Determining drug dose in the era of targeted therapies: playing it (un)safe?

Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under deve...

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Bibliographic Details
Published in:Blood cancer journal (New York) 2022-08, Vol.12 (8), p.123-123, Article 123
Main Authors: Skånland, Sigrid S., Tjønnfjord, Geir E.
Format: Article
Language:English
Subjects:
631/67/1059/602
692/699/67/1059/602
Biomarkers
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Cytotoxicity
Design
Drug dosages
FDA approval
Hematology
Leukemia
Lymphoma
Medical research
Oncology
Patients
Pharmacodynamics
Review
Review Article
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Summary:Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.
ISSN:2044-5385
2044-5385
DOI:10.1038/s41408-022-00720-7