Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting

Purpose To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. Methods ER analyses were conducted using pooled NS...

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Vydáno v:Cancer chemotherapy and pharmacology Ročník 84; číslo 6; s. 1257 - 1267
Hlavní autoři: Morrissey, Kari M., Marchand, Mathilde, Patel, Hina, Zhang, Rong, Wu, Benjamin, Phyllis Chan, H., Mecke, Almut, Girish, Sandhya, Jin, Jin Y., Winter, Helen R., Bruno, René
Médium: Journal Article
Jazyk:angličtina
Vydáno: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2019
Springer Nature B.V
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ISSN:0344-5704, 1432-0843, 1432-0843
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Abstract Purpose To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. Methods ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. Results No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a C max above and below the predicted C max for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. Conclusion Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
AbstractList To determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens.PURPOSETo determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens.ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups.METHODSER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups.No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles.RESULTSNo significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles.Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.CONCLUSIONAtezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
PurposeTo determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens.MethodsER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups.ResultsNo significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles.ConclusionAtezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
To determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a C above and below the predicted C for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
PURPOSE: To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. METHODS: ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. RESULTS: No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cₘₐₓ above and below the predicted Cₘₐₓ for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. CONCLUSION: Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
Purpose To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens. Methods ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups. Results No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a C max above and below the predicted C max for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles. Conclusion Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
Author Girish, Sandhya
Patel, Hina
Winter, Helen R.
Jin, Jin Y.
Morrissey, Kari M.
Zhang, Rong
Marchand, Mathilde
Phyllis Chan, H.
Mecke, Almut
Bruno, René
Wu, Benjamin
Author_xml – sequence: 1
  givenname: Kari M.
  orcidid: 0000-0001-9025-4036
  surname: Morrissey
  fullname: Morrissey, Kari M.
  email: morrissey.kari@gene.com
  organization: Clinical Pharmacology, Genentech, Inc
– sequence: 2
  givenname: Mathilde
  surname: Marchand
  fullname: Marchand, Mathilde
  organization: Certara Strategic Consulting, Certara
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  givenname: Hina
  surname: Patel
  fullname: Patel, Hina
  organization: Safety Science Oncology, Genentech Inc
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  givenname: Rong
  surname: Zhang
  fullname: Zhang, Rong
  organization: Clinical Pharmacology, Genentech, Inc
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  givenname: Benjamin
  surname: Wu
  fullname: Wu, Benjamin
  organization: Clinical Pharmacology, Genentech, Inc
– sequence: 6
  givenname: H.
  surname: Phyllis Chan
  fullname: Phyllis Chan, H.
  organization: Clinical Pharmacology, Genentech, Inc
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  givenname: Almut
  orcidid: 0000-0002-9183-0047
  surname: Mecke
  fullname: Mecke, Almut
  organization: Biostatistics, F. Hoffmann-La Roche, Ltd
– sequence: 8
  givenname: Sandhya
  surname: Girish
  fullname: Girish, Sandhya
  organization: Clinical Pharmacology, Genentech, Inc
– sequence: 9
  givenname: Jin Y.
  surname: Jin
  fullname: Jin, Jin Y.
  organization: Clinical Pharmacology, Genentech, Inc
– sequence: 10
  givenname: Helen R.
  surname: Winter
  fullname: Winter, Helen R.
  organization: Clinical Pharmacology, Genentech, Inc, Seattle Genetics
– sequence: 11
  givenname: René
  orcidid: 0000-0003-0200-039X
  surname: Bruno
  fullname: Bruno, René
  organization: Clinical Pharmacology, Genentech/Roche
BackLink https://www.ncbi.nlm.nih.gov/pubmed/31542806$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright The Author(s) 2019
Cancer Chemotherapy and Pharmacology is a copyright of Springer, (2019). All Rights Reserved. © 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Copyright_xml – notice: The Author(s) 2019
– notice: Cancer Chemotherapy and Pharmacology is a copyright of Springer, (2019). All Rights Reserved. © 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Issue 6
Keywords PD-L1
Population pharmacokinetics
Exposure–response
Atezolizumab
Language English
License 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.
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Snippet Purpose To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell...
To determine the exposure-response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer...
PurposeTo determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung...
PURPOSE: To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell...
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StartPage 1257
SubjectTerms Adult
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - adverse effects
Antibodies, Monoclonal, Humanized - pharmacokinetics
Bladder cancer
Body weight
Cancer Research
carcinoma
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - mortality
Carcinoma, Transitional Cell - drug therapy
Carcinoma, Transitional Cell - mortality
Clinical Trials, Phase I as Topic
Clinical Trials, Phase III as Topic
Computer Simulation
Datasets as Topic
Dosage
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug development
Female
Humans
Immunotherapy
Infusions, Intravenous
lung neoplasms
Lung Neoplasms - drug therapy
Lung Neoplasms - mortality
Male
Medicine
Medicine & Public Health
Models, Biological
Monoclonal antibodies
Monte Carlo Method
Non-small cell lung carcinoma
Oncology
Original
Original Article
pharmacokinetics
Pharmacology/Toxicology
Randomized Controlled Trials as Topic
Safety
Survival Analysis
Targeted cancer therapy
Treatment Outcome
Urologic Neoplasms - drug therapy
Urologic Neoplasms - mortality
Urothelial cancer
Urothelial carcinoma
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Title Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting
URI https://link.springer.com/article/10.1007/s00280-019-03954-8
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