Abstract 1257P
Background
Tepotinib is a highly selective, potent, mesenchymal–epithelial transition factor (MET) inhibitor approved in Japan and the US, for the treatment of either unresectable, advanced or recurrent (Japan), or metastatic (US) NSCLC harboring MET exon 14 skipping alterations. The primary objective of this study was to investigate the effect of hepatic impairment (HI) on the pharmacokinetics (PK) of tepotinib.
Methods
An open-label, parallel-group, phase I study (NCT03546608) included participants with mild (Child–Pugh A) and moderate (Child–Pugh B) HI, and healthy controls with normal hepatic function (age/weight/gender-matched to Child-Pugh B participants) (N=6 per group). All participants received a single-dose of 500 mg (450 mg active moiety) tepotinib orally once daily. PK samples were collected at intervals from predose to Day 15 (healthy controls) or Day 22 (participants with HI). The free fraction of tepotinib was also determined. PK parameters included maximum plasma concentrations (Cmax) and area under the curve extrapolated to infinity (AUC0-∞).
Results
Total tepotinib exposure was similar in participants with mild HI and control participants, with estimates of geometric mean ratios for Cmax and AUC0-∞ from an analysis of variance close to 100% (Table). For participants with moderate HI, total tepotinib Cmax and AUC0-∞ values were 12% and 29% lower compared to control participants (Table). In contrast to total tepotinib exposure, mean unbound tepotinib AUC0-∞ was 13% and 24% higher in participants with mild and moderate HI, respectively, compared to control participants. Tepotinib was well tolerated in participants with mild or moderate HI. Table: 1257P
| Comparison | Total tepotinib PK parameter | Geometric mean ratio (90% confidence interval) |
| Mild hepatic impairment versus normal hepatic function | AUC0-∞ | 94.99 (64.75, 139.35) |
| Cmax | 102.45 (80.90, 129.73) | |
| Moderate hepatic impairment versus normal hepatic function | AUC0-∞ | 87.92 (59.93, 128.98) |
| Cmax | 71.02 (56.08, 89.93) |
Conclusions
No clinically relevant changes in total or unbound tepotinib exposure were observed in participants with mild or moderate HI, compared to participants with normal hepatic function. These data indicate that, in patients with MET exon 14 skipping NSCLC, no dose modification is required in patients with mild to moderate HI.
Clinical trial identification
NCT03546608.
Editorial acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Syneos Health, London, UK.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany.
Disclosure
T. Marbury: Financial Interests, Personal, Full or part-time Employment: Orlando Clinical Research Center; Financial Interests, Personal, Stocks/Shares: Orlando Clinical Research Center. Ö. Yalkinoglu: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. A. Becker: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. A. Krebs-Brown: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. A. Bytyqi: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. A. Port: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. R. Strotmann: Financial Interests, Personal, Full or part-time Employment: Merck KGaA.