Targeting MET amplification in non–small cell lung cancer: encouraging results with vebreltinib from the phase II KUNPENG study

During the past two decades, the therapeutic landscape of non-small cell lung cancer (NSCLC) has been transformed by identification of oncogenic driver alterations and development of targeted therapies. Molecularly directed treatments against EGFR mutations as well as ALK and ROS1 rearrangements have substantially improved clinical outcomes in selected NSCLC patient populations (1,2). Nevertheless, several genomically defined subgroups remain therapeutically challenging, including tumors harboring alterations in the MET signaling pathway. MET exon 14 skipping mutations are now established therapeutic targets with MET inhibitors such as tepotinib and capmatinib approved by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (3). Moreover, MET amplification is the most frequent known off-target mechanism of acquired resistance in EGFR-mutant NSCLC patients receiving Osimertinib, as it results in overexpression, auto-aggregation, and ligand-independent activation of the MET receptor protein causing persistent reactivation of the RAS-RAF-MAPK, PI3K-AKT, and STAT signaling pathways downstream of EGFR (4). For this reason, combination treatments targeting both EGFR and MET are justified (5).

Yet, the clinical significance of MET amplification as a primary oncogenic driver and therapeutic target remains less clear. De novo MET amplification occurs in approximately 1–5% of NSCLC cases. It may function either as a primary oncogenic driver or rarely as co-alteration in other types of genomically defined (EGFR-mutated, KRAS-mutated, ALK-rearranged) NSCLC subgroups, in which it may represent a mechanism of intrinsic resistance to targeted therapies (6-12). NSCLC patients with high-level MET-amplification often experience advanced disease with unfavorable clinical outcomes and historically have limited effective targeted treatment options (13). Although several MET-tyrosine kinase inhibitors (MET-TKIs) have been investigated in this setting, the clinical activity has been inconsistent, partly reflecting heterogeneity in biomarker definitions and patient selection criteria across studies (14-16). Previous clinical trials evaluating MET-TKIs in patients with de novo MET-amplified NSCLC, including the GEOMETRY mono-1 study with capmatinib and the AcSé trial with crizotinib, have reported heterogeneous clinical activity, with responses observed predominantly in tumors harboring high-level MET amplification (14,15). Consequently, the optimal therapeutic strategy for this subgroup of patients remains an area of active investigation.

In this context, Wu and colleagues recently reported the results of the phase 2 KUNPENG study, evaluating vebreltinib, a highly selective MET-TKI, in 86 patients with MET amplification-driven advanced NSCLC (17). The KUNPENG study provides encouraging efficacy signals, but its broader clinical impact hinges on resolving persistent challenges in defining clinically relevant MET amplification. In total, 145 patients with locally advanced or metastatic disease harboring de novo MET alterations such as MET exon 14 (METex14) skipping mutations or MET amplification were enrolled. The study investigators first reported the promising results of vebreltinib in the patients with METex14 skipping mutations with objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) of 75%, 96%, 14.3 months, and 20.3 months, respectively (18). Subsequently, the investigators described the effect of vebreltinib in patients with MET amplification, which was defined by a gene copy number (GCN) of six or greater and confirmed by a central laboratory utilizing fluorescence in situ hybridization (FISH) (17). Importantly, the recruited patients had not previously received any MET inhibitor, and either had disease progression following platinum-based chemotherapy or were ineligible for chemotherapy (cohort 2) or declined chemotherapy (cohort 3). Vebreltinib demonstrated promising antitumor activity with an ORR assessed by a masked independent review committee (MIRC) of 48.8% and a DCR of 77.9%. Responses were observed in both chemotherapy-treated and chemotherapy-naïve patients, with ORRs of 43.3% and 51.8% as well as a DCR of 73.3% and 80.4%, respectively. Antitumor activity appeared numerically higher in chemotherapy-naïve patients than in those previously treated with chemotherapy. Although not statistically significant, these differences raise the possibility that targeting MET amplification earlier may provide greater clinical benefit, particularly if MET amplification represents a dominant oncogenic driver before the spontaneous or therapy-induced emergence of additional resistance mechanisms.

The median duration of response for all patients was 12.1 months, suggesting frequent and durable responses in a substantial proportion of patients. In addition, the mPFS was 7.4 months (8.3 months in chemotherapy-naïve, and 7.3 months in chemotherapy-treated patients), and the mOS reached 13.9 months (17). These findings are particularly notable when considered in the context of previous studies evaluating MET-targeted therapies in MET-amplified NSCLC. In the GEOMETRY mono-1 trial, capmatinib demonstrated an ORR of approximately 29% in previously treated patients with high-level MET amplification and a GCN ≥10 (14). Similarly, the AcSé trial investigating crizotinib in MET-amplified NSCLC reported an ORR of around 32% in patients with GCN ≥6 (15). As also pointed out by Wu et al. (17), cross-trial comparisons should be interpreted cautiously due to differences in study design and patient populations with MET-amplified NSCLC. Yet, the response rate approaching 50% observed with vebreltinib suggests promising clinical activity in this difficult-to-treat population.

The interpretation of MET amplification remains a major challenge for the clinical implementation of MET-targeted therapies. A noteworthy observation from the KUNPENG study was that clinical responses were relatively similar across different levels of MET amplification levels. The latter were determined centrally using FISH with a GCN threshold of six and stratifying patients into subgroups with values 6< GCN <10, 10< GCN <15, and GCN ≥15. As ORRs were broadly comparable across these categories a GCN threshold of six may identify patients who could benefit from vebreltinib. However, it remains uncertain whether this cutoff reliably captures tumors truly driven by MET amplification, particularly because distinguishing focal MET amplification from the less clinically relevant chromosome 7 polysomy may be challenging (4,19,20). FISH is still the reference technique for evaluating MET copy number alterations in NSCLC tissue samples given its high sensitivity, minimal false negative rate, and possibility of differentiating focal MET amplification from polysomy. Thus, FISH has been widely used in MET-inhibitor trials, yet, it is not sufficiently standardized to allow ideal comparisons of different studies (4,20,21). Particularly, the MET GCN gain associated with clinically significant MET protein overexpression and sensitivity to anti-MET therapy remains unclear (4,19-23). In this respect, MET/CEP7 ratio ≥2 is considered more indicative of true gene amplification, while increased MET GCN alone may reflect either focal MET amplification or polysomy. The former is more likely to confer oncogenic dependency, whereas polysomy may represent a secondary phenomenon rather than a true driver alteration (19,20). Consequently, defining amplification solely by absolute GCN thresholds, without considering the MET/CEP7 ratio, may affect patient selection for MET-targeted therapies (6,8,11,14,19,20).

Although targeted next-generation sequencing (NGS) panels are increasingly implemented in routine diagnostics, NGS is less sensitive than FISH in distinguishing focal gene amplification from polysomy. Additional limitations of NGS with respect to detecting MET amplification are the lack of consensus on cut-off values, the risk of insufficient tumor cell content and purity for sensitive detection in the material utilized, and challenges related to tumor heterogeneity resulting in clonal MET amplification. These challenges reflect in a poor concordance between NGS and FISH detection and in NGS often being unable to detect clonal MET amplifications otherwise morphologically revealed by FISH (11,20,24). Nevertheless, NGS is important for detecting co-alterations that may affect the response to targeted treatment. Oncogenic co-alterations have been more frequently reported in tumors with low- or intermediate-level MET amplification, whereas high-level amplification is more likely a dominant oncogenic driver, further highlighting the biological heterogeneity of MET-amplified NSCLC (11,19).

In this respect, although patients with EGFR or KRAS mutations and ALK or ROS1 rearrangements were excluded from the KUNPENG study to enrich for MET amplification-driven disease, the broader genomic context of the tumors in the accrued patients remains largely undefined. Information regarding other potential co-occurring genomic alterations was not reported, hence the extent to which MET amplification represents the dominant oncogenic driver across all included tumors and the effect of possible co-alterations on the response to vebreltinib cannot be fully determined. Although MET amplification has been reported to occur at equal frequencies in pulmonary adenocarcinoma and squamous cell carcinoma without or with EGFR or KRAS co-mutations (22), only 9% of the 86 cases enrolled in the study had squamous histology vs. 86% with adenocarcinoma and 5% with other histological NSCLC subtypes (17). No clear correlation between histological subtype and response to vebreltinib was presented. Ten of the 21 patients that had brain metastasis at baseline showed systemic response (ORR 47.6%) with a median systemic duration of response of 11.0 months (17).

The safety profile of vebreltinib in the study appear manageable and largely consistent with that reported for other MET-TKIs (14,15,17). The most common treatment-related adverse events (AEs) included peripheral edema, hypoproteinemia, hypocalcemia, and hypoalbuminemia. Grade 3 or higher treatment-related AEs occurred in approximately one-third of patients, most frequently involving abnormalities in liver function tests. Treatment discontinuation due to AEs was infrequent. Although one death possibly related to treatment-associated liver dysfunction was reported, the overall tolerability profile of vebreltinib appeared acceptable. Importantly, no unexpected safety signals were identified, suggesting that the toxicity profile of vebreltinib largely reflects a class effect associated with MET inhibition (14-17).

Despite the encouraging results, other limitations of the KUNPENG study should be acknowledged. First, the study employed a single-arm design without a comparator group, limiting the ability to directly evaluate the relative benefit of vebreltinib compared with other systemic therapies. Additional statistical caution is warranted because cohorts 2 and 3 were initially designed separately and then merged after slow data collection, with the merged analysis adopting the hypothesis framework originally defined for cohort 2. Combined with a single-arm design, the use of a historical benchmark for response, and multiple exploratory subgroup analyses without multiple comparison correction, these features allow the results to be considered promising, but do not yet justify routine adoption outside clinical trials. Secondly, the sample size was relatively small, and subgroup analyses should therefore be interpreted cautiously. In addition, the study population consisted predominantly of Chinese male patients (90%), which may limit the generalizability of the findings to broader and more diverse patient populations. Approximately one quarter of patients had brain metastases at baseline, highlighting the clinical relevance of central nervous system involvement in MET-altered NSCLC (6,7,13). However, intracranial efficacy was not formally assessed, as response evaluation in the KUNPENG study was limited to systemic disease. Consequently, the ability of vebreltinib to control intracranial disease remains unclear.

In addition, the authors’ “Research in context” section highlights a broader issue related to MET nomenclature. Their literature search included the term “mesenchymal-epithelial transition” as a synonym for MET. However, this terminology does not correspond to the official gene nomenclature. The MET gene originates from the historical designation “MNNG HOS transforming gene”, and the interpretation of MET as “mesenchymal-epithelial transition” has been identified as a misleading expansion that has persisted in scientific publications for more than a decade (25). Although this nomenclature issue does not materially affect the interpretation of the trial results, it underscores the importance of using standardized gene terminology and validated synonyms when conducting systematic literature searches.

Nevertheless, the KUNPENG study represents an important step forward in the ongoing effort to develop effective targeted therapies for patients with MET amplification-driven NSCLC (17). The results provide evidence that selective inhibition of MET can yield meaningful clinical responses in these patients, particularly in those with limited treatment options after chemotherapy. Looking ahead, further clinical investigation will be essential to confirm these findings and clarify the optimal role of vebreltinib in clinical practice. A phase III randomized trial comparing vebreltinib with standard treatment in patients with MET amplification–driven advanced NSCLC is currently being initiated (NCT06970782).

Notably, the KUNPENG study by Wu and colleagues (17) highlights the increasing importance of comprehensive molecular profiling in NSCLC. As genomic testing becomes more widely implemented in routine clinical practice, the identification of less common but clinically actionable alterations such as MET amplification will likely increase. However, given that FISH is more sensitive than NGS for detecting MET amplification—both in genomic DNA from tissue samples and, even more so, in circulating cellfree DNA from plasma (11,19,24,26)—optimal identification of this therapeutic target and accurate prediction of benefit from MET inhibitors would require complementing the emerging NGS‑only paradigm for molecular testing of diagnostic NSCLC biopsies with FISH.

In addition to MET-TKIs, antibody-drug conjugates (ADCs) targeting the MET protein have recently expanded the therapeutic options for NSCLC with MET alterations. Telisotuzumab vedotin (Teliso-V) is a MET-directed ADC designed to treat NSCLC by delivering a cytotoxic payload (the microtubule inhibitor monomethyl auristatin E) directly to tumor cells overexpressing the MET protein. Teliso-V received FDA accelerated approval in May 2025 for previously treated, locally advanced/metastatic, non-squamous NSCLC with high MET overexpression, defined as ≥50% of tumor cells with strong (3+) membrane MET immunostaining on an FDA-approved immunohistochemistry (IHC) assay. This approval underscores the therapeutic significance of MET protein expression as a distinct biomarker, although MET overexpression, MET amplification, and MET exon 14 skipping are not interchangeable biomarkers, given that MET overexpression has been reported in 30–70% of NSCLC patients, suggesting that it can be caused by mechanisms other than MET amplification or exon 14 skipping (27). In this respect, the proportion of patients in the KUNPENG MET-amplified cohort (selected by FISH-determined GCN ≥6, not by MET-IHC) who would have fulfilled the Teliso-V eligibility criterion cannot be reliably estimated.

Indeed, continued efforts to refine biomarker definitions and develop more effective targeted agents will be essential to ensure that patients with rare oncogenic drivers may benefit from the advances of precision oncology treatments. Ultimately, the clinical success of MET-directed therapies will depend not only on the development of potent inhibitors but also on the ability to accurately identify by standardized methods subset of tumors in which MET amplification represents a true oncogenic dependency likely to be effectively targeted by these inhibitors.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0403/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0403/coif). E.M.U. reports research grants from AstraZeneca and Merck; speaker fees from Amgen, Bayer, Janssen, MSD, and Regeneron; travel support related to participation in international scientific meeting from AstraZeneca, Bristol-Myers Squibb, MSD, and Roche; and payment for participation in Advisory Board from AstraZeneca and Pfizer. M.G. received research funding from Merck and speaker honoraria from Pfizer, AstraZeneca, and Thermo Fisher Scientific. J.B.S. received consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Janssen, and Roche; honoraria for lectures from Bristol-Myers Squibb, Janssen; support for attending meetings and/or travel from AstraZeneca, Janssen, Merck; and payment for participation in Advisory Board from AstraZeneca, Bristol-Myers Squibb, Genmab, Janssen, Merck, and Roche. E.S.R. received research grants from Sanofi and Takeda; honoraria for lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Roche, and Takeda; travel support related to participation in international scientific meeting from AstraZeneca; and payment for participation in Advisory Board from AstraZeneca, Daiichi Sankyo, MSD, Roche and Takeda. The authors have no other conflicts of interest to declare.

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