Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study

Tudor Ciuleanu, Thomas Brodowicz, Christoph Zielinski, Joo Hang Kim, Maciej Krzakowski, Eckart Laack, Yi Long Wu, Isabel Bover, Stephen Begbie, Valentina Tzekova, Branka Cucevic, Jose Rodrigues Pereira, Sung Hyun Yang, Jayaprakash Madhavan, Katherine P. Sugarman, Patrick Peterson, William J. John, Kurt Krejcy, Chandra P. Belani

Research output: Contribution to journalArticle

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Abstract

Background: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. Methods: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m2, day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B12, folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. Findings: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4·3 months [95% CI 4·1-4·7] vs 2·6 months [1·7-2·8]; hazard ratio [HR] 0·50, 95% CI 0·42-0·61, p<0·0001) and overall survival (13·4 months [11·9-15·9] vs 10·6 months [8·7-12·0]; HR 0·79, 0·65-0·95, p=0·012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0·0001), specifically fatigue (22 [5%] vs one [1%], p=0·001) and neutropenia (13 [3%] vs 0, p=0·006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0·0001). Interpretation: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Funding: Eli Lilly.

Original languageEnglish (US)
Pages (from-to)1432-1440
Number of pages9
JournalThe Lancet
Volume374
Issue number9699
DOIs
StatePublished - Sep 21 2009

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Pemetrexed
Non-Small Cell Lung Carcinoma
Placebos
Maintenance
Disease-Free Survival
Poisons
Therapeutics
Folic Acid Antagonists
Survival
Vitamin B 12
Neutropenia
Platinum
Folic Acid
Double-Blind Method
Pharmaceutical Preparations
Antineoplastic Agents
Dexamethasone
Fatigue
Disease Progression

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Ciuleanu, Tudor ; Brodowicz, Thomas ; Zielinski, Christoph ; Kim, Joo Hang ; Krzakowski, Maciej ; Laack, Eckart ; Wu, Yi Long ; Bover, Isabel ; Begbie, Stephen ; Tzekova, Valentina ; Cucevic, Branka ; Pereira, Jose Rodrigues ; Yang, Sung Hyun ; Madhavan, Jayaprakash ; Sugarman, Katherine P. ; Peterson, Patrick ; John, William J. ; Krejcy, Kurt ; Belani, Chandra P. / Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer : a randomised, double-blind, phase 3 study. In: The Lancet. 2009 ; Vol. 374, No. 9699. pp. 1432-1440.
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abstract = "Background: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. Methods: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m2, day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B12, folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. Findings: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4·3 months [95{\%} CI 4·1-4·7] vs 2·6 months [1·7-2·8]; hazard ratio [HR] 0·50, 95{\%} CI 0·42-0·61, p<0·0001) and overall survival (13·4 months [11·9-15·9] vs 10·6 months [8·7-12·0]; HR 0·79, 0·65-0·95, p=0·012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5{\%}] vs three [1{\%}]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16{\%}] vs nine [4{\%}]; p<0·0001), specifically fatigue (22 [5{\%}] vs one [1{\%}], p=0·001) and neutropenia (13 [3{\%}] vs 0, p=0·006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51{\%}] vs 149 [67{\%}]; p=0·0001). Interpretation: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Funding: Eli Lilly.",
author = "Tudor Ciuleanu and Thomas Brodowicz and Christoph Zielinski and Kim, {Joo Hang} and Maciej Krzakowski and Eckart Laack and Wu, {Yi Long} and Isabel Bover and Stephen Begbie and Valentina Tzekova and Branka Cucevic and Pereira, {Jose Rodrigues} and Yang, {Sung Hyun} and Jayaprakash Madhavan and Sugarman, {Katherine P.} and Patrick Peterson and John, {William J.} and Kurt Krejcy and Belani, {Chandra P.}",
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Ciuleanu, T, Brodowicz, T, Zielinski, C, Kim, JH, Krzakowski, M, Laack, E, Wu, YL, Bover, I, Begbie, S, Tzekova, V, Cucevic, B, Pereira, JR, Yang, SH, Madhavan, J, Sugarman, KP, Peterson, P, John, WJ, Krejcy, K & Belani, CP 2009, 'Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study', The Lancet, vol. 374, no. 9699, pp. 1432-1440. https://doi.org/10.1016/S0140-6736(09)61497-5

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer : a randomised, double-blind, phase 3 study. / Ciuleanu, Tudor; Brodowicz, Thomas; Zielinski, Christoph; Kim, Joo Hang; Krzakowski, Maciej; Laack, Eckart; Wu, Yi Long; Bover, Isabel; Begbie, Stephen; Tzekova, Valentina; Cucevic, Branka; Pereira, Jose Rodrigues; Yang, Sung Hyun; Madhavan, Jayaprakash; Sugarman, Katherine P.; Peterson, Patrick; John, William J.; Krejcy, Kurt; Belani, Chandra P.

In: The Lancet, Vol. 374, No. 9699, 21.09.2009, p. 1432-1440.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer

T2 - a randomised, double-blind, phase 3 study

AU - Ciuleanu, Tudor

AU - Brodowicz, Thomas

AU - Zielinski, Christoph

AU - Kim, Joo Hang

AU - Krzakowski, Maciej

AU - Laack, Eckart

AU - Wu, Yi Long

AU - Bover, Isabel

AU - Begbie, Stephen

AU - Tzekova, Valentina

AU - Cucevic, Branka

AU - Pereira, Jose Rodrigues

AU - Yang, Sung Hyun

AU - Madhavan, Jayaprakash

AU - Sugarman, Katherine P.

AU - Peterson, Patrick

AU - John, William J.

AU - Krejcy, Kurt

AU - Belani, Chandra P.

PY - 2009/9/21

Y1 - 2009/9/21

N2 - Background: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. Methods: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m2, day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B12, folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. Findings: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4·3 months [95% CI 4·1-4·7] vs 2·6 months [1·7-2·8]; hazard ratio [HR] 0·50, 95% CI 0·42-0·61, p<0·0001) and overall survival (13·4 months [11·9-15·9] vs 10·6 months [8·7-12·0]; HR 0·79, 0·65-0·95, p=0·012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0·0001), specifically fatigue (22 [5%] vs one [1%], p=0·001) and neutropenia (13 [3%] vs 0, p=0·006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0·0001). Interpretation: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Funding: Eli Lilly.

AB - Background: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. Methods: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m2, day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B12, folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. Findings: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4·3 months [95% CI 4·1-4·7] vs 2·6 months [1·7-2·8]; hazard ratio [HR] 0·50, 95% CI 0·42-0·61, p<0·0001) and overall survival (13·4 months [11·9-15·9] vs 10·6 months [8·7-12·0]; HR 0·79, 0·65-0·95, p=0·012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0·0001), specifically fatigue (22 [5%] vs one [1%], p=0·001) and neutropenia (13 [3%] vs 0, p=0·006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0·0001). Interpretation: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. Funding: Eli Lilly.

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