Abstract 5455
Background
Acid-inhibitory drugs (e.g. proton pump inhibitors - PPIs) increase intragastric pH, which may decrease solubility, bioavailability, and efficacy of oral cancer drugs. Furthermore, polypharmacy in cancer patients is common and different requirements for treatment with or without food can impact compliance. Tepotinib is an oral, highly selective MET inhibitor being investigated in patients with solid tumors with MET dysregulation (METex14 mutations or MET amplification). In the pivotal clinical trial, tepotinib has been administered with breakfast; this represents the intended posology. Tepotinib has pH-dependent low solubility, suggesting that food intake and/or co-administration with a PPI may impact bioavailability. We investigated the effects of the PPI omeprazole and food on tepotinib.
Methods
In a 3-period, cross-over study, healthy volunteers (n = 12) received 500 mg/day tepotinib as a single dose 30 mins after a continental breakfast (treatment A) and co-administered on Day 5 after receiving omeprazole (40 mg QD for 5 days) under fasted conditions (treatment B) and after a continental breakfast (treatment C). The impact of omeprazole on the AUC0-t, AUC0-∞, and Cmax of tepotinib under fed conditions was evaluated comparing treatments A and C; corresponding ratios of the geometric least-squares means (GLSM) (90% CI) were reported. In a separate study, food effect was investigated in healthy volunteers (n = 12) by administering single doses of 500 mg tepotinib under fasted state and after a high-fat, high-calorie breakfast.
Results
In the first study, there was a negligible effect of omeprazole co-administration on the bioavailability of tepotinib under fed conditions. The GLSM ratios (90% CI) for treatment C/A were 1.09 (1.01, 1.17) for AUC0-t; 1.10 (1.02, 1.19) for AUC0-∞; and 1.04 (0.93, 1.17) for Cmax. In the second study, the ratio (90% CI) of “high-fat” /”fasted” for tepotinib AUC0-∞ was 1.87 (1.64, 2.13) and for Cmax was 2.37 (2.16, 2.59).
Conclusions
The intended posology of tepotinib, i.e. with food, is in agreement with the moderate food effect (approximately 2-fold increase in exposure of tepotinib). When tepotinib is administered at 500 mg/day together with food, co-administration of PPI is not expected to have clinically relevant drug interactions.
Clinical trial identification
NCT03531762 and NCT03629223.
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
R. Strotmann: 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. N. Mammasse: Full / Part-time employment: Merck Healthcare KGaA. Ö. Yalkinoglu: Full / Part-time employment: Merck Healthcare KGaA. All other authors have declared no conflicts of interest.
Resources from the same session
3305 - A phase I dose-escalation and expansion trial of intratumorally administered CV8102, alone and in combination with anti-PD-1 in patients with advanced solid tumors
Presenter: Jürgen Krauss
Session: Poster Display session 1
Resources:
Abstract
5353 - Phase 1/2 Study of 9-ING-41, a small molecule selective Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined with Chemotherapy, in Patients with Refractory Hematological Malignancies or Solid Tumors
Presenter: Benedito Carneiro
Session: Poster Display session 1
Resources:
Abstract
3946 - Trial in progress: a Phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumors (NCT03447314).
Presenter: Aaron Hansen
Session: Poster Display session 1
Resources:
Abstract
3449 - Radiographic Phenotyping to Identify Intracranial Disseminated Recurrence in Brain metastases Treated With Radiosurgery Using Contrast-enhanced MR Imaging
Presenter: CheYu Hsu
Session: Poster Display session 1
Resources:
Abstract
4553 - Association between TP53 mutations and efficacy of Osimertinib for brain metastasis from EGFR-mutant lung cancer
Presenter: Lijuan Chen
Session: Poster Display session 1
Resources:
Abstract
4942 - Response assessment of melanoma brain metastases treated by stereotactic radiotherapy or immunotherapy or both: a comparison of RECIST 1.1, RANO and iRANO criteria
Presenter: Emilie Le Rhun
Session: Poster Display session 1
Resources:
Abstract
3529 - Management of multiple brain metastases by Staged SRS focusing on utmost risk lesions
Presenter: shaoqun Li
Session: Poster Display session 1
Resources:
Abstract
5315 - Whole brain radiotherapy plus simultaneous in-field boost versus whole brain radiotherapy plus fractionated stereotactic radiotherapy for multiple brain metastases of non-small cell lung cancer
Presenter: Lu Li
Session: Poster Display session 1
Resources:
Abstract
1116 - 3D based texture analysis serving as potential diagnostic factor in discriminating primary central nervous system lymphoma from metastatic brain tumors: A preliminary study
Presenter: Wen Guo
Session: Poster Display session 1
Resources:
Abstract
5344 - Global trends in population-based survival for 303,169 adults diagnosed with glioblastoma in 44 countries during 2000-2014 (CONCORD-3)
Presenter: Fabio Girardi
Session: Poster Display session 1
Resources:
Abstract