Abstract 584P
Background
Tepotinib is a highly selective, potent MET inhibitor that has shown clinical activity in patients with NSCLC harboring MET exon 14 (METex14) skipping. The objective of this analysis was to evaluate the relationship between tepotinib and both safety and efficacy endpoints in patients with solid tumours.
Methods
Data from patients receiving tepotinib 30 mg to 1400 mg QD from four completed phase I/II studies (NCT01014936, NCT01832506, NCT01988493, NCT02115373) and one ongoing phase II study (VISION, NCT02864992) were used for exposure-safety analysis (n=499); exposure-efficacy analysis was performed using data from VISION cohort A (NSCLC patients with METex14 skipping receiving tepotinib 500 mg QD; n=146). Exposure metrics of area under the curve over 24h (AUC24h) for safety, and at steady state (AUCτ,ss ) for efficacy were derived from a population pharmacokinetic (PK) model. Safety or laboratory endpoints related to potential identified risks were evaluated, including edema (time to first event and maximum severity grade), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and serum lipase/amylase levels. Efficacy endpoints were objective response (OR) and duration of response (DOR) based on independent/investigator assessment.
Results
Overall, no association of tepotinib exposure with safety or efficacy was observed. There was no clear association between exposure and first occurrence of edema event or severity of edema. There was no association between lipase elevation and tepotinib exposure. An observed trend towards increased amylase, and transient increases in AST and ALT, did not appear to be correlated with tepotinib exposure. There was no apparent difference in exposure for responders and non-responders by either assessment; the OR rate was similar in all exposure quartiles. There was also no apparent association between exposure and DOR.
Conclusions
A flat exposure-response relationship was identified within the observed exposure range at dose levels of 30 –1400 mg QD for safety and across the exposures observed in VISION at the clinical dose of 500 mg for efficacy. The exposure-response analyses confirm that 500 mg QD is an appropriate dose for tepotinib to be used in the clinic.
Clinical trial identification
NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.
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, Germany.
Funding
Merck KGaA, Germany.
Disclosure
P.K. Paik: Advisory/Consultancy: Takeda; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Calithera; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Celgene; Advisory/Consultancy: Boehringer Ingelheim. W. Xiong: Full/Part-time employment: Merck, Lausanne, Switzerland. S.F. Hietala: Full/Part-time employment: Pharmetheus AB, Uppsala, Sweden. J. Nyberg: Full/Part-time employment: Pharmetheus AB, Uppsala, Sweden. O. Papasouliotis: Full/Part-time employment: Merck, Lausanne, Switzerland. R. Anziano: Full/Part-time employment: Pharmetheus AB, Uppsala, Sweden. K. Berghoff: Full/Part-time employment: Merck KGaA. A. Johne: Full/Part-time employment: Merck KGaA. P. Girard: Full/Part-time employment: Merck, Lausanne, Switzerland. R. Strotmann: Full/Part-time employment: Merck KGaA, Darmstadt, Germany.