Background: METamp is an oncogenic driver occurring in 1–5% of NSCLCs that confers a poor prognosis and lacks approved targeted therapies. Tepotinib, a highly selective MET inhibitor, provided durable response in NSCLC with MET exon 14 (METex14) skipping in Cohort A of the Phase II VISION trial (NCT02864992). VISION Cohort B evaluated tepotinib in pts with advanced NSCLC and METamp, as detected by a convenient and minimally invasive liquid biopsy assay, in the absence of METex14 skipping. Methods: Pts with locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, 0–2 prior lines of therapy, EGFR/ALK wild-type status, no METex14 skipping, and METamp by liquid biopsy (Guardant360^®; MET gene copy number ≥2.5) received oral tepotinib 500 mg QD (450 mg active moiety). The primary endpoint was objective response (RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety. The data cut-off was July 1, 2020. Results: Among 24 enrolled pts, median age was 63.4 years (range: 38–73), 21 pts (88%) were male, 21 (88%) had ECOG PS 1 and 21 (88%) were smokers. Tepotinib was given to 7 pts (29%) in first line (1L), 10 pts (42%) in second line (2L) and 7 pts (29%) in third line (3L). As of November 2020, treatment was ongoing for > 1 year in 5 pts (1L, n = 2; 2L, n = 2; 3L, n = 1). Objective response rate (ORR) by IRC was 42% (10/24 pts) overall, 71% (5/7 pts) in 1L, 30% (3/10 pts) in 2L and 29% (2/7 pts) in 3L (Table). Median DOR by IRC was not estimable (NE; 95% confidence interval [CI]: 2.8 months–NE). Investigator-assessed outcomes were similar. Five pts (20.8%) discontinued due to adverse events (AEs), which were considered unrelated to tepotinib. Treatment-related AEs were reported in 16 pts (67%; Grade 3/4, 7 pts [29%]) and included peripheral edema (9 pts [38%]; Grade 3/4, 2 pts [8%]), generalized edema (4 pts [17%]; Grade 3/4, 2 pts [8%]) and constipation (4 pts [17%]; Grade 3/4, 0 pts). Conclusions: In the first study of a MET inhibitor in NSCLC with METamp prospectively detected by liquid biopsy, tepotinib showed high and clinically meaningful activity, especially in 1L, and was generally well tolerated. Tepotinib warrants further evaluation in NSCLC with METamp. Clinical trial information: NCT02864992