko, Orest; Trukhyn, Dmytro; Ursol, Grygoriy; Vynnychenko, Ihor; Nguyen, Tien Quang; Pham, Xuan Dung.
In: The Lancet, Vol. 393, No. 10183, 04.05.2019, p. 1819-1830.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042)
T2 - a randomised, open-label, controlled, phase 3 trial
AU - Mok, Tony S.K.
AU - Wu, Yi Long
AU - Kudaba, Iveta
AU - Kowalski, Dariusz M.
AU - Cho, Byoung Chul
AU - Turna, Hande Z.
AU - Castro, Gilberto
AU - Srimuninnimit, Vichien
AU - Laktionov, Konstantin K.
AU - Bondarenko, Igor
AU - Kubota, Kaoru
AU - Lubiniecki, Gregory M.
AU - Zhang, Jin
AU - Kush, Debra
AU - Lopes, Gilberto
AU - Gomez Aubin, Gonzalo
AU - Fein, Luis
AU - Kaen, Diego
AU - Kowalyszyn, Ruben
AU - Lerzo, Guillermo
AU - Martinengo, Gaston
AU - Molina, Matias
AU - Richardet, Eduardo
AU - Picon, Pablo
AU - Varela, Mirta
AU - Zarba, Juan Jose
AU - de Azevedo, Sergio Jobim
AU - Barrios, Carlos Henrique
AU - Beato, Carlos
AU - Cerny, Carlos Alexandre Sydow
AU - De Marchi, Pedro Rafael Martins
AU - Fernandes, Gustavo
AU - Franke, Fabio Andre
AU - Freitas, Helano
AU - Girotto, Gustavo
AU - Lopes, Valeria
AU - Santos, Lucas
AU - Costa, Marcos Andre
AU - Shimada, Andrea Kazumi
AU - Smaletz, Oren
AU - Soares, Joao Paulo Holanda
AU - Victorino, Ana Paula
AU - Ferreira, Carlos
AU - Koleva, Marchela
AU - Koynov, Krassimir
AU - Micheva, Rumyana
AU - Deliverski, Tsvetan
AU - Milanova, Zhasmina
AU - Doganov, Boyan
AU - Cheng, Susanna
AU - De Angelis, Flavia
AU - Speranza, Giovanna
AU - Juergens, Rosalyn Anne
AU - Ksienski, Doran
AU - Fenton, David
AU - Aren, Osvaldo
AU - Caglevic, Christian
AU - Galindo, Hector
AU - Rey, Felipe
AU - Chang, Jianhua
AU - Chen, Gongyan
AU - Chen, Xi
AU - Ouyang, Xuenong
AU - Cheng, Ying
AU - Ding, Zhenyu
AU - Hou, Mei
AU - Fan, Yun
AU - Feng, Jifeng
AU - He, Jianxing
AU - He, Yong
AU - Hu, Yi
AU - Li, Wei
AU - Liu, Xiaoqing
AU - Liu, Zhe
AU - Lu, Shun
AU - Qin, Shukui
AU - Tang, Qiyou
AU - Wang, Buhai
AU - Wang, Kai
AU - Zhang, Li
AU - Zhang, Xin
AU - Zhao, Jun
AU - Wang, Jie
AU - Zhou, Caicun
AU - Zhou, Jianying
AU - Zhou, Qing
AU - Cardona, Andres
AU - Duarte, Ricardo
AU - Gomez Wolff, Luis
AU - Zambrano, Angela
AU - Vallejo, Marcela
AU - Havel, Libor
AU - Kolek, Vitezslav
AU - Kolman, Petr
AU - Koubkova, Leona
AU - Petruzelka, Lubos
AU - Popelkova, Patrice
AU - Roubec, Jaromir
AU - Vanasek, Jaroslav
AU - Vlasek, Tomas
AU - Jaal, Jana
AU - Kuusk, Gerli
AU - Avendano, Oscar
AU - Castro, Hugo
AU - Lopez, Karla
AU - Sandoval, Mario
AU - Ho, Chung Man James
AU - Lo, Sing Hung
AU - Laczo, Ibolya
AU - Piko, Bela
AU - Ostoros, Gyula
AU - Aoe, Keisuke
AU - Fujisaka, Yasuhito
AU - Hirashima, Tomonori
AU - Horiike, Atsushi
AU - Hosomi, Yukio
AU - Hotta, Katsuyuki
AU - Ichiki, Masao
AU - Imamura, Fumio
AU - Iwamoto, Yasuo
AU - Kasahara, Kazuo
AU - Katakami, Nobuyuki
AU - Kato, Terufumi
AU - Murakami, Shuji
AU - Kawaguchi, Tomoya
AU - Kishi, Kazuma
AU - Kurata, Takayasu
AU - Torii, Yoshitaro
AU - Nakahara, Yasuharu
AU - Nishimura, Takashi
AU - Ohira, Tatsuo
AU - Saka, Hideo
AU - Sawa, Toshiyuki
AU - Seki, Nobuhiko
AU - Sugawara, Shunichi
AU - Takahashi, Kazuhisa
AU - Takigawa, Nagio
AU - Tanaka, Hiroshi
AU - Yamada, Kazuhiko
AU - Yokoyama, Takuma
AU - Yokoyama, Toshihide
AU - Yoshioka, Hiroshige
AU - Purkalne, Gunta
AU - Stara, Zinaida
AU - Cesas, Alvydas
AU - Cicenas, Saulius
AU - Zemaitis, Marius
AU - How, Soon Hin
AU - Liam, Chong Kin
AU - Ong, Choo Khoon
AU - Tho, Lye Mun
AU - Arrieta Rodriguez, Oscar
AU - de The Bustamante Valles, Flor
AU - Hernandez Hernandez, Carlos
AU - Mas, Luis
AU - Vera, Luis
AU - Salas, Jorge
AU - Tejada, Hermes
AU - Edusma-Dy, Regina
AU - Galvez, Christina
AU - Ladrera, Guia Elena Imelda
AU - Tan Chun Bing, Jerry
AU - Jassem, Jacek
AU - Kalinka-Warzocha, Ewa
AU - Karaszewska, Boguslawa
AU - Kazarnowicz, Andrzej
AU - Lesniewski Kmak, Krzysztof
AU - Ramlau, Rodryg
AU - Araujo, Antonio
AU - Barata, Fernando
AU - Gil, Nuno
AU - Hespanhol, Venceslau
AU - Alexandru, Aurelia
AU - Dediu, Mircea
AU - Cherciu, Nelly
AU - Ciurescu, Daniel
AU - Ganea, Doina
AU - Miron, Lucian
AU - Sirbu, Daniela
AU - Turdean, Maria
AU - Emelyanov, Sergey
AU - Karaseva, Nina
AU - Kuzina, Lyudmila
AU - Lazarev, Sergey
AU - Lifirenko, Igor
AU - Bolotina, Larisa
AU - Lipatov, Oleg
AU - Ovchinnikova, Elena
AU - Matrosova, Marina
AU - Alyasova, Anna
AU - Poltoratsky, Artem
AU - Taranov, Pavel
AU - Zarubenkov, Oleg
AU - Cohen, Graham
AU - Dreosti, Lydia
AU - Seolwane, Freddy
AU - Hall, Jacqueline
AU - Hart, Gregory
AU - Jordaan, Christa
AU - Buddu, Sayeuri
AU - Botha, Michiel
AU - Landers, Gregory
AU - Rappaport, Bernardo
AU - Ruff, Paul
AU - Shepherd, Lucinda
AU - Szpak, Waldemar
AU - Ahn, Myung Ju
AU - Kim, Joo Hang
AU - Bergstrom, Per
AU - Ohman, Ronny
AU - Griph, Hakan
AU - Betticher, Daniel
AU - Ochsenbein, Adrian
AU - Zippelius, Alfred
AU - Chan, Gee Chen
AU - Chiu, Chao Hua
AU - Hsia, Te Chun
AU - Su, Wu Chou
AU - Yang, Chih Hsin
AU - Ativitavas, Touch
AU - Danchaivijitr, Pongwut
AU - Seetalarom, Kasan
AU - Sookprasert, Aumkhae
AU - Sriuranpong, Virote
AU - Altundag, Ozden
AU - Cay Senler, Filiz
AU - Erman, Mustafa
AU - Goksel, Tuncay
AU - Goker, Erdem
AU - Ozyilkan, Ozgur
AU - Seker, Mesut
AU - Gumus, Mahmut
AU - Yumuk, Fulden
AU - Adamchuk, Grigory
AU - Ivashchuk, Oleksandr
AU - Ponomarova, Olga
AU - Rusyn, Andrii
AU - Shevnya, Sergii
AU - Shparyk, Yaroslav
AU - Sinielnikov, Ivan
AU - Andrusenko, Orest
AU - Trukhyn, Dmytro
AU - Ursol, Grygoriy
AU - Vynnychenko, Ihor
AU - Nguyen, Tien Quang
AU - Pham, Xuan Dung
N1 - Funding Information: This study was funded by Merck Sharp & Dohme. We thank the patients and their families and caregivers for participating in this trial and all the investigators and site personnel. At Merck Sharp & Dohme, we thank Roger Dansey for critical review of the manuscript, Lu Xu for assistance with statistical analyses, Jim Betzel and Sara Sadowski for study support, and Melanie A Leiby for medical writing and editorial assistance. Funding Information: TSKM is a member of the board of directors for AstraZeneca, Chi-Med, and Sanomics, has received grants or research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, and XCovery, speakers' fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Taiho, and Takeda Oncology, honoraria from ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Fishawack Facilitate, Ignyta, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex Pharmaceuticals, Pfizer, Roche/Genentech, SFJ Pharmaceuticals, Takeda Oncology, and Vertex Pharmaceuticals, is a major stockholder in Sanomics, and is an advisory board member for ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, ChiMed, Cirina, Clovis Oncology, Eli Lilly, Fishawack Facilitate, geneDecode Co, Ignyta, Janssen, Pfizer, Merck Serono, Merck Sharp & Dohme, Novartis, Roche/Genentech, SFJ Pharmaceuticals, Takeda, and Vertex Pharmaceuticals. Y-LW has received honoraria from AstraZeneca, Eli Lilly, Pfizer, Pierre Fabre, Roche, and Sanofi, has had a consulting or advisory role with AstraZeneca, Boehringer Ingelheim, Merck, and Roche, and has received research funding to his institution from Boehringer Ingelheim and Roche. BCC has received honoraria from AstraZeneca, Boehringer Ingelheim, and Roche, has acted as a consultant or adviser for AstraZeneca, Roche and Boehringer Ingelheim, been a member of the speakers' bureau for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis, and has received research funding from AstraZeneca, Bayer, Novartis, and Yuhan. GC has held consulting or advisory roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche, been a member of the speakers' bureau for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis, and payment for travel, accommodation, and expenses from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. KK has received research funding from Boehringer Ingelheim, Ono, and Taiho. GML, JZ and DK are employees of Merck Sharp & Dohme. GL has received research funding to the institution from AstraZeneca, EMD Serono, and Merck & Co. The other authors declare no competing interests. Publisher Copyright: © 2019 Elsevier Ltd
PY - 2019/5/4
Y1 - 2019/5/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064607320&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064607320&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(18)32409-7
DO - 10.1016/S0140-6736(18)32409-7
M3 - Article
C2 - 30955977
AN - SCOPUS:85064607320
VL - 393
SP - 1819
EP - 1830
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10183
ER -