P85.02 NGS could not Replace FISH Regarding to MET Amplification as an Optimal Biomarker

Abstract

MET-driven tumors. We investigated the activity of tepotinib in preclinical models and patients with baseline BM in the Phase II VISION study. Methods: Brain penetration was assessed in Wistar rats (n¼3) at tepotinib dose 3.66 mg/kg/h intravenously by determining unbound brain (f u br ) and plasma (f u pl ) concentrations using liquid chromatography with tandem mass spectrometry. Preclinical efficacy was assessed in two patient-derived xenografts (PDX) obtained from BM harboring high MET amplification (MET copy number gain: 11 for LU5349 and 24 for LU5406). NOD-SCID mice with PDX orthotopically implanted into the brain (n¼10/group) were treated with tepotinib 125 mg/kg or vehicle control orally once daily. Intracranial tumor growth was monitored by gadolinium-based MRI. Patients enrolled in VISION Cohort A with METex14 skipping NSCLC and asymptomatic BM (prior brain-specific therapy allowed) received tepotinib 500 mg once daily. Endpoints included systemic response per RECIST v1.1, duration of response (DOR), and progression-free survival (PFS) by independent review committee (IRC). Results: The fraction of unbound tepotinib in rat brain tissue (f u br ¼ 0.4%) was low compared with plasma (f u pl ¼ 4%), indicating high binding in the brain. Upon treatment with tepotinib, both PDX tumors from MET-driven NSCLC BM regressed significantly in orthotopic brain models (mean tumor volume reduction of 63% for LU5406 and 84% for LU5349). VISION Cohort A enrolled 22 patients with baseline BM (identified by IRC or investigator assessment), whose demographic characteristics were similar to the overall population (N¼152). As of July 1, 2020, 21 patients with baseline BM had 9 months' follow-up and were included in efficacy analyses. Confirmed systemic best overall response was partial response in 11 patients for an ORR (95% confidence interval [CI]) of 52.4% (29.8, 74.3), which was comparable to that in overall population (table ). Median DOR (95% CI) was 9.5 months (5.5, not estimable), and median PFS (95% CI) was 9.5 months (5.7, 11.2). Case studies illustrating response of brain lesions in VISION patients will also be presented.