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

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ESMO: Oncology Pro


Abstract 1286P


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).


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).


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


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 Institute


Clinical Institute

Neurosciences (Brain & Spine)