Background: Vebreltinib (PLB1001), a potent and highly selective c-MET inhibitor, demonstrated superior objective response rate (ORR) benefits in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients (pts) with MET exon 14 (METex14) skipping mutations in the previous analysis of the phase II KUPENG study. Here we present results from 2.5 years of follow-up of pts in KUNPENG. Methods: In this Phase Ⅱ, open-label, multicenter, and multi-cohort study, tumor tissue was assessed for METex14 skipping mutation using next-generation sequencing (NGS) from CAP or CLIA certificated local or central laboratories. Pts in Cohort 1 received 200 mg of vebreltinib twice daily (28 days per cycle) until discontinuation criteria were met. The primary endpoint was ORR assessed by blinded independent review committee (BIRC). Results: Between Jan 17, 2020 and Feb 09,2021, 52 pts were enrolled in Cohort 1. As of the data cutoff date (Aug 09, 2023), the median duration of follow-up was 19.1 months (range, 1.0-42.7) and the median duration of treatment was 9.9 months (range, 0.6-42.7). Per BIRC assessment, the ORR was 75% (95% CI: 61.1-86.0), the disease control rate (DCR) was 96.2% (95% CI 86.8-99.5), the median duration of response (DoR) was 16.5 months (95% CI 9.2-19.4), the median time to response (TTR) was 1.0 month (95% CI 1.0-2.8), the median progression-free survival (PFS) was 14.3 months (95% CI 6.4-18.2), and the median overall survival (OS) was 20.3 months (95% CI 16.2-29.7). The 3-year OS rate was 35.1%. Subgroup analyses showed the ORR was 100.0%, 66.7%, 85.7% and 100.0% among pts with any baseline brain metastases (N=5), pts with any baseline liver metastases (N=6), pts aged 75 years and older (N=21) and pts with co-occurring of MET amplification (N=12), respectively. The most common (≥20%) treatment-related adverse events (TRAEs) in all the 135 pts enrolled in this study were peripheral edema (56.3%), hypoalbuminemia (27.4%), hypoproteinemia (25.9%) and anemia (20.7%). TRAEs were mainly grade 1 or 2. No new safety signals were reported with long-term vebreltinib treatment. Conclusions: Vebreltinib consistently showed promising efficacy and favorable safety in NSCLC pts with METex14 mutations. Clinical trial information: NCT04258033.