Abstract 5373
Background
Tepotinib is an oral, highly selective MET inhibitor being investigated in MET-driven solid tumors. Cancer patients often receive co-medications, many of which are subject to cytochrome P450 3A (CYP3A) or P-glycoprotein (P-gp)-dependent pharmacokinetics.
The potential of tepotinib to alter the exposure to such drugs was investigated in two clinical drug-drug interaction (DDI) trials.
Methods
The effect of multiple doses of the RP2D of tepotinib (500 mg QD) on the exposure of single doses of the sensitive CYP3A4 substrate midazolam and the sensitive P-gp substrate dabigatran etexilate were tested in healthy subjects, using randomized single-sequence two-period cross-over designs. The primary endpoints were Cmax and AUC for the respective probe drugs; their corresponding ratios of the geometric least-squares means (GLSM) (90% CI) in the presence/absence of tepotinib were reported. Additional PK measures, safety and tolerability were also evaluated.
Results
Most participants were male (12/12 midazolam; 19/20 dabigatran etexilate); mean age 34 years (range 19–44). There was no increase in midazolam exposure with co-administration of tepotinib (Table), suggesting that no effect on the metabolism of CYP3A is to be expected. Co-administration of tepotinib led to a 39–45% increase in dabigatran etexilate exposure. No clinically relevant effects on laboratory values, vital signs or ECG parameters were observed or reported as an AE.Table:
480P
CYP3A substrate (Midazolam) Ratio of GLSM% (90% CI) | P-gp substrate (Dabigratan) Ratio of GLSM% (90% CI) | |
---|---|---|
Tepotinib + Midazolam / Midazolam | Tepotinib + Dabigatran etexilate / Dabigatran etexilate | |
AUC0-t | 1.01 (0.89; 1.15) | 1.51 (1.27; 1.80) |
AUC0-∞ | 1.01 (0.89; 1.15) | 1.45 (1.23; 1.70) |
Cmax | 1.04 (0.87;1.24) | 1.38 (1.22; 1.58) |
AUC0-t, area under the plasma concentration-time curve from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification;
AUC0-∞, area under the plasma concentration-time curve from time zero (= dosing time) extrapolated to infinity; Cmax, maximum plasma concentration observed; GLSM, geometric least-squares mean.
Conclusions
After multiple doses of tepotinib at the RP2D (500 mg QD), there was no relevant exposure increase of the sensitive CYP3A substrate midazolam, and a < 2-fold mean exposure increase of the sensitive P-gp substrate dabigatran etexilate, indicating that tepotinib is a weak P-gp inhibitor. Tepotinib was considered safe and well tolerated in these studies of healthy volunteers. In summary, the potential of tepotinib to cause clinically relevant DDI with CYP3A4- or P-gp-dependent drugs at the intended posology is considered low.
Clinical trial identification
NCT03492437 and NCT03628339.
Editorial acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Sandra Cuscó, PhD of Bioscript Group (Macclesfield, UK).
Legal entity responsible for the study
Merck Healthcare KGaA.
Funding
Merck Healthcare KGaA.
Disclosure
Ö. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. A. Becker: Full / Part-time employment: Merck Healthcare KGaA. A. Krebs-Brown: Full / Part-time employment: Merck Healthcare KGaA. R. Strotmann: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.
Resources from the same session
3683 - Impact of Radiotherapy on efficacy of anti-programmed death 1 (PD-1) antibodies in metastatic NSCLC
Presenter: Evangeline Samuel
Session: Poster Display session 1
Resources:
Abstract
3924 - Pembrolizumab frontline monotherapy in patients with NSCLC and high PD-L1 expression: Real World Data from a European Cohort with focus on subgroups of interest
Presenter: Giannis Mountzios
Session: Poster Display session 1
Resources:
Abstract
3970 - Patients with metastatic non-small cell lung cancer and PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Martin Sebastian
Session: Poster Display session 1
Resources:
Abstract
5350 - The efficacy and safety of pembrolizumab as a first-line therapy in PD-L1 50% positive advanced NSCLC (HOPE-001)
Presenter: Motohiro Tamiya
Session: Poster Display session 1
Resources:
Abstract
3832 - Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS)
Presenter: Giulio Metro
Session: Poster Display session 1
Resources:
Abstract
4082 - Real-world (RW) treatment patterns and outcomes for second-line (2L) therapy and beyond in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC receiving a first-line (1L) first- or second-generation (1G/2G) EGFR tyrosine kinase inhibitor (TKI)
Presenter: Riyaz Shah
Session: Poster Display session 1
Resources:
Abstract
2855 - Impact of ramucirumab (RAM) + erlotinib (ERL) on EGFR mutations in circulating tumor DNA – The 1st report of a biomarker study in Japanese patients from RELAY: Global Ph3 study of ERL + RAM or placebo (PL) in 1L metastatic NSCLC with EGFR activating mutations
Presenter: Kazuto Nishio
Session: Poster Display session 1
Resources:
Abstract
2911 - Apatinib combined with EGFR - TKI in treating advanced non-small cell lung cancer with EGFR - TKI resistance
Presenter: Ruifen Tian
Session: Poster Display session 1
Resources:
Abstract
2100 - Updated analysis of a phase I trial of afatinib (Afa) and bevacizumab (Bev) in chemo-naïve patients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-mutations: OLCSG1404
Presenter: Takashi Ninomiya
Session: Poster Display session 1
Resources:
Abstract
4325 - Multiple synchronous mechanisms may contribute to osimertinib resistance in non-small cell lung cancer (NSCLC) patients: insights of the MATCH-R study
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract