MO01.46 Tepotinib Activity in Brain Metastases (BM): Preclinical Models and Clinical Data from MET Exon 14 (METex14) Skipping NSCLC

Abstract

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 patients from the VISION study (NCT02864992). Penetration of the blood–brain barrier was assessed in Wistar rats (n=3) at 3.66 mg/kg/h intravenous 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 (PDXs) from BM harboring high MET amplification (gain in copy number: LU5349 = 11, LU5406 = 24) grown in NOD-SCID mice. Subcutaneous PDXs (n=5/group) or PDXs 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, patients with METex14 skipping NSCLC received tepotinib 500 mg once daily. Systemic objective response per RECIST v1.1 by independent review committee (IRC) was a preplanned analysis in patients with baseline BM 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 being lower than in plasma (fu br = 0.4%, fu pl = 4%). Unbound tepotinib concentrations in the brain were 25% of plasma (Kp u,u = 0.25). Tepotinib treatment resulted in tumor regression in both PDXs (mean % tumor volume: –84% in LU5349, –63% in LU5406). As of 1 Jan 2020, 22/152 patients enrolled in Cohort A had baseline BM, with similar characteristics and comparable systemic response data (table) to the overall population. Tepotinib administration resulted in tumor regression in MET-driven lung cancer BM PDX models. Clinical activity in patients with NSCLC harboring METex14 skipping with baseline BM was consistent with the overall population in VISION. Cohort C aims to assess intracranial response. Previously presented at ESMO Congress 2020, “FNP:1286P”, “Santiago Viteri et al.” - Reused with permission