Tumor growth inhibition modeling in patients with second line biliary tract cancer and first line non-small cell lung cancer based on bintrafusp alfa trials
© 2023 Merck KGaA and The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab. Individual drug exposure was estimated from previously developed population PK models. Population tumor dynamics models were developed for each drug-indication combination, and covariate evaluations performed using nonlinear mixed-effects modeling (NLME) and ML (elastic net and random forest models) approaches. The three tumor dynamics' model structures all included linear tumor growth components and exponential tumor shrinkage. The final BTC model included the effect of drug exposure (area under the curve) and several covariates (demographics, disease-related, and genetic mutations). Drug exposure was not significant in either of the NSCLC models, which included two, disease-related, covariates in the BA arm, and none in the pembrolizumab arm. The covariates identified by univariable NLME and ML highly overlapped in BTC but showed less agreement in NSCLC analyses. Hyperprogression could be identified by higher tumor growth and lower tumor kill rates and could not be related to BA exposure. Tumor size over time was quantitatively characterized in two tumor types and under two treatments. Factors potentially related to tumor dynamics were assessed using NLME and ML approaches; however, their net impact on tumor size was considered as not clinically relevant.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
CPT: pharmacometrics & systems pharmacology - 13(2024), 1 vom: 03. Jan., Seite 143-153 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Milenković-Grišić, Ana-Marija [VerfasserIn] |
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| Anmerkungen: |
Date Completed 15.01.2024 Date Revised 15.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/psp4.13068 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a © 2023 Merck KGaA and The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab. Individual drug exposure was estimated from previously developed population PK models. Population tumor dynamics models were developed for each drug-indication combination, and covariate evaluations performed using nonlinear mixed-effects modeling (NLME) and ML (elastic net and random forest models) approaches. The three tumor dynamics' model structures all included linear tumor growth components and exponential tumor shrinkage. The final BTC model included the effect of drug exposure (area under the curve) and several covariates (demographics, disease-related, and genetic mutations). Drug exposure was not significant in either of the NSCLC models, which included two, disease-related, covariates in the BA arm, and none in the pembrolizumab arm. The covariates identified by univariable NLME and ML highly overlapped in BTC but showed less agreement in NSCLC analyses. Hyperprogression could be identified by higher tumor growth and lower tumor kill rates and could not be related to BA exposure. Tumor size over time was quantitatively characterized in two tumor types and under two treatments. Factors potentially related to tumor dynamics were assessed using NLME and ML approaches; however, their net impact on tumor size was considered as not clinically relevant | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Mould, Diane R |e verfasserin |4 aut | |
| 700 | 1 | |a Vugmeyster, Yulia |e verfasserin |4 aut | |
| 700 | 1 | |a Mrowiec, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Machl, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Girard, Pascal |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatakrishnan, Karthik |e verfasserin |4 aut | |
| 700 | 1 | |a Khandelwal, Akash |e verfasserin |4 aut | |
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