Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): A randomised, double-blind, phase 3 trial

Charles Butts, Mark A. Socinski, Paul L. Mitchell, Nick Thatcher, Libor Havel, Maciej Krzakowski, Sergiusz Nawrocki, Tudor Eliade Ciuleanu, Lionel Bosquée, José Manuel Trigo, Alexander Spira, Lise Tremblay, Jan Nyman, Rodryg Ramlau, Gun Wickart-Johansson, Peter Ellis, Oleg Gladkov, José Rodrigues Pereira, Wilfried Ernst Erich Eberhardt, Christoph HelwigAndreas Schröder, Frances A. Shepherd

Research output: Contribution to journalArticle

Abstract

Background: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. Findings: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5-29·2) with tecemotide versus 22·3 months (19·6-25·5) with placebo (adjusted HR 0·88, 0·75-1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6-36·8) compared with 20·6 months (17·4-23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64-0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6-23·1] vs 24·6 months [18·8-33·0], respectively; adjusted HR 1·12, 0·87-1·44; p=0·38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. Interpretation: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding: Merck KGaA (Darmstadt, Germany).

Original languageEnglish (US)
Pages (from-to)59-68
Number of pages10
JournalThe Lancet Oncology
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Chemoradiotherapy
Non-Small Cell Lung Carcinoma
Placebos
Survival
Random Allocation
L-BLP25
Dyspnea
Population
Pneumonia
Central Nervous System
Neoplasm Metastasis
Lipopeptides
Immunotherapy
Cyclophosphamide
Germany
Disease Progression

ASJC Scopus subject areas

  • Oncology

Cite this

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START) : A randomised, double-blind, phase 3 trial. / Butts, Charles; Socinski, Mark A.; Mitchell, Paul L.; Thatcher, Nick; Havel, Libor; Krzakowski, Maciej; Nawrocki, Sergiusz; Ciuleanu, Tudor Eliade; Bosquée, Lionel; Trigo, José Manuel; Spira, Alexander; Tremblay, Lise; Nyman, Jan; Ramlau, Rodryg; Wickart-Johansson, Gun; Ellis, Peter; Gladkov, Oleg; Pereira, José Rodrigues; Eberhardt, Wilfried Ernst Erich; Helwig, Christoph; Schröder, Andreas; Shepherd, Frances A.

In: The Lancet Oncology, Vol. 15, No. 1, 01.01.2014, p. 59-68.

Research output: Contribution to journalArticle

Butts, C, Socinski, MA, Mitchell, PL, Thatcher, N, Havel, L, Krzakowski, M, Nawrocki, S, Ciuleanu, TE, Bosquée, L, Trigo, JM, Spira, A, Tremblay, L, Nyman, J, Ramlau, R, Wickart-Johansson, G, Ellis, P, Gladkov, O, Pereira, JR, Eberhardt, WEE, Helwig, C, Schröder, A & Shepherd, FA 2014, 'Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): A randomised, double-blind, phase 3 trial', The Lancet Oncology, vol. 15, no. 1, pp. 59-68. https://doi.org/10.1016/S1470-2045(13)70510-2
Butts, Charles ; Socinski, Mark A. ; Mitchell, Paul L. ; Thatcher, Nick ; Havel, Libor ; Krzakowski, Maciej ; Nawrocki, Sergiusz ; Ciuleanu, Tudor Eliade ; Bosquée, Lionel ; Trigo, José Manuel ; Spira, Alexander ; Tremblay, Lise ; Nyman, Jan ; Ramlau, Rodryg ; Wickart-Johansson, Gun ; Ellis, Peter ; Gladkov, Oleg ; Pereira, José Rodrigues ; Eberhardt, Wilfried Ernst Erich ; Helwig, Christoph ; Schröder, Andreas ; Shepherd, Frances A. / Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START) : A randomised, double-blind, phase 3 trial. In: The Lancet Oncology. 2014 ; Vol. 15, No. 1. pp. 59-68.
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abstract = "Background: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. Findings: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95{\%} CI 22·5-29·2) with tecemotide versus 22·3 months (19·6-25·5) with placebo (adjusted HR 0·88, 0·75-1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65{\%}) of 829 patients assigned to tecemotide was 30·8 months (95{\%} CI 25·6-36·8) compared with 20·6 months (17·4-23·9) for the 268 (65{\%}) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64-0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35{\%}) patients in the tecemotide group and the 142 (35{\%}) patients in the placebo group (19·4 months [95{\%} CI 17·6-23·1] vs 24·6 months [18·8-33·0], respectively; adjusted HR 1·12, 0·87-1·44; p=0·38). Grade 3-4 adverse events seen with a greater than 2{\%} frequency with tecemotide were dyspnoea (49 [5{\%}] of 1024 patients in the tecemotide group vs 21 [4{\%}] of 477 patients in the placebo group), metastases to central nervous system (29 [3{\%}] vs 6 [1{\%}]), and pneumonia (23 [2{\%}] vs 12 [3{\%}]). Serious adverse events with a greater than 2{\%} frequency with tecemotide were pneumonia (30 [3{\%}] in the tecemotide group vs 14 [3{\%}] in the placebo group), dyspnoea (29 [3{\%}] vs 13 [3{\%}]), and metastases to central nervous system (32 [3{\%}] vs 9 [2{\%}]). Serious immune-related adverse events did not differ between groups. Interpretation: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding: Merck KGaA (Darmstadt, Germany).",
author = "Charles Butts and Socinski, {Mark A.} and Mitchell, {Paul L.} and Nick Thatcher and Libor Havel and Maciej Krzakowski and Sergiusz Nawrocki and Ciuleanu, {Tudor Eliade} and Lionel Bosqu{\'e}e and Trigo, {Jos{\'e} Manuel} and Alexander Spira and Lise Tremblay and Jan Nyman and Rodryg Ramlau and Gun Wickart-Johansson and Peter Ellis and Oleg Gladkov and Pereira, {Jos{\'e} Rodrigues} and Eberhardt, {Wilfried Ernst Erich} and Christoph Helwig and Andreas Schr{\"o}der and Shepherd, {Frances A.}",
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language = "English (US)",
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TY - JOUR

T1 - Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START)

T2 - A randomised, double-blind, phase 3 trial

AU - Butts, Charles

AU - Socinski, Mark A.

AU - Mitchell, Paul L.

AU - Thatcher, Nick

AU - Havel, Libor

AU - Krzakowski, Maciej

AU - Nawrocki, Sergiusz

AU - Ciuleanu, Tudor Eliade

AU - Bosquée, Lionel

AU - Trigo, José Manuel

AU - Spira, Alexander

AU - Tremblay, Lise

AU - Nyman, Jan

AU - Ramlau, Rodryg

AU - Wickart-Johansson, Gun

AU - Ellis, Peter

AU - Gladkov, Oleg

AU - Pereira, José Rodrigues

AU - Eberhardt, Wilfried Ernst Erich

AU - Helwig, Christoph

AU - Schröder, Andreas

AU - Shepherd, Frances A.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. Findings: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5-29·2) with tecemotide versus 22·3 months (19·6-25·5) with placebo (adjusted HR 0·88, 0·75-1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6-36·8) compared with 20·6 months (17·4-23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64-0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6-23·1] vs 24·6 months [18·8-33·0], respectively; adjusted HR 1·12, 0·87-1·44; p=0·38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. Interpretation: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding: Merck KGaA (Darmstadt, Germany).

AB - Background: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. Findings: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5-29·2) with tecemotide versus 22·3 months (19·6-25·5) with placebo (adjusted HR 0·88, 0·75-1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6-36·8) compared with 20·6 months (17·4-23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64-0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6-23·1] vs 24·6 months [18·8-33·0], respectively; adjusted HR 1·12, 0·87-1·44; p=0·38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. Interpretation: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding: Merck KGaA (Darmstadt, Germany).

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