Abstract
Introduction: Exposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor.Methods: This was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (<= 195 ng/mL). On day 1, the area under the plasma curve (AUC(0-24,ss)) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22-26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still <= 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2-4 months) of the boosting effect.Results: The mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC(0-24ss) (AUC osimertinib + AUC AZ5104) was 60%, (range 19%-192%). The boosting effect was consistent over time. No grade >= 2 toxicity was observed.Conclusion: Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.
Original language | English |
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Pages (from-to) | 97-102 |
Number of pages | 6 |
Journal | Lung Cancer |
Volume | 171 |
DOIs | |
Publication status | Published - 1 Sept 2022 |
Keywords
- Osimertinib
- Cobicistat
- Pharmacokinetic boosting
- NSCLC
- CYP3A4
- TENOFOVIR DISOPROXIL FUMARATE
- INITIAL TREATMENT
- HIV-1 INFECTION
- DOUBLE-BLIND
- RITONAVIR
- EMTRICITABINE
- ELVITEGRAVIR
- INHIBITOR
- EXPOSURE
- PHASE-3