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Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer

Palbociclib, ribociclib, and abemaciclib have been investigated in combination with aromatase inhibitors as first-line therapy for metastatic hormone receptor-positive breast cancer (PALOMA-2, MONALEESA-2 and MONALEESA-7, MONARCH-3 trials, respectively); pivotal trials led to absolute median progres...

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Autores principales: Tanguy, Marie-Laure, Cabel, Luc, Berger, Fréderique, Pierga, Jean-Yves, Savignoni, Alexia, Bidard, Francois-Clement
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018749/
https://www.ncbi.nlm.nih.gov/pubmed/29951582
http://dx.doi.org/10.1038/s41523-018-0068-4
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author Tanguy, Marie-Laure
Cabel, Luc
Berger, Fréderique
Pierga, Jean-Yves
Savignoni, Alexia
Bidard, Francois-Clement
author_facet Tanguy, Marie-Laure
Cabel, Luc
Berger, Fréderique
Pierga, Jean-Yves
Savignoni, Alexia
Bidard, Francois-Clement
author_sort Tanguy, Marie-Laure
collection PubMed
description Palbociclib, ribociclib, and abemaciclib have been investigated in combination with aromatase inhibitors as first-line therapy for metastatic hormone receptor-positive breast cancer (PALOMA-2, MONALEESA-2 and MONALEESA-7, MONARCH-3 trials, respectively); pivotal trials led to absolute median progression-free survival (PFS) gain of about 15 months. We aimed to estimate, for each trial, the statistical power to demonstrate a significant gain in overall survival (OS). Power was calculated with Freedman’s formula. Given the allocation ratio and the number of events, power was computed as a function of hazard ratio. We focused on four specific hazard ratio values (0.94, 0.89, 0.81, and 0.77), which are estimated to correspond to absolute 3, 6, 12, and 15 months gain in OS, respectively. For these calculations, the type I error rate was stated at 5% with a two-sided test, and we assumed that the risk of death was constant over time. PALOMA-2 and MONALEESA trials have an almost similar power despite different allocation ratios, while MONARCH-3 has a more limited power. Overall, the power of the four trials to demonstrate a statistically significant improvement in OS is less than 70% if the prolongation in median OS is ≤12 months, whatever the OS data maturity. This analysis shows that OS results are jeopardized by limited powers, and a meta-analysis might be required to demonstrate OS benefit. Conversely, if a significant OS improvement is observed in some but not at all trials, this discrepancy might be more attributable to chance than to a truly different drug efficacy.
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spelling pubmed-60187492018-06-27 Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer Tanguy, Marie-Laure Cabel, Luc Berger, Fréderique Pierga, Jean-Yves Savignoni, Alexia Bidard, Francois-Clement NPJ Breast Cancer Perspective Palbociclib, ribociclib, and abemaciclib have been investigated in combination with aromatase inhibitors as first-line therapy for metastatic hormone receptor-positive breast cancer (PALOMA-2, MONALEESA-2 and MONALEESA-7, MONARCH-3 trials, respectively); pivotal trials led to absolute median progression-free survival (PFS) gain of about 15 months. We aimed to estimate, for each trial, the statistical power to demonstrate a significant gain in overall survival (OS). Power was calculated with Freedman’s formula. Given the allocation ratio and the number of events, power was computed as a function of hazard ratio. We focused on four specific hazard ratio values (0.94, 0.89, 0.81, and 0.77), which are estimated to correspond to absolute 3, 6, 12, and 15 months gain in OS, respectively. For these calculations, the type I error rate was stated at 5% with a two-sided test, and we assumed that the risk of death was constant over time. PALOMA-2 and MONALEESA trials have an almost similar power despite different allocation ratios, while MONARCH-3 has a more limited power. Overall, the power of the four trials to demonstrate a statistically significant improvement in OS is less than 70% if the prolongation in median OS is ≤12 months, whatever the OS data maturity. This analysis shows that OS results are jeopardized by limited powers, and a meta-analysis might be required to demonstrate OS benefit. Conversely, if a significant OS improvement is observed in some but not at all trials, this discrepancy might be more attributable to chance than to a truly different drug efficacy. Nature Publishing Group UK 2018-06-26 /pmc/articles/PMC6018749/ /pubmed/29951582 http://dx.doi.org/10.1038/s41523-018-0068-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Perspective
Tanguy, Marie-Laure
Cabel, Luc
Berger, Fréderique
Pierga, Jean-Yves
Savignoni, Alexia
Bidard, Francois-Clement
Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
title Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
title_full Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
title_fullStr Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
title_full_unstemmed Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
title_short Cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
title_sort cdk4/6 inhibitors and overall survival: power of first-line trials in metastatic breast cancer
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018749/
https://www.ncbi.nlm.nih.gov/pubmed/29951582
http://dx.doi.org/10.1038/s41523-018-0068-4
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