Dose selection of novel anticancer drugs: exposing the gap between selected and required doses.

Historically, 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.

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Declaration of interests NPvE has received research grants from Astellas and Ipsen. NM received consultancy fees from Janssen-Cilag, Bayer, Astellas Pharma, AstraZeneca, Pfizer, and Merck Sharp and Dohme, and research funding (all paid to the institution) from Janssen-Cilag, Astellas Pharma, AstraZeneca/Merck, and Bristol Myers Squibb Foundation. KB received consultancy fees (all paid to the institution) from Merck Sharp and Dohme and Pierre Fabre. HG's institution has received research grants or compensation for patients in studies from Bayer, Boehringer Ingelheim, Deciphera, AmmaxBio, Abbisko, Springworks, Amgen, Pfizer, Novartis, and Servier. GSS received research support (all paid to the institution) from Agendia, AstraZeneca, Merck Sharp and Dohme, Novartis, Roche, and Seagen, and serves on advisory boards for Biovica and Seagen. AJdL reports financial interests and institutional research grants from Bristol Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, and AstraZeneca; and non-financial interests from Merck Serono and Roche. NWCJvdD has received research support (all paid to the institution) from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier. JJWMJ has received research support (all paid to the institution) from Novartis and Bristol Myers Squibb; serves as president for Apps for Care and Science, a non-profit foundation supported by AbbVie, Alexion, Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Janssen-Cilag, Novartis, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, and Takeda; and has received honoraria (all paid to the institution) from AbbVie, Novartis, Pfizer, and Incyte. MCM has received research support (all paid to the institution) from Beigene, consultancy fees (all paid to the institution) from Janssen-Cilag, CDR-life, BMC, and GlaxoSmithKline; fees for speakers bureau (all paid to the institution) from Siemens and Janssen-Cilag; and hospitality from Janssen-Cilag. All other authors declare no competing interests.