Vebreltinib, a highly potent and selective c-MET (mesenchymal-epithelial transition) inhibitor, offers a promising treatment option for patients with MET exon 14 skipping mutation (METex14) in non-small cell lung cancer (NSCLC). Can it provide a safe and effective therapy for these patients?

A study titled Vebreltinib for Advanced Non–Small Cell Lung Cancer Harboring c-Met Exon 14 Skipping Mutation: A Multicenter, Single-Arm, Phase II KUNPENG Study published in the Journal of Clinical Oncology (IF=42) on July 26, 2024, may provide an answer. The study evaluated the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101) in patients with locally advanced or metastatic NSCLC harboring c-MET alterations. The results demonstrated that Vebreltinib showed promising efficacy and a good safety profile in patients with METex14-mutated NSCLC.

Over the past decade, there has been significant progress in targeted therapies for NSCLC, particularly for unique genetic alterations. Among these, alterations in the MET gene play a crucial role in tumorigenesis, including MET exon 14 skipping mutations (METex14), gene amplifications, gene fusions, and protein overexpression. Importantly, the METex14 mutation has been identified as an independent prognostic factor associated with reduced survival in NSCLC patients.

To find more effective treatments for NSCLC patients with METex14 mutations, both in previously treated and treatment-naïve patients, various tyrosine kinase inhibitors (TKIs) have achieved objective response rates (ORRs) ranging from 49.2% to 68%. However, these therapies have been associated with a significant incidence of grade 3 or higher treatment-related adverse events (TRAEs), including 34.8% for tepotinib, 37.6% for capmatinib, 46% for savolitinib, and 54% for gumarontinib. This highlights the need for therapies that balance efficacy with manageable safety profiles.

The KUNPENG study aimed to further investigate the efficacy and safety of vebreltinib in patients with locally advanced or metastatic NSCLC carrying METex14 mutations. As of August 9, 2022, 52 patients were enrolled in the cohort, with 35 patients (67.3%) being treatment-naïve. The ORR was 75% (95% CI, 61.1 – 86). In treatment-naïve patients, the ORR was 77.1% (95% CI, 59.9 to 89.6), while in previously treated patients, the ORR was 70.6% (95% CI, 44.0 to 89.7). The disease control rate was 96.2%, with a median duration of response (DoR) of 15.9 months, median progression-free survival (PFS) of 14.1 months, and median overall survival (OS) of 20.7 months. The most common treatment-related adverse events were peripheral edema (82.7%), QT interval prolongation (30.8%), and increased serum creatinine (28.8%).

In conclusion, this study provides evidence supporting the efficacy and safety of vebreltinib in patients with locally advanced or metastatic METex14-positive NSCLC, demonstrating its ability to induce strong and durable responses with a favorable safety profile. Vebreltinib has emerged as a viable therapeutic candidate for patients with METex14-positive NSCLC.

Reference: https://ascopubs.org/doi/10.1200/JCO.23.02363#tab-contributors