Highlight
– The KUNPENG trial reported an objective response rate (ORR) of 48.8% for vebreltinib in patients with high-level MET-amplified non-small-cell lung cancer (NSCLC).
– Antitumor activity was observed in both chemotherapy-naive and previously treated patient populations.
– The safety profile was manageable, with treatment-related adverse events predominantly involving liver function abnormalities.
– Vebreltinib represents a potent Type Ib MET inhibitor specifically targeting the gene copy number threshold of six or higher.
Background: The Challenge of MET-Driven NSCLC
In the era of precision oncology, the identification of Mesenchymal-Epithelial Transition (MET) gene alterations has transformed the treatment landscape for non-small-cell lung cancer (NSCLC). MET dysregulation typically manifests in two primary forms: MET exon 14 (METex14) skipping mutations and MET amplification. While METex14 skipping has seen the approval of several targeted therapies, de novo MET amplification remains a challenging clinical entity with limited effective options.
MET amplification, characterized by an increase in gene copy number (GCN), acts as a primary oncogenic driver in approximately 1% to 5% of treatment-naive NSCLC cases. Furthermore, it is a frequent mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Historically, treatment responses in patients with MET amplification using multi-kinase inhibitors or earlier-generation MET inhibitors have been inconsistent, often due to insufficient potency or lack of selectivity. Vebreltinib (also known as Bozitinib) is a highly selective, potent, and reversible Type Ib MET inhibitor designed to provide deeper inhibition of the MET signaling pathway. The KUNPENG study was initiated to evaluate whether this specificity translates into meaningful clinical outcomes for patients with advanced MET-amplified NSCLC.
The KUNPENG Study Design
KUNPENG (NCT04258033) was a multicenter, multi-cohort, single-arm, phase 2 trial conducted across 17 specialized medical centers in China. The study focused on patients with locally advanced or metastatic NSCLC harboring MET dysregulation. This analysis specifically evaluates Cohorts 2 and 3, which targeted patients with high-level MET amplification, defined as a GCN of six or higher via fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS).
Patient Population and Enrollment
The study enrolled patients who were MET inhibitor-naive and aged 18 years or older. Cohort 2 included patients who had progressed after standard chemotherapy or were ineligible for it. Cohort 3 included patients who had refused chemotherapy. Due to accrual dynamics, these cohorts were merged to provide a comprehensive analysis of vebreltinib in the MET-amplified setting. A total of 145 patients were enrolled across the study, with 86 patients meeting the specific criteria for the MET amplification cohorts (30 pretreated and 56 treatment-naive).
Intervention and Endpoints
Participants received vebreltinib at a dose of 200 mg orally twice daily in 21-day cycles until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was the objective response rate (ORR), as determined by a masked independent review committee (IRC) using RECIST version 1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Key Findings: Efficacy and Clinical Response
The KUNPENG trial achieved its primary objective, demonstrating significant clinical activity in the MET-amplified population. Of the 86 patients in the full analysis set, 42 achieved a partial response, resulting in an IRC-confirmed ORR of 48.8% (95% CI 38.3–59.4).
Efficacy in Subgroups
One of the most notable findings was the consistency of response across treatment lines. In patients who were chemotherapy-naive, the ORR remained high, suggesting that vebreltinib could be a viable first-line option for those with high GCN MET amplification. Even in the pretreated population, the drug demonstrated the ability to overcome prior resistance to cytotoxic agents. The median follow-up time was 18.6 months, allowing for a stable assessment of the durability of these responses.
Durability and Survival
While the primary focus was ORR, the study also tracked the longevity of the clinical benefit. The responses were generally durable, reflecting the high selectivity of the drug for the MET kinase domain. Detailed PFS and OS data continue to mature, but the initial signals suggest a therapeutic benefit that exceeds historical benchmarks for non-targeted therapy in this molecular subgroup.
Safety and Tolerability Profile
The safety profile of vebreltinib in the KUNPENG trial was consistent with the known class effects of selective MET inhibitors. Treatment-related adverse events (TRAEs) occurred in the majority of patients, with grade 3 or higher TRAEs reported in 31% (27 of 86) of the cohort.
Adverse Events of Interest
The most common grade 3 or worse TRAEs involved liver function abnormalities, such as elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. These were reported by investigators in 9% of patients. Serious TRAEs occurred in 19% of patients. Clinical management of these events typically involved dose interruptions or reductions, highlighting the need for vigilant hepatic monitoring during treatment.
Notably, 11 treatment-emergent adverse events (TEAEs) led to death during the study. However, only one death—attributed to abnormal liver function—was considered possibly related to the vebreltinib treatment by the investigators. This underscores the potency of the drug and the requirement for clinician familiarity with its toxicity profile.
Expert Commentary: Contextualizing the Results
The KUNPENG results represent a significant milestone for MET-amplified NSCLC. For years, MET amplification has been a “difficult” target due to the heterogeneity of GCN thresholds used in various trials. By using a GCN of six or higher, the KUNPENG investigators targeted a population with a high degree of MET dependency, which likely contributed to the robust 48.8% ORR.
When compared to other MET inhibitors like capmatinib or tepotinib, vebreltinib shows a highly competitive efficacy profile. For instance, in the GEOMETRY mono-1 trial, capmatinib showed varying response rates depending on the GCN level, with the highest responses seen in patients with GCN 10 or higher. Vebreltinib’s performance at a GCN threshold of six suggests it may capture a broader range of sensitive patients. However, the single-arm nature of the study and the specific Chinese demographic mean that international, randomized phase 3 trials are necessary to confirm these findings and establish vebreltinib as a global standard of care.
Furthermore, the focus on de novo amplification in this trial provides clear evidence for vebreltinib’s role as a primary driver-targeted therapy. Future research should also explore its efficacy in the acquired resistance setting, particularly in combination with EGFR inhibitors, where MET amplification is a known escape pathway.
Conclusion
Vebreltinib has demonstrated impressive antitumor activity and a manageable safety profile in patients with advanced NSCLC driven by high-level MET amplification. These findings from the KUNPENG trial offer a new therapeutic pathway for a patient population that has long lacked effective targeted options. As molecular profiling becomes more routine in clinical practice, vebreltinib stands as a potent tool for clinicians managing MET-driven lung cancer.
Funding and ClinicalTrials.gov
This study was funded by Beijing Pearl Biotechnology and Avistone Biotechnology. The trial is registered with ClinicalTrials.gov under the identifier NCT04258033.
References
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2. Wolf J, Seto T, Han JY, et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(10):944-957.
3. Paik PK, Felip E, Veillon R, et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med. 2020;383(10):931-943.
4. Camidge DR, Otterson GA, Clark JW, et al. Crizotinib in patients with MET-amplified NSCLC: updated results from the PROFILE 1001 study. J Thorac Oncol. 2021;16(6):1025-1035.