Cargando…

Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer

BACKGROUND: A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharma...

Descripción completa

Detalles Bibliográficos
Autores principales: Long, G V, Tykodi, S S, Schneider, J G, Garbe, C, Gravis, G, Rashford, M, Agrawal, S, Grigoryeva, E, Bello, A, Roy, A, Rollin, L, Zhao, X
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290887/
https://www.ncbi.nlm.nih.gov/pubmed/30215677
http://dx.doi.org/10.1093/annonc/mdy408
_version_ 1783380173119291392
author Long, G V
Tykodi, S S
Schneider, J G
Garbe, C
Gravis, G
Rashford, M
Agrawal, S
Grigoryeva, E
Bello, A
Roy, A
Rollin, L
Zhao, X
author_facet Long, G V
Tykodi, S S
Schneider, J G
Garbe, C
Gravis, G
Rashford, M
Agrawal, S
Grigoryeva, E
Bello, A
Roy, A
Rollin, L
Zhao, X
author_sort Long, G V
collection PubMed
description BACKGROUND: A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure–response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen. PATIENTS AND METHODS: Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials. RESULTS: Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3–4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified. CONCLUSIONS: The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care. CLINICAL TRIAL NUMBERS: NCT01721772, NCT01668784, NCT01673867, NCT01642004
format Online
Article
Text
id pubmed-6290887
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-62908872018-12-21 Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer Long, G V Tykodi, S S Schneider, J G Garbe, C Gravis, G Rashford, M Agrawal, S Grigoryeva, E Bello, A Roy, A Rollin, L Zhao, X Ann Oncol Original Articles BACKGROUND: A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure–response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen. PATIENTS AND METHODS: Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials. RESULTS: Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3–4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified. CONCLUSIONS: The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care. CLINICAL TRIAL NUMBERS: NCT01721772, NCT01668784, NCT01673867, NCT01642004 Oxford University Press 2018-11 2018-09-12 /pmc/articles/PMC6290887/ /pubmed/30215677 http://dx.doi.org/10.1093/annonc/mdy408 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Long, G V
Tykodi, S S
Schneider, J G
Garbe, C
Gravis, G
Rashford, M
Agrawal, S
Grigoryeva, E
Bello, A
Roy, A
Rollin, L
Zhao, X
Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
title Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
title_full Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
title_fullStr Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
title_full_unstemmed Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
title_short Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
title_sort assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290887/
https://www.ncbi.nlm.nih.gov/pubmed/30215677
http://dx.doi.org/10.1093/annonc/mdy408
work_keys_str_mv AT longgv assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT tykodiss assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT schneiderjg assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT garbec assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT gravisg assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT rashfordm assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT agrawals assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT grigoryevae assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT belloa assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT roya assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT rollinl assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer
AT zhaox assessmentofnivolumabexposureandclinicalsafetyof480mgevery4weeksflatdosingscheduleinpatientswithcancer