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Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer

OBJECTIVES: In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting fo...

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Autores principales: Feliciano, Josephine Louella, McLoone, Dylan, Xu, Yingxin, Quek, Ruben G.W., Kuznik, Andreas, Pouliot, Jean-Francois, Gullo, Giuseppe, Rietschel, Petra, Guyot, Patricia, Konidaris, Gerasimos, Chan, Keith, Keeping, Sam, Wilson, Florence R., Freemantle, Nick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110970/
https://www.ncbi.nlm.nih.gov/pubmed/37082098
http://dx.doi.org/10.3389/fonc.2022.1081729
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author Feliciano, Josephine Louella
McLoone, Dylan
Xu, Yingxin
Quek, Ruben G.W.
Kuznik, Andreas
Pouliot, Jean-Francois
Gullo, Giuseppe
Rietschel, Petra
Guyot, Patricia
Konidaris, Gerasimos
Chan, Keith
Keeping, Sam
Wilson, Florence R.
Freemantle, Nick
author_facet Feliciano, Josephine Louella
McLoone, Dylan
Xu, Yingxin
Quek, Ruben G.W.
Kuznik, Andreas
Pouliot, Jean-Francois
Gullo, Giuseppe
Rietschel, Petra
Guyot, Patricia
Konidaris, Gerasimos
Chan, Keith
Keeping, Sam
Wilson, Florence R.
Freemantle, Nick
author_sort Feliciano, Josephine Louella
collection PubMed
description OBJECTIVES: In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression. METHODS: Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring). RESULTS: In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction—the most suitable method based on published guidelines and trial characteristics—produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction. CONCLUSIONS: After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.
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spelling pubmed-101109702023-04-19 Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer Feliciano, Josephine Louella McLoone, Dylan Xu, Yingxin Quek, Ruben G.W. Kuznik, Andreas Pouliot, Jean-Francois Gullo, Giuseppe Rietschel, Petra Guyot, Patricia Konidaris, Gerasimos Chan, Keith Keeping, Sam Wilson, Florence R. Freemantle, Nick Front Oncol Oncology OBJECTIVES: In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression. METHODS: Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring). RESULTS: In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction—the most suitable method based on published guidelines and trial characteristics—produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction. CONCLUSIONS: After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis. Frontiers Media S.A. 2023-04-04 /pmc/articles/PMC10110970/ /pubmed/37082098 http://dx.doi.org/10.3389/fonc.2022.1081729 Text en Copyright © 2023 Feliciano, McLoone, Xu, Quek, Kuznik, Pouliot, Gullo, Rietschel, Guyot, Konidaris, Chan, Keeping, Wilson and Freemantle https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Feliciano, Josephine Louella
McLoone, Dylan
Xu, Yingxin
Quek, Ruben G.W.
Kuznik, Andreas
Pouliot, Jean-Francois
Gullo, Giuseppe
Rietschel, Petra
Guyot, Patricia
Konidaris, Gerasimos
Chan, Keith
Keeping, Sam
Wilson, Florence R.
Freemantle, Nick
Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
title Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
title_full Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
title_fullStr Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
title_full_unstemmed Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
title_short Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
title_sort impact of the treatment crossover design on comparative efficacy in empower-lung 1: cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10110970/
https://www.ncbi.nlm.nih.gov/pubmed/37082098
http://dx.doi.org/10.3389/fonc.2022.1081729
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