• Catharina J P Op 't Hoog, Niven Mehra, Marc Maliepaard, Kalijn Bol, Hans Gelderblom, Gabe S Sonke, Adrianus J de Langen, van de DonkNiels W C JNWCJDepartment of Hematology, Amsterdam University Medical Center, location Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands., JanssenJeroen J W MJJWMDepartment of Hematology, Radboud University Medical Center, Nijmegen, Netherlands., Monique C Minnema, Nielka P van Erp, and Emmy Boerrigter.
• Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands.
• Lancet Oncol. 2024 Aug 1; 25 (8): e340e351e340-e351.

AbstractHistorically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs.Copyright © 2024 Elsevier Ltd. All rights reserved.

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