PMID- 34752995 OWN - NLM STAT- MEDLINE DCOM- 20220324 LR - 20220324 IS - 2059-7029 (Electronic) IS - 2059-7029 (Linking) VI - 6 IP - 6 DP - 2021 Dec TI - Dose selection and tolerability of anticancer agents evaluated by the European Medicines Agency in the period 2015-2020. PG - 100301 LID - S2059-7029(21)00263-5 [pii] LID - 10.1016/j.esmoop.2021.100301 [doi] LID - 100301 AB - BACKGROUND: Novel anticancer agents are initially evaluated in a palliative setting in phase I studies. The benefit-risk applying the selected dose from these phase I studies can be considered acceptable at time of registration, however, it is unknown if the optimal dose has been selected during drug development. METHODS: The European Medicines Agency (EMA) European Public Assessment Reports (EPARs) overview was used to select anticancer agents evaluated between 2015 and 2020. The dose selection and tolerability data of EMA assessed anticancer agents was analysed to evaluate dose selection. RESULTS: Sixty EPARs were included for analysis. A dose-response relation was identified in five dossiers (8%). The maximum tolerated dose (MTD) was the selected dose for 15 anticancer agents (25%). The MTD was not determined in 27 out of 60 cases (59%). When the MTD was determined but not applied as final dose, the most frequently used dose selection criteria were the combination of toxicity, exposure response, pharmacokinetic data and pharmacodynamic data (in 7 out of 18 cases). Data on tolerability were analysed separately for protein kinase inhibitors and monoclonal antibodies as the dosing interval and mitigation of adverse events (AEs) differs. The median discontinuation, dose reduction and dose interruption rates due to AEs of protein kinase inhibitors were 10%, 26% and 45% for monotherapy and 13%, 47% and 55% for combination therapy, respectively. The median discontinuation rates due to AEs for monoclonal antibodies were 8% for monotherapy and 26% for combination therapy. CONCLUSION: The dose-response relationship has not been established for the majority of the registered anticancer agents. The selected posology is often poorly tolerable as reflected by the high discontinuation and dose reduction rates. Due to the absence of dose-response data, it is often unknown if the optimal dose has been selected for anticancer agents. CI - Copyright (c) 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Maliepaard, M AU - Maliepaard M AD - College ter Beoordeling van Geneesmiddelen, Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, the Netherlands; Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, the Netherlands. FAU - Carree, W AU - Carree W AD - College ter Beoordeling van Geneesmiddelen, Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, the Netherlands. FAU - van Bussel, M T J AU - van Bussel MTJ AD - College ter Beoordeling van Geneesmiddelen, Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, the Netherlands. Electronic address: m.v.bussel@cbg-meb.nl. LA - eng PT - Journal Article DEP - 20211106 PL - England TA - ESMO Open JT - ESMO open JID - 101690685 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) SB - IM MH - Antibodies, Monoclonal MH - *Antineoplastic Agents/adverse effects MH - Humans MH - Protein Kinase Inhibitors PMC - PMC8586755 OTO - NOTNLM OT - anticancer agents OT - dose selection OT - tolerability COIS- Disclosure The authors have declared no conflicts of interest. EDAT- 2021/11/10 06:00 MHDA- 2022/03/25 06:00 PMCR- 2021/11/06 CRDT- 2021/11/09 20:15 PHST- 2021/07/14 00:00 [received] PHST- 2021/10/07 00:00 [revised] PHST- 2021/10/14 00:00 [accepted] PHST- 2021/11/10 06:00 [pubmed] PHST- 2022/03/25 06:00 [medline] PHST- 2021/11/09 20:15 [entrez] PHST- 2021/11/06 00:00 [pmc-release] AID - S2059-7029(21)00263-5 [pii] AID - 100301 [pii] AID - 10.1016/j.esmoop.2021.100301 [doi] PST - ppublish SO - ESMO Open. 2021 Dec;6(6):100301. doi: 10.1016/j.esmoop.2021.100301. Epub 2021 Nov 6.