Application of the model-informed drug development paradigm to datopotamab deruxtecan dose selection for late-stage development.
CPT Pharmacometrics Syst Pharmacol
; 13(1): 23-28, 2024 Jan.
Article
em En
| MEDLINE
| ID: mdl-37915242
ABSTRACT
To replace the conventional maximum tolerated dose (MTD) approach, a paradigm for dose optimization and dose selection that relies on model-informed drug development (MIDD) approaches has been proposed in oncology. Here, we report our application of an MIDD approach during phase I to inform dose selection for the late-stage development of datopotamab deruxtecan (Dato-DXd). Dato-DXd is a TROP2-directed antibody-drug conjugate being developed for advanced/metastatic non-small cell lung cancer (NSCLC) and other tumors. Data on pharmacokinetics (PKs), efficacy, and safety in NSCLC were collected in the TROPION-PanTumor01 phase I dose-expansion and -escalation study over a wide dose range of 0.27-10 mg/kg administered every 3 weeks. Population PK and exposure-response analyses were performed iteratively at three data cutoffs to inform dose selection. The 6 mg/kg dose was identified as the optimal dose by the second data cutoff analysis and confirmed by the subsequent third data cutoff analysis. The 6 mg/kg dose was more tolerable (i.e., lower rates of interstitial lung disease, stomatitis, and mucosal inflammation) than the MTD (8 mg/kg) and was more efficacious than 4 mg/kg (simulated mean objective response rate 23.8% vs. 18.6%; mean hazard ratio of progression-free survival 0.74) - a candidate dose studied just below 6 mg/kg. Therefore, the 6 mg/kg dose was judged to afford the optimal benefit-risk balance. This case study demonstrated the utility of an MIDD approach for dose optimization and dose selection.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
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Imunoconjugados
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Neoplasias Pulmonares
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article