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E-Poster Display

1286P - Activity of tepotinib in brain metastases (BM): Preclinical models and clinical data from patients (pts) with MET exon 14 (METex14) skipping NSCLC

Date

17 Sep 2020

Session

E-Poster Display

Presenters

Santiago Viteri

Citation

Annals of Oncology (2020) 31 (suppl_4): S754-S840. 10.1016/annonc/annonc283

Authors

S. Viteri1, J. Mazieres2, R. Veillon3, E. Felip4, X. Le5, M.C. Garassino6, T.S. Stanton7, M. Morise8, J. Lee9, S. Matsumoto10, F. De Marinis11, T. Wehler12, A. Clark13, M. Friese-Hamim14, C. Stroh14, R. Bruns15, G. Otto16, P.K. Paik17

Author affiliations

  • 1 Dr Rosell Oncology Institute, Dexeus University Hospital, QuironSalud Group, 08028 - Barcelona/ES
  • 2 Chu De Toulouse, Institut Universitaire du Cancer, 30030 - Toulouse/FR
  • 3 Chu Bordeaux, service des maladies respiratoires, Bordeaux/FR
  • 4 Department Of Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona/ES
  • 5 Department Of Thoracic Head And Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston/US
  • 6 Department Of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan/IT
  • 7 -, St. Joseph Health Cancer Center, 95403 - Santa Rosa/US
  • 8 Department Of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya/JP
  • 9 Department Of Internal Medicine, Seoul National University College of Medicine, Seoul/KR
  • 10 Department Of Thoracic Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba/JP
  • 11 Division Of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan/IT
  • 12 Department Of Radio-oncology, University Hospital Saarland, Homburg/DE
  • 13 Translational Innovation Platform, Oncology, EMD Serono Research & Development Institute, Inc., Billerica/US
  • 14 Translational Innovation Platform, Oncology, Merck KGaA, Darmstadt/DE
  • 15 Department Of Biostatistics, Merck KGaA, Darmstadt/DE
  • 16 Clinical Oncology Development, Merck KGaA, Darmstadt/DE
  • 17 Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York/US
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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.

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