Model‐informed Evidence for Clinical Non‐inferiority of Every‐2‐Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer

Clinical Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 116(4), P. 1071 - 1081

Published: Aug. 12, 2024

Cetuximab was initially developed and approved as a first‐line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m 2 Q1W 400 loading dose). An every‐2‐weeks schedule (500 Q2W) recently by several health authorities. Being synchronized chemotherapy, Q2W should improve patients' convenience healthcare resource utilization. Herein, we present evidence of non‐inferiority cetuximab, compared dosing using pharmacometrics modeling clinical trial simulation (CTS). Pooled data from five phase I–III trials 852 KRAS wild‐type mCRC treated or cetuximab were modeled population exposure–tumor size (TS) model linked to overall survival (OS); exposure derived previously established pharmacokinetic model. A semi‐mechanistic TS adapted the Claret incorporated killing rate proportional area under concentration‐time curve over weeks (AUC) Eastern Cooperative Oncology Group (ECOG) status covariate on baseline TS. The OS Weibull hazard ECOG, TS, primary tumor location, predicted percent change at 8 covariates. Model‐based simulations revealed indistinguishable early shrinkage between vs. cetuximab. CTS evaluated (predefined margin 1.25) 1,000 trials, each 2,000 virtual receiving (1:1), demonstrated 94% cases. Taken together, these analyses provide model‐based potential benefits providers.

Language: Английский

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Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Oct. 14, 2024

BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) angiopoietin-2 (Ang-2). A comprehensive biomarker modeling approach presented here supported dose finding for 836880.

Language: Английский

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FDA’s Project Optimus: The “Paradigm-Shifting” Initiative for Oncology Drug Development

ICSA book series in statistics, Journal Year: 2024, Volume and Issue: unknown, P. 31 - 68

Published: July 30, 2024

Language: Английский

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Integrated modeling of biomarkers, survival and safety in clinical oncology drug development

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: unknown, P. 115476 - 115476

Published: Nov. 1, 2024

Model-based approaches, including population pharmacokinetic-pharmacodynamic modeling, have become an essential component in the clinical phases of oncology drug development. Over past two decades, models evolved to describe temporal dynamics biomarkers and tumor size, treatment-related adverse events, their links survival. Integrated models, defined here as that incorporate at least pharmacodynamic/ outcome variables, are applied answer development questions through simulations, e.g. support exploration alternative dosing strategies study designs subgroups patients or other indications. It is expected these pharmacometric approaches will be expanded regulatory authorities place further emphasis on early individualized dosage optimization inclusive patient-focused strategies. This review provides overview integrated literature, examples considerations need made when applying advanced outlook expansion model-informed anticancer drugs.

Language: Английский

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Revolutionizing cancer treatment: Exploring novel immunotherapeutics, checkpoints, bispecifics, and vaccines in development

Advances in immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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