Activity of tepotinib in brain metastases (BM): Preclinical models and clinical data from patients (pts) with MET exon 14 (METex14) skipping NSCLC
Abstract
Abstract 1286P
Background
BM occur in 20–40% of NSCLC harboring METex14 skipping. We investigated the activity of the MET inhibitor tepotinib in BM in preclinical models and in pts from the VISION study (NCT02864992).
Methods
Penetration of the blood–brain barrier was assessed in Wistar rats (n=3) at 3.66 mg/kg/h iv tepotinib by determining the unbound brain (fu br)-to-plasma (fu pl) concentration or exposure ratio (Kp u,u). Efficacy was assessed in two lung cancer patient-derived xenografts (PDX) from BM harboring high MET amplification (MET gain in copy number: LU5349 = 11, LU5406 = 24) grown in NOD-SCID mice. Subcutaneous PDX (n=5/group) or PDX orthotopically implanted into the brain (n=10/group) were treated with tepotinib 125 mg/kg or vehicle control orally once daily. Intracranial tumor growth was monitored by gadolinium-based MRI. In VISION Cohort A, pts with METex14 skipping NSCLC received tepotinib 500 mg once daily. Systemic objective response, as assessed per RECIST v1.1 by independent review committee (IRC) was a preplanned analysis in pts with baseline brain lesions identified by IRC (BM-IRC) or investigator assessment (BM-INV).
Results
Preclinical data indicated high binding of tepotinib in the brain, with unbound tepotinib in brain tissue lower than in plasma (fu br = 0.4%, fu pl = 4%). Concentrations of unbound tepotinib in the brain were 25% of plasma (Kp u,u = 0.25).Tepotinib treatment resulted in tumor regression in both PDX models (mean % tumor volume: –84% in LU5349, –63% in LU5406). As of 1 Jan 2020, 22/152 pts enrolled in Cohort A had baseline BM, with similar baseline pt characteristics and comparable systemic response data (Table) as the overall population. Table: 1286P BM-IRC BM-INV Number of patients with BM; n Non-target lesions 14 12 Target lesions 0 1 Objective response rate, % (95% CI) 57.1% (28.9, 82.3) 53.8% (25.1, 80.8) Best overall response; n Partial response 8 7 Stable disease 3 3
Conclusions
Tepotinib administration resulted in tumor regression in MET-driven lung cancer BM PDX models. Clinical activity in pts with NSCLC harboring METex14 skipping with baseline BM was consistent with the overall population in VISION. Cohort C aims to assess intracranial response.
Clinical trial identification
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, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany.
Disclosure
S. Viteri: Advisory/Consultancy: AbbVie; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: MSD; Travel/Accommodation/Expenses: OSE Pharma; Travel/Accommodation/Expenses: Merck. J. Mazieres: Advisory/Consultancy: Roche; Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis. R. Veillon: Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (self): BMS; Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Research grant/Funding (self): Takeda; Research grant/Funding (self): AbbVie; Research grant/Funding (self): Merck. E. Felip: Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy: Guardant Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy: Janssen; Advisory/Consultancy: Samsung; Speaker Bureau/Expert testimony: Medscape; Speaker Bureau/Expert testimony: prIME Oncology; Speaker Bureau/Expert testimony: Touchtime; Research grant/Funding (self): Fundación Merck Salud; Research grant/Funding (self): Grant for Oncology Innovation (GOI); Officer/Board of Directors: Grifols (Independent Member). X. Le: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Eli Lilly; Advisory/Consultancy: EMD Serono; Research grant/Funding (self): Boehringer Ingelheim. M.C. Garassino: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Sanofi; Speaker Bureau/Expert testimony: Otsuka Pharma; Speaker Bureau/Expert testimony: Incyte; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS. T.S. Stanton: Honoraria (self), Travel/Accommodation/Expenses: BMS; Honoraria (self): Ipsen; Honoraria (self): Axess Oncology; Honoraria (self): Intellisphere. M. Morise: Honoraria (self), Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Chugai; Research grant/Funding (self): EMD; Research grant/Funding (self): Kissei; Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Ono; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (self): Taiho; Honoraria (self), Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: MSD. S. Matsumoto: Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Pfizer; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Chugai Pharma; Honoraria (self), Research grant/Funding (self): MSD; Honoraria (self): Lilly; Honoraria (self): Merck Serono. F. De Marinis: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS; Speaker Bureau/Expert testimony: Pfizer. A. Clark: Full/Part-time employment: EMD Serono Research & Development Institute, Inc., Billerica, MA, US, a business of Merck KGaA, Darmstadt, Germany. M. Friese-Hamim: Full/Part-time employment: Merck KGaA, Darmstadt, Germany. C. Stroh: Full/Part-time employment: Merck KGaA, Darmstadt, Germany. R. Bruns: Full/Part-time employment: Merck KGaA, Darmstadt, Germany. G. Otto: Full/Part-time employment: Merck KGaA, Darmstadt, Germany. P.K. Paik: Advisory/Consultancy: AbbVie; Advisory/Consultancy: BMS; Advisory/Consultancy: Calithera; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Lilly; Advisory/Consultancy: Takeda; Research grant/Funding (self), Research grant/Funding (institution): EMD Serono. All other authors have declared no conflicts of interest.
