Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer

Leena Gandhi; Delvys Rodríguez-Abreu; Shirish Gadgeel; Emilio Esteban; Enriqueta Felip; Flávia De Angelis; Manuel Domine; Philip Clingan; Maximilian J Hochmair; Steven F Powell; Susanna Y-S Cheng; Helge G Bischoff; Nir Peled; Francesco Grossi; Ross R Jennens; Martin Reck; Rina Hui; Edward B Garon; Michael Boyer; Belén Rubio-Viqueira; Silvia Novello; Takayasu Kurata; Jhanelle E Gray; John Vida; Ziwen Wei; Jing Yang; Harry Raftopoulos; M Catherine Pietanza; Marina C Garassino; KEYNOTE-189 Investigators; Michael Boyer; Victoria Bray; Baerin Ben Houghton; Jens Benn Sørensen; Karin Holmskov Hansen; Miroslaw Jan Stelmach; William V. Walsh; John Wrangle; Stephen H. Wrzesinski

doi:10.1056/nejmoa1801005

Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer

Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-ViqueiraSilvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino, KEYNOTE-189 Investigators, Michael Boyer, Victoria Bray, Baerin Ben Houghton, Jens Benn Sørensen, Karin Holmskov Hansen, Miroslaw Jan Stelmach, William V. Walsh, John Wrangle, Stephen H. Wrzesinski

Institut for Klinisk Medicin

2051 Citationer (Scopus)

Abstract

BACKGROUND First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab- combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebocombination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Originalsprog	Engelsk
Tidsskrift	The New England Journal of Medicine
Vol/bind	378
Udgave nummer	22
Sider (fra-til)	2078-2092
ISSN	0028-4793
DOI	https://doi.org/10.1056/nejmoa1801005
Status	Udgivet - 31 maj 2018

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Gandhi, L., Rodríguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., Domine, M., Clingan, P., Hochmair, M. J., Powell, S. F., Cheng, S. Y.-S., Bischoff, H. G., Peled, N., Grossi, F., Jennens, R. R., Reck, M., Hui, R., Garon, E. B., Boyer, M., ... Wrzesinski, S. H. (2018). Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 378(22), 2078-2092. https://doi.org/10.1056/nejmoa1801005

Gandhi, L, Rodríguez-Abreu, D, Gadgeel, S, Esteban, E, Felip, E, De Angelis, F, Domine, M, Clingan, P, Hochmair, MJ, Powell, SF, Cheng, SY-S, Bischoff, HG, Peled, N, Grossi, F, Jennens, RR, Reck, M, Hui, R, Garon, EB, Boyer, M, Rubio-Viqueira, B, Novello, S, Kurata, T, Gray, JE, Vida, J, Wei, Z, Yang, J, Raftopoulos, H, Pietanza, MC, Garassino, MC, KEYNOTE-189 Investigators, Boyer, M, Bray, V, Houghton, BB, Sørensen, JB, Hansen, KH, Stelmach, MJ, Walsh, WV, Wrangle, J & Wrzesinski, SH 2018, 'Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer', The New England Journal of Medicine, bind 378, nr. 22, s. 2078-2092. https://doi.org/10.1056/nejmoa1801005

@article{291031f72edd46d78dcfcba67f653832,

title = "Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer",

abstract = "BACKGROUND First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab- combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebocombination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.",

keywords = "Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized/adverse effects, Antineoplastic Agents, Immunological/adverse effects, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Carcinoma, Non-Small-Cell Lung/drug therapy, Disease-Free Survival, Double-Blind Method, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Lung Neoplasms/drug therapy, Male, Middle Aged",

author = "Leena Gandhi and Delvys Rodr{\'i}guez-Abreu and Shirish Gadgeel and Emilio Esteban and Enriqueta Felip and {De Angelis}, Fl{\'a}via and Manuel Domine and Philip Clingan and Hochmair, {Maximilian J} and Powell, {Steven F} and Cheng, {Susanna Y-S} and Bischoff, {Helge G} and Nir Peled and Francesco Grossi and Jennens, {Ross R} and Martin Reck and Rina Hui and Garon, {Edward B} and Michael Boyer and Bel{\'e}n Rubio-Viqueira and Silvia Novello and Takayasu Kurata and Gray, {Jhanelle E} and John Vida and Ziwen Wei and Jing Yang and Harry Raftopoulos and Pietanza, {M Catherine} and Garassino, {Marina C} and {KEYNOTE-189 Investigators} and Michael Boyer and Victoria Bray and Houghton, {Baerin Ben} and S{\o}rensen, {Jens Benn} and Hansen, {Karin Holmskov} and Stelmach, {Miroslaw Jan} and Walsh, {William V.} and John Wrangle and Wrzesinski, {Stephen H.}",

year = "2018",

month = may,

day = "31",

doi = "10.1056/nejmoa1801005",

language = "English",

volume = "378",

pages = "2078--2092",

journal = "The New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "22",

}

TY - JOUR

T1 - Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer

AU - Gandhi, Leena

AU - Rodríguez-Abreu, Delvys

AU - Gadgeel, Shirish

AU - Esteban, Emilio

AU - Felip, Enriqueta

AU - De Angelis, Flávia

AU - Domine, Manuel

AU - Clingan, Philip

AU - Hochmair, Maximilian J

AU - Powell, Steven F

AU - Cheng, Susanna Y-S

AU - Bischoff, Helge G

AU - Peled, Nir

AU - Grossi, Francesco

AU - Jennens, Ross R

AU - Reck, Martin

AU - Hui, Rina

AU - Garon, Edward B

AU - Boyer, Michael

AU - Rubio-Viqueira, Belén

AU - Novello, Silvia

AU - Kurata, Takayasu

AU - Gray, Jhanelle E

AU - Vida, John

AU - Wei, Ziwen

AU - Yang, Jing

AU - Raftopoulos, Harry

AU - Pietanza, M Catherine

AU - Garassino, Marina C

AU - KEYNOTE-189 Investigators

AU - Boyer, Michael

AU - Bray, Victoria

AU - Houghton, Baerin Ben

AU - Sørensen, Jens Benn

AU - Hansen, Karin Holmskov

AU - Stelmach, Miroslaw Jan

AU - Walsh, William V.

AU - Wrangle, John

AU - Wrzesinski, Stephen H.

PY - 2018/5/31

Y1 - 2018/5/31

N2 - BACKGROUND First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab- combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebocombination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

AB - BACKGROUND First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab- combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebocombination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal, Humanized/adverse effects

KW - Antineoplastic Agents, Immunological/adverse effects

KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Kaplan-Meier Estimate

KW - Lung Neoplasms/drug therapy

KW - Male

KW - Middle Aged

U2 - 10.1056/nejmoa1801005

DO - 10.1056/nejmoa1801005

M3 - Journal article

C2 - 29658856

SN - 0028-4793

VL - 378

SP - 2078

EP - 2092

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

IS - 22

ER -

Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer

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