Dose selection and tolerability of anticancer agents evaluated by the European Medicines Agency in the period 2015-2020

Abstract

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.

Keywords: anticancer agents; dose selection; tolerability.

Figure 1

Overview of used dose selection criteria. ^aFor pabinostat the dose response was determined. ^bFor blinatumomab the efficacy was dose dependent. ^cFor daratumumab, the 16 mg/kg dose level had an acceptable safety profile and resulted in higher and deeper response rates as compared to the 8 mg/kg dose level. ^dFor venetoclax doses from 150 to 1200 mg led to the selection of 400 mg. The observed response rate was not different when comparing results for subjects treated at 400 mg versus those treated at higher doses. ^eFor Lenvima® a clear dose response trend was observed. EPARs, European Public Assessment Reports; MTD, maximum tolerated dose; PAM, post-authorisation measure; PD, pharmacodynamics; PK, pharmacokinetics.

Figure 2

Overview of dose selection criteria protein kinase inhibitors. ^aFor Lenvima® a clear dose response trend was observed. MTD, maximum tolerated dose; PAM, post-authorisation measure; PD, pharmacodynamics; PK, pharmacokinetics.

Figure 3

Overview of dose selection criteria monoclonal antibodies. ^aFor blinatumomab the efficacy was dose dependent. ^bFor daratumumab, the 16 mg/kg dose level had an acceptable safety profile and resulted in higher and deeper response rates as compared to the 8 mg/kg dose level. MTD, maximum tolerated dose; PAM, post-authorisation measure; PD, pharmacodynamics; PK, pharmacokinetics.

Figure 4

Discontinuation, dose reduction and dose interruptions due to adverse events of protein kinase inhibitors (monotherapy). AEs, adverse events; MTD, maximum tolerated dose.

Figure 5

Discontinuation, dose reduction and dose interruptions due to adverse events of monoclonal antibodies (monotherapy). AEs, adverse events; IgG1, immunoglobulin G1.

Figure 6

Discontinuation, dose reduction and dose interruptions due to adverse events of other anticancer agents (monotherapy). AEs, adverse events; MTD, maximum tolerated dose.