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Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy
Trametinib, a selective inhibitor of mitogen‐activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression‐free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permit...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864810/ https://www.ncbi.nlm.nih.gov/pubmed/27172483 http://dx.doi.org/10.1002/cam4.643 |
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author | Latimer, Nicholas R. Bell, Helen Abrams, Keith R. Amonkar, Mayur M. Casey, Michelle |
author_facet | Latimer, Nicholas R. Bell, Helen Abrams, Keith R. Amonkar, Mayur M. Casey, Michelle |
author_sort | Latimer, Nicholas R. |
collection | PubMed |
description | Trametinib, a selective inhibitor of mitogen‐activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression‐free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching‐adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank‐preserving structural failure time model, inverse probability of censoring weights, and a two‐stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent‐to‐treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first‐line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method. |
format | Online Article Text |
id | pubmed-4864810 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-48648102016-05-27 Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy Latimer, Nicholas R. Bell, Helen Abrams, Keith R. Amonkar, Mayur M. Casey, Michelle Cancer Med Clinical Cancer Research Trametinib, a selective inhibitor of mitogen‐activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression‐free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching‐adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank‐preserving structural failure time model, inverse probability of censoring weights, and a two‐stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent‐to‐treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first‐line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method. John Wiley and Sons Inc. 2016-01-27 /pmc/articles/PMC4864810/ /pubmed/27172483 http://dx.doi.org/10.1002/cam4.643 Text en © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Clinical Cancer Research Latimer, Nicholas R. Bell, Helen Abrams, Keith R. Amonkar, Mayur M. Casey, Michelle Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy |
title | Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy |
title_full | Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy |
title_fullStr | Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy |
title_full_unstemmed | Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy |
title_short | Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy |
title_sort | adjusting for treatment switching in the metric study shows further improved overall survival with trametinib compared with chemotherapy |
topic | Clinical Cancer Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864810/ https://www.ncbi.nlm.nih.gov/pubmed/27172483 http://dx.doi.org/10.1002/cam4.643 |
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