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RESEARCH QUESTION

1) Is systemic exposure (i.e. AUC) enhanced if osimertinib is boosted by cobicistat in patients with low blood concentrations receiving a standard osimertinib dose?

2) Is a similar exposure (bioequivalence) achieved when 80 mg osimertinib only is replaced by a reduced 40 mg osimertinib dose combined with cobicistat?

 

HYPOTHESIS

Osimertinib is one of the new expensive targeted agents in oncology. Since osimertinib is metabolized by CYP3A4, it is assumed that combination with a strong CYP3A4 inhibitor results in increased osimertinib exposure. Our hypothesis is that we can reduce the daily osimertinib dose by concomitant treatment with a booster like cobicistat. Our final aim is to reduce annual costs of such anti-cancer agents, while maintaining efficacy.

 

STUDY DESIGN

Exploratory study

 

STUDY POPULATION

EGFR-T790M+ NSCLC patients having a complete or partial response on osimertinib and not using concurrent drugs which are substrate, inhibitor or inducer of CYP3A.

 

INTERVENTION

Adding cobicistat plus reducing the osimertinib dose

 

OUTCOME MEASURES

Similar pharmacokinetics i.e. AUC, tolerability, safety and cost-effectiveness.

 

SAMPLE SIZE

To prove bioequivalence (osimertinib 80 mg vs. osimertinib 40 mg + cobicistat), with a one-sided alpha of 0.05, a power of 80% (1-ß = 0.8) and taking a 10% drop-out rate into account, 54 patients need to be included in the exploratory study. Furthermore, 20 patients with low osimertinib exposure will participate in a pilot feasibility study.

 

DATA ANALYSIS

We will report categorical data as absolute numbers or percentages, and continuous data as mean (SD) or median with interquartile ranges where appropriate.

A paired t-test will be used to compare the pharmacokinetic parameters between non-boosted and osimertinib boosted based dosing. A cost-utility analysis will estimate the cost-effectiveness of introducing a CYP3A-booster plus TDM, while reducing the daily osimertinib dose. This may lead to annual savings of >14 million euro.

 

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