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Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma
PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure–response relationship for progression-fre...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373189/ https://www.ncbi.nlm.nih.gov/pubmed/30406840 http://dx.doi.org/10.1007/s00280-018-3723-4 |
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author | Jones, Robin L. Mo, Gary Baldwin, John R. Peterson, Patrick M. Ilaria, Robert L. Conti, Ilaria Cronier, Damien M. Tap, William D. |
author_facet | Jones, Robin L. Mo, Gary Baldwin, John R. Peterson, Patrick M. Ilaria, Robert L. Conti, Ilaria Cronier, Damien M. Tap, William D. |
author_sort | Jones, Robin L. |
collection | PubMed |
description | PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure–response relationship for progression-free survival (PFS), overall survival (OS), and safety. METHODS: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (C(min1)) and the average concentration throughout treatment (C(avg)). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles. RESULTS: PFS and OS were described by models with an exponential hazard function and inhibitory E(MAX) functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (EC(min1)50 = 82.0 µg/mL, EC(avg)50 = 179 µg/mL) and OS (EC(min1)50 = 66.1 µg/mL, EC(avg)50 = 134 µg/mL) corresponded to the median and 25th percentile of C(min1)/C(avg) in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels. CONCLUSIONS: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial. |
format | Online Article Text |
id | pubmed-6373189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-63731892019-03-01 Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma Jones, Robin L. Mo, Gary Baldwin, John R. Peterson, Patrick M. Ilaria, Robert L. Conti, Ilaria Cronier, Damien M. Tap, William D. Cancer Chemother Pharmacol Original Article PURPOSE: Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure–response relationship for progression-free survival (PFS), overall survival (OS), and safety. METHODS: PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (C(min1)) and the average concentration throughout treatment (C(avg)). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles. RESULTS: PFS and OS were described by models with an exponential hazard function and inhibitory E(MAX) functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (EC(min1)50 = 82.0 µg/mL, EC(avg)50 = 179 µg/mL) and OS (EC(min1)50 = 66.1 µg/mL, EC(avg)50 = 134 µg/mL) corresponded to the median and 25th percentile of C(min1)/C(avg) in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels. CONCLUSIONS: PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial. Springer Berlin Heidelberg 2018-11-08 2019 /pmc/articles/PMC6373189/ /pubmed/30406840 http://dx.doi.org/10.1007/s00280-018-3723-4 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. |
spellingShingle | Original Article Jones, Robin L. Mo, Gary Baldwin, John R. Peterson, Patrick M. Ilaria, Robert L. Conti, Ilaria Cronier, Damien M. Tap, William D. Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
title | Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
title_full | Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
title_fullStr | Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
title_full_unstemmed | Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
title_short | Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
title_sort | exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373189/ https://www.ncbi.nlm.nih.gov/pubmed/30406840 http://dx.doi.org/10.1007/s00280-018-3723-4 |
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