Abstract 23P
Background
Exposure to osimertinib (osi), a 3rd generation TKI for treatment of non-small cell lung cancer (NSCLC) and a sensitizing epidermal growth factor receptor (EGFR) mutation is variable between patients (pts). We evaluated the boosting capacity of cobicistat (cobi), a strong Cytochrome P450 3A (CYP3A)-inhibitor, on osi exposure in pts with NSCLC and low osi plasma trough concentration.
Methods
This was a pharmacokinetic, proof-of-concept, multicenter clinical trial (NCT03858491). Pts with NSCLC treated with osi were eligible when their steady state osi plasma trough concentration was low (<195 ng/mL) and they did not use any CYP3A-affecting drugs/products. On day 1, the area under the plasma concentration-time curve (AUC0-24,ss) of osi and its metabolite (AZ5104) were calculated using a limited sampling strategy. Cobi treatment (150 mg QD) was started on day 2. After three weeks of combined use, a second AUC0-24,ss of osi and AZ5104 was determined. Cobi dose could be escalated if the osi trough concentration was still <195 ng/mL and no toxicity was reported. The primary endpoint was the increase in osi exposure and the secondary endpoint was toxicity. Cobi could be continued during the expanded access phase, with additional follow-up of osi exposure within 2 – 4 months after the last AUC0-24,ss.
Results
In total 11 pts were included and cobi addition led to an increase in osi exposure in all 11 pts. The mean increase in total AUC0-24ss (AUC0-24ss osi + AUC0-24ss AZ5104 combined) was 60%, (range 19%-192%), with 73% (19% - 192%) and 38% (21% - 52%) for female and male pts, respectively. The increase in total AUC0-24ss was mainly driven by an increase of the osi AUC0-24ss, while AZ5104 AUC0-24ss remained largely similar, as the proportion of AZ5104 of the total AUC0-24ss decreased from 10% (baseline) to 7% (boost). Three pts underwent dose-escalation of cobi (150 mg BID (n = 3) and 150 mg QID (n = 1)), but no definitive effect was observed. The boosting effect of cobi was consistent over time and no grade ≥2 toxicity was observed.
Conclusions
Pharmacokinetic boosting of osi with cobi in pts with NSCLC was feasible without increasing toxicity, while a wide variation in boosting was seen.
Clinical trial identification
NCT03858491.
Legal entity responsible for the study
The author.
Funding
ZonMW (the Netherlands Organisation for Health Research and Development).
Disclosure
The author has declared no conflicts of interest.