Targeting MET in advanced and metastatic non-small cell lung cancer: a literature review of the current landscape

Introduction

Background

An improved understanding of the molecular pathways that promote malignant proliferation and the discovery of targetable oncogenic driver mutations has been revolutionary for the management of non-small cell lung cancer (NSCLC). In 2004, the discovery of an activating mutation in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), which predicted marked response to the first-generation EGFR tyrosine kinase inhibitor (TKI), gefitinib, laid the foundation for the field of precision therapy in NSCLC and opened the door for such oncogenic driver mutations to become targets for therapeutic development (1). The opportunity to “personalize” cancer care with molecular-targeted therapy has since expanded significantly, with the identification of actionable, oncogenic alterations in ALK, ROS1, RET, NTRK, BRAF, HER2, KRAS, NRG1, and MET. As our understanding of the genomic landscape has expanded, we have not only identified more actionable driver oncogenes and expanded development of selective inhibitors, but have also begun to develop an appreciation for the true complexity of this space. There is great molecular and clinical heterogeneity even within a single mutation family, resulting in variable clinical behavior and drug sensitivity (1). Data continues to emerge allowing us to target molecular driver alterations in the front- and subsequent-line settings, understand the impact of co-mutations, and manage emerging mechanisms of resistance.

MET is a proto-oncogene located on chromosome 7 that encodes the c-mesenchymal-epithelial transition factor protein (c-MET), a high-affinity tyrosine kinase receptor for the hepatocyte growth factor (HGF) (2). It is normally expressed at low levels primarily in epithelial cells and plays an important role in cellular differentiation, proliferation, survival, embryonic development, wound healing, and tissue regeneration (3). Dysregulation through either ligand-dependent or ligand-independent pathways can therefore lead to excessive cell proliferation, angiogenesis, tumor invasion, and metastasis. MET alterations, including most notably MET exon 14 skipping mutation (METex14), MET amplification (MET AMP), MET overexpression (MET OE), and MET fusion (MET FUS), have been observed as both primary oncogenic drivers and drivers of acquired resistance to targeted therapy in NSCLC. In fact, MET AMP is among the most common mechanisms of resistance to EGFR-targeted therapy, accounting for approximately 7–18% of acquired resistance mutations (4).

Rationale and knowledge gap

The landscape of MET dysregulation is complex and understanding the pathogenic and prognostic role of different types of MET alterations has been challenging. Early attempts to identify a “druggable” molecular driver mutation were generally unsuccessful until the discovery of METex14 (5). Prior to 2025, there were only two United States (U.S.) Food and Drug Administration (FDA)-approved therapies for MET-altered NSCLC (capmatinib and tepotinib), both type Ib MET TKIs approved for METex14. In May 2025, telisotuzumab vedotin-ttlv (Teliso-V), an antibody-drug conjugate (ADC) targeting MET, was granted accelerated approval by the FDA for the subsequent line treatment of adults with advanced/metastatic, non-squamous NSCLC with high MET OE. This approval expanded the treatment landscape for the first time both in terms of drug class and targeted MET alteration since the initial approval of capmatinib in 2020. There is a large volume of ongoing work focused on developing a better understanding of the range of targetable mechanisms of MET axis dysregulation, with the goal of developing innovative therapeutic approaches with distinct toxicity profiles that will allow us to address a wider range of MET alterations in the front- and subsequent lines, manage emerging treatment resistance, and better tailor treatment to individual patients. A synthesized understanding of the most current data and future directions is critical to improve outcomes for a larger group of patients with MET-altered NSCLC.

Objective

In this review, we aim to provide a comprehensive summary of the current landscape of MET axis alterations, including updated data regarding the identification and management of METex14, MET AMP, MET OE, and MET FUS in advanced/metastatic NSCLC. We evaluate MET as a primary pathologic driver and as a mechanism of acquired resistance to targeted therapies. We review both established and emerging approaches to targeting the MET axis, including the very recent approval of Teliso-V, an ADC targeting MET OE. We evaluate updated trial data supporting approved and investigational therapies through September 2025, including recent phase II results regarding cabozantinib in MET-altered NSCLC as well as recent reports of overall survival (OS) for two key trials (FLAURA2, MARIPOSA) focused on reducing acquired resistance to EGFR-targeted therapy. We also explore the role of immunotherapy (IO) among patients with MET alterations. Finally, we evaluate key challenges that remain and areas of promising investigation for this complex patient population. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1007/rc).

Methods

A non-systematic literature review was performed using keywords related to MET alterations and targeted therapy in advanced and metastatic NSCLC. There was no predefined inclusion or exclusion criteria, or formal quality appraisal performed. The topics covered, articles selected, and data reviewed were based on author discretion and experience, with an emphasis on relevant and rigorous primary and secondary literature published within the last 10 years. Table 1 provides a summary of the search strategy.

Mechanisms of MET-axis dysregulation

METex14

Stabilization and degradation of the MET receptor are processes regulated by the intracellular juxtamembrane domain, which is encoded by exon 14 of the MET gene. Specifically, when tyrosine residue Y1003 within this domain is bound by the casitas-B-lineage lymphoma (CBL) E3 ubiquitin ligase, MET is ubiquitylated and the MET receptor is internalized and degraded (6). Point mutations, insertions, and deletions in exon 14 can disrupt this pathway and result in tumorigenesis (7). Point mutations account for nearly 50% of these alterations and cause skipping of exon 14 during pre-messenger ribonucleic acid (mRNA) splicing (6,8). This leads to decreased ubiquitination of MET, increased half-life of the MET receptor, delayed receptor downregulation after stimulation with HGF, and prolonged down-stream signaling (6,7). Historically, immunohistochemistry (IHC) was used to identify these mutations, however this method was found to have a clinically significant false negative rate. Currently, the most sensitive method for detection of METex14 is next generation sequencing (NGS). Both ribonucleic acid (RNA)- and deoxyribonucleic acid (DNA)-based methods can be used, though both have inherent limitations and therefore a combination approach is preferred (6,9).

METex14 has been reported in about 2–4% of cases of NSCLC and typically occurs independently of other targetable molecular driver mutations (8,10,11). In a large-scale evaluation seeking to characterize METex14 in NSCLC using whole transcriptome sequencing, over 21,000 NSCLC tumor samples underwent complete genomic profiling with both DNA- and RNA-based sequencing (8); 2.47% of the tumors harbored METex14, of which 49.5% were point mutations at donor splice sites. Compared to patients with wild-type (WT) NSCLC, METex14 was more common among females (56.7% vs. 43.3%, P<0.05), older patients (median age 77 vs. 69 years, P<0.0001), and light or never smokers (P<0.001). Among patients with tumors harboring METex14, the most common histology was adenocarcinoma (60.8%), followed by squamous cell carcinoma (10.7%), sarcomatoid (3.9%), adenosquamous carcinoma (2.8%), and large cell carcinoma (0.2%) (8). The remaining 21.6% of cases were classified as “other NSCLC” (mixed histology or incomplete histologic information available).

MET AMP

MET AMP is characterized by an increase in the WT MET gene copy number (GCN) on chromosome 7, resulting in overexpression of the c-MET protein (6). This effectively reduces or eliminates the need for ligand activation of the receptor, resulting in sustained or altered signaling (12). MET AMP may occur as either a de novo mutation or, more commonly, as an acquired mutation after targeted therapy against another oncogenic driver such as EGFR. De novo WT MET AMP as the sole oncogenic driver in NSCLC is considered to be a rare occurrence, with MET AMP more commonly occurring together with another oncogenic driver (13). In some cases, MET AMP may accompany METex14, which is thought to potentiate the oncogene addicted state (13). Notably, while concomitant MET AMP among patients with METex14 does not seem to impact response to MET inhibition, studies of patients with MET AMP in the absence of METex14 suggest that higher levels of MET AMP increase response to MET inhibition (14,15). There also appears to be less overlap with other oncogenic drivers at higher levels of MET AMP, suggesting that there is in fact a role of MET AMP as an independent driver (14).

“High-level” MET AMP is considered an emerging biomarker in NSCLC, and work is ongoing to standardize the way that we identify and define this alteration in a clinically meaningful way. Currently, MET AMP is most effectively detected by fluorescent in situ hybridization (FISH), though NGS may also be used. As a continuous variable, the threshold for “high-level” amplification is evolving, and outcomes differ depending on the assay used for testing. Using FISH, MET AMP may be defined by the number of gene copies per cell (MET GCN), though this method does not distinguish gene amplification (thought to drive oncogenesis) from chromosome 7 duplication (unlikely to drive oncogenesis) (4,6). Alternatively, a FISH probe designed to detect the ratio between the number of copies of MET and the centromere of chromosome 7 (CEP7) can help to distinguish between true MET AMP (MET GCN gain) vs. polysomy (chromosome 7 duplication). MET-to-CEP7 ratios (MET/CEP7) ranging 1.8–2.2 have been used in different studies to define MET AMP, and the subjective nature of manual FISH analysis contributes further to inconsistent results between trials and in clinical application (14,16,17). In one study evaluating the efficacy of crizotinib among patients with advanced/metastatic MET AMP NSCLC, responses were found to vary by level of amplification as defined by MET/CEP7 ratio (18). In this study, MET AMP was classified as high (MET/CEP7 ≥4), medium (MET/CEP7 >2.2 to <4), or low (MET/CEP7 ≥1.8 to ≤2.2). Among 38 patients with MET AMP treated with crizotinib, those with high-level MET AMP responded to crizotinib with the highest objective response rate (ORR). Notably, responses were observed among patients with MET AMP without concurrent METex14, and response rates among patients with MET AMP were higher when patients with other oncogenic drivers were excluded. Within the limitations of the small sample size, these findings support both the role of high-level MET AMP as an independent oncogenic driver and the potential for clinical benefit from MET inhibition in this setting (18). These findings also highlight the critical importance of defining standardized diagnostic thresholds to inform interpretation of efficacy outcomes and selection of patients who will benefit most from targeted therapy.

Finally, NGS can also be used to detect MET AMP. Similarly, standardized values defining MET AMP using NGS are not well established and outcomes can vary significantly between assays and sampling methods (tissue, plasma) (6). Per the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC (Version 8.2025), for tissue NGS-based results, a GCN ≥10 is consistent with “high-level” MET AMP (19). Cohort B of the phase II VISION trial used a GCN ≥2.5 as detected by liquid biopsy to define “high-level” MET AMP, which selected ~1.5–2% of NSCLCs, corresponding to the same fraction of patients with “high-level” MET AMP detected using a cutoff of ≥10 in tissue biopsies (17). In this cohort, tepotinib demonstrated antitumor activity with an ORR of 41.7%, though the investigation was halted due to early progression in about 1/3 of patients within the first 3 months of treatment. This trial is discussed in greater detail in the section on Type IB MET TKIs. It is included briefly here to demonstrate the ongoing variability between standing guidelines and methods used in large trials to identify MET AMP, and associated challenges interpreting results.

De novo MET AMP is estimated to occur in about 1–5% of cases of NSCLC and is associated with poor prognosis (13). Acquired MET AMP is much more common, found in up to 20–25% of patients with EGFR-mutated (EGFRm) NSCLC after progression on an EGFR TKI. Notably, definitive characterization of the epidemiology and clinical implications of MET AMP is limited by the challenges described above, including variability of diagnostic techniques and poorly defined threshold values across studies. With suspected impact on prognosis for a large population of patients as well as potential for clinical benefit in response to MET-targeted therapy, further work is needed to standardize diagnostic and treatment strategies for MET AMP NSCLC.

MET OE

The most common cause of MET protein overexpression is thought to be transcriptional up-regulation of the MET protein receptor without associated gene amplification (16,20). Similar to MET AMP, overexpression of the receptor may effectively reduce or eliminate the need for ligand activation and result in sustained or altered signaling (12). The true clinical and therapeutic significance of MET OE remains poorly defined and highly debated, however (13,16). While high levels of MET expression do appear to be associated with poor prognosis in NSCLC, the predictive value of MET OE as well as efficacy of MET inhibitors (METi) in the absence of other MET alterations is unclear (6,16,21). Difficulty characterizing the implications of MET OE is multifactorial, with contributions including uncertainty regarding whether measures of MET OE reliably predict MET receptor activation, significant variability in the diagnostic classification of MET OE, and inconsistent data regarding sensitivity to MET targeted therapy (4).

Recall that MET is activated by the binding of HGF to the extracellular domain of the protein, resulting in homodimerization, and trans- and auto-phosphorylation of tyrosine kinases in the catalytic domain and c-terminus. This ultimately allows binding of adapter proteins that facilitate activation of several downstream pathways, many of which have been implicated in tumorogenesis, including PI3K, MAPK, and STAT3 (22). While some studies have demonstrated a correlation between overexpression of the MET protein receptor (c-MET) and ligand-activated or phosphorylated MET (p-MET), this does not appear to be true in all cases (22). This has led to questions regarding whether MET OE can truly be used as a marker for activated MET signaling. Notably, high expression of two forms of p-MET (cytoplasmic expression of Y1003 and nuclear expression of Y1365) have been shown to be negative predictors for OS (7,12). p-MET expression, in addition to c-MET expression, remain biomarkers of interest and areas of active investigation in the targeted management of NSCLC.

MET expression is most effectively assessed via IHC. Due to great intratumoral heterogeneity and experimental variability, there are again significant challenges reliably defining MET OE (22). Strength of IHC staining is typically interpreted on a scale of 0–3+, with MET OE commonly, though not consistently, defined as a score of 2+ or 3+ in ≥50% of cells (4,6,21,23). Alternatively, an H-score ranging 0–300 may be used, with a score >150–200 typically indicating overexpression (4,23). Studies that have looked specifically at subsets of patients with MET OE (variably defined) have not consistently shown response to METi. Notably, while MET OE may co-occur with METex14 or MET AMP, expression level as measured by IHC is felt to be a poor surrogate for either alteration, and should not be used as a screening tool in this setting (13,21).

MET OE in NSCLC has a variable, though overall quite high, incidence, ranging anywhere from about 15–75% depending on assay used for detection and positive threshold (6,7,16,20,23). This is a poorly defined, though rapidly growing space with implications on a potentially large population of patients. In May 2025, Teliso-V, a c-MET-directed antibody and microtubule inhibitor conjugate, became the first U.S. FDA approved therapy specifically for the use in patients with high c-MET OE as determined by IHC (details elaborated in the section on ADCs). The therapeutic significance of MET expression in patients with NSCLC will likely continue to evolve with additional investigations.

MET FUS

MET FUS occurs when a chromosomal translocation leads to fusion of MET with a portion of another gene. This is extremely rare in NSCLC, with a frequency of <1% (24). One study searched for patients with NSCLC harboring MET FUS within the routine molecular screening program of the national Network Genomic Medicine in Germany (25). They found a cohort of nine patients with NSCLC and MET FUS primarily identified by RNA sequencing. The overall frequency was 0.29% [95% confidence interval (CI): 0.15–0.55%] and cases were exclusively adenocarcinoma. There were five different fusion partners: KIF5B, TRIM4, ST7, PRKAR2B, and CAPZA2, with several breakpoint mutations including MET Exon 2, 3, 6, 14, 15, and 20. Four patients received a MET TKI in the second line. Two of those patients had a partial response (PR), one had stable disease (SD), and one (with co-occurring TP53 mutation) had progressive disease (PD). While MET FUS remains an area of ongoing investigation in NSCLC, several challenges are highlighted here. First, given the rarity of this alteration, clinical experience and feasibility of large trials is limited. Further, MET FUS are highly heterogeneous, with various fusion partners and breakpoint mutations as demonstrated in the trial above, and it may be limiting to generalize detection and treatment strategies across this diverse subgroup. Larger sample sizes are needed to better characterize MET FUS as potentially targetable molecular drivers.

Targeting the MET axis

Diverse mechanisms of MET axis dysregulation offer multiple unique therapeutic approaches. Several strategies have been evaluated and are currently under investigation to target different parts of the MET axis, including MET TKIs, anti-MET and anti-HGF antibodies, bispecific antibodies (B-Abs), and ADCs (4,6). The role of immune checkpoint inhibitors (ICIs) in MET-altered NSCLC is complex, and highly personalized therapy depending on patient and tumor characteristics is necessary.

Multi-kinase METi and selective MET TKIs

TKIs are small molecule inhibitors that block the activation of tyrosine kinases, such as MET, by binding to their active site and preventing expected ligand binding and downstream signaling. MET TKIs can be divided into three groups based on their structure and specific binding mechanism (6). Type I and II MET TKIs are both competitive inhibitors of adenosine triphosphate (ATP), while type III MET TKIs bind allosterically outside the ATP pocket. Type I inhibitors bind MET in its active conformation, while type II inhibitors bind MET in its inactive conformation. Type I inhibitors are further subdivided into groups “IA” and “IB” based on their selectivity. While both subtypes function by filling the ATP-binding pocket, binding to the activation loop (A-loop), and blocking catalytic activation, type IA MET TKIs are considered “non-selective” inhibitors based on their interaction with the solvent front residue G1163, which is not specific to MET. Conversely, type IB MET TKIs selectively interact with MET via the Y1230 residue (6).

Type IA MET TKIs

Crizotinib is a non-selective, small molecule, type IA inhibitor that exerts action against several tyrosine kinases, including MET, ALK, ROS1, and RON. While it has demonstrated some efficacy against METex14 and MET AMP, it has only been FDA approved for the treatment of advanced/metastatic NSCLC harboring ALK and ROS1 rearrangements. In 2018, the FDA granted crizotinib breakthrough therapy designation for the treatment of patients with metastatic NSCLC with METex14 after progression on prior platinum-based chemotherapy. This was based on the results of the phase I PROFILE 1001 trial, the first prospective trial to demonstrate that MET inhibition is active in NSCLC harboring METex14 (Table 2). In an expansion cohort including 69 patients with advanced/metastatic NSCLC harboring METex14, the ORR was 32% (95% CI: 21–45%) (26). Median progression-free survival (mPFS) was 7.3 months (95% CI: 5.4–9.1), and median overall survival (mOS) was 20.5 months (95% CI: 14.3–21.8, immature at the time of publication). These outcomes were noted to exceed responses observed with second-line (2L) chemotherapy and to be comparable to responses seen with first-line (1L) platinum doublet-chemotherapy in advanced/metastatic NSCLC, though with an ORR significantly lower compared to therapies targeting other molecular drivers such as EGFR (26), and compared to more selective METi.

In a subset analysis of PROFILE 1001, 38 patients with MET AMP as defined by MET/CEP7 ≥1.8 were evaluated and also demonstrated response to crizotinib, with the highest ORR (38.1%, 95% CI: 18.1–61.6%) seen among those with the highest level of amplification (Table 2) (18). Patients were considered to have high (MET/CEP7 ≥4, n=21), medium (MET/CEP7 >2.2 to <4, n=14), or low (MET/CEP7 ≥1.8 to ≤2.2, n=3) amplification as assessed by FISH. mOS was 11.0 months (95% CI: 7.1–15.9) across the entire population, with the longest OS again observed in the highest amplification group (11.4 months, 95% CI: 7.2–19.3). Notably, response was seen in 100% (n=15) of evaluable patients without concurrent METex14, supporting the use of gene amplification as measured by MET/CEP7, independent from discrete gene rearrangement, as an actionable therapeutic target. In this study, a direct comparison between MET AMP detection methods was conducted and demonstrated some, though not absolute, concordance. Among 19 patients with adequate tissue available for retrospective NGS, 8/9 (88.9%), 6/7 (85.7%), and 1/3 (33.3%) patients with high, medium, and low amplification, respectively, had MET AMP detectable by NGS (GCN ≥6). This included all patients who responded to crizotinib. Ten patients with high MET AMP as defined by MET/CEP7 ≥4 (excluding two with concurrent EGFRm) had no objective response to crizotinib, however, indicating that this classification of MET AMP does not necessarily guarantee response to METi. While the data from this subset analysis support MET AMP as an actionable subtype overall, significant limitations remain, including variability of diagnostic techniques, poorly defined threshold values, and lack of understanding of concomitant clinical and pathologic factors influencing response to therapy.

Cohort B of the phase II METROS trial (27), which evaluated crizotinib among patients with METex14 or MET AMP (MET/CEP7 >2.2) NSCLC, as well as the phase II AcSe trial (28), which evaluated crizotinib among patients with a MET mutation, MET AMP (GCN ≥6), or ROS-1 translocation, found less robust response rates among patients with MET alterations (Table 2). Overall, studies of crizotinib in MET-altered NSCLC have not yet demonstrated sufficient benefit to warrant regulatory approval for this indication.

Ensartinib is another non-selective, multi-kinase inhibitor that demonstrates type IA activity against MET. It was recently FDA approved in December 2024 for the treatment of ALK-positive NSCLC. In a study evaluating ensartinib in patients with NSCLC harboring METex14, robust outcomes were observed in two cohorts (Table 2) (29). In cohort 1, ensartinib was administered for compassionate use to 18 patients with advanced/metastatic NSCLC with METex14 [as determined by reverse transcriptase polymerase chain reaction (RT-PCR) or NGS] and without EGFR mutation or ALK fusion. In cohort 2 (phase II trial cohort), patients had to meet the same requirements as cohort 1 and further had to be TKI naïve with progression after at least one prior cycle of platinum-based chemotherapy. Among 29 total evaluable patients, ORR and disease control rate (DCR) were 67% and 94% in cohort 1, and 73% and 91% in cohort 2, respectively. Notably, the adverse event (AE) profile differed from most other MET TKIs, for which peripheral edema is typically observed as one of the most common class-based side effect. In this study, rash was the most common treatment-related AE (trAE), seen in 59% of patients (any grade). Peripheral edema was only seen in 10% of patients (29).

More recently, the phase II EMBRACE trial evaluated the safety and efficacy of ensartinib in the subsequent line setting (no prior MET-TKI) among patients with NSCLC harboring METex14 (Table 2) (30). Results were again robust, with ORR 53.3% (95% CI: 35.5–71.2%) and DCR 86.7% (95% CI: 74.5–98.8%). Rash was again the most common trAE (46.7%) and peripheral edema was seen in only 13.3%. While not yet FDA approved for the use in MET-altered NSCLC, ensartinib represents another encouraging targeted treatment option for patients with METex14. If ongoing studies demonstrate sustained and durable response with persistence of a safety profile that is distinct from other MET TKIs, ensartinib has the potential to expand the treatment landscape, particularly for patients unable to tolerate other MET TKIs due to severe peripheral edema.

Type IB MET TKIs

Until May of 2025, capmatinib and tepotinib, two selective type IB MET TKIs, were the only agents approved in the US for the indication of targeting MET in NSCLC. Both are approved for patients with advanced/metastatic NSCLC harboring METex14. These approvals were based on the GEOMETRY mono-1 and the VISION trials, respectively (Table 3). Both trials demonstrated robust systemic and central nervous system (CNS) anti-tumor activity.

GEOMETRY mono-1 was a multi-cohort, phase 2 trial evaluating the safety and efficacy of capmatinib for the treatment of advanced/metastatic, MET-altered NSCLC (31,32). The study included adults with stage IIIB–IV, EGFR WT and ALK negative, MET-altered (METex14 or MET AMP) NSCLC. Patients were assigned to cohorts based on MET status (GCN ≥10, GCN 6–9, GCN 4–5, GCN <4, or METex14 and any GCN) and prior lines of therapy (no prior therapy or 1–2 prior lines of therapy). Of note, for patients with METex14, any GCN was allowed. However, for patients enrolled into a MET AMP cohort, no concurrent METex14 was allowed. Cohorts 1b (1–2 prior lines of therapy, GCN 6–9), 2 (1–2 prior lines of therapy, GCN 4–5), and 3 (1–2 prior lines of therapy, GCN <4) were closed due to futility.

In an updated, final analysis of 160 patients with advanced/metastatic NSCLC harboring METex14, robust safety and efficacy outcomes were noted to be durable after a median follow-up of 46.4 months, particularly in the 1L (32). An ORR of 68% (95% CI: 55.0–79.7%) was observed among treatment naïve patients (cohorts 5b and 7), one of the highest response rates reported to date with MET TKIs in this setting. ORR was 44% (95% CI: 34.1–54.3%) among previously treated patients (cohorts 4 and 6). Considering 28 patients with METex14 and evaluable brain metastases (BM) at baseline [13 received prior intracranial radiation therapy (RT)], 57% had intracranial complete response (CR) or PR, including nine with CR.

Considering patients with MET AMP, an interim analysis demonstrated ORRs of 12% (95% CI: 4–26%), 9% (95% CI: 3–20%), and 7% (95% CI: 1–22%) among previously treated patients with GCN 6–9, 4–5, and <4, respectively, leading to the closure of these cohorts for futility (31). Among 84 patients with GCN ≥10, ORR was 29% (95% CI:19–41%) of 69 previously treated patients and 40% (95% CI: 16–68%) of 15 treatment naïve patients. Median DOR (mDOR) was 8.3 months (95% CI: 4.2–15.4) and 7.5 months (95% CI: 2.6–14.3), and mPFS was 4.1 months (95% CI: 2.9–4.8) and 4.2 months (95% CI: 1.4–6.9), respectively (31). In an exploratory analysis conducted as part of the updated, final analysis described above, higher ORRs were observed among patients with focal MET AMP as compared to non-focal MET AMP, and patients with focal MET AMP also had numerically higher MET gene expression (32). This data suggests that patients with focal MET AMP and high MET gene expression may also benefit from targeted therapy with capmatinib, though sample sizes were small. Among all patients in the study at the time of data update (n=373, data cutoff March 2020), peripheral edema (47%) and nausea (35%) were the most common AEs (32). Toxicity profile was noted to be consistent with what was previously reported, with no new safety signals.

Overall, Geometry mono-1 has demonstrated long-term evidence for the use of capmatinib in the front- and subsequent-lines for advanced/metastatic NSCLC harboring METex14 and reemphasizes the need for further refinement of our identification and management of patients with MET AMP.

The VISION trial was a multi-cohort, phase 2 trial evaluating the safety and efficacy of tepotinib for the treatment of advanced/metastatic, MET-altered NSCLC. The study included patients with stage IIIB–IV, EGFR WT and ALK negative, MET-altered (METex14 or MET AMP) NSCLC. Patients were assigned to cohorts based on MET status (cohort A: METex14; cohort B: MET AMP with no METex14; cohort C: METex14 confirmatory of cohort A) (38).

In an updated analysis of 313 patients across cohorts A and C (METex14, detected by tissue and/or liquid NGS), 149 patients had received prior therapy and 164 patients were treatment naïve (33). Durable and clinically meaningful responses to tepotinib were seen in both groups, though particularly in the 1L setting. Among previously treated patients, ORR was 45.0% (95% CI: 36.8–53.3%), mDOR was 12.6 months (95% CI: 9.5–18.5), mPFS was 11.0 months (95% CI: 8.2–13.7), and mOS was 19.3 months (95% CI: 15.6–22.3). Responses were higher among treatment naïve patients, with ORR 57.3% (95% CI: 49.4–65.0%), mDOR 46.4 months [95% CI: 13.8–not evaluable (NE)], mPFS 12.6 months (95% CI: 9.7–17.7), and mOS 21.3 months (95% CI: 14.2–25.9). CNS efficacy was demonstrated in 57 patients with baseline BM, with an ORR (systemic and CNS) of 56.1% (95% CI: 42.4–69.3%). Among 15 patients with baseline BM evaluable by Response Assessment in Neuro-Oncology (RANO) criteria (12 with prior brain RT), intracranial ORR was 66.7% (95% CI: 38.4–88.2%). Peripheral edema was the most common trAE (67.1%) observed with tepotinib, consistent with a known class effect of MET TKIs.

In an updated analysis of 24 patients enrolled in cohort B (high-level MET AMP, detected by liquid biopsy assay with MET GCN ≥2.5, no concomitant METex14, EGFR, or ALK mutation), ORR was 41.7% (95% CI: 22.1–63.4%) (17). ORR was higher among treatment naïve patients (71.4%) compared to those who had received one (27.3%) or two (33.3%) prior lines of therapy. Notably, PD was the best response in 20.8% of all patients. The study was stopped early before enrollment of the planned sample size (n=60) due to high rate of early progression during the first 3 months. While some anti-tumor activity was observed among patients with MET AMP as defined in this cohort, classifying and targeting MET AMP in a clinically meaningful way and identifying patients who will benefit most from targeted therapy remains challenging. These are areas of ongoing investigation.

Overall, data from the VISION trial continue to support global approvals for the use of tepotinib in the front- and subsequent-lines for patients with advanced/metastatic NSCLC harboring METex14 (33). “High-level MET AMP” remains an emerging biomarker, with diagnostic thresholds and clinical utility that continue to be refined. Tepotinib and capmatinib are treatment considerations in this space (19).

Other type IB MET TKIs are under investigation for the use in patients with primary MET alterations, including savolitinib (approved in China) (34,35), gumarontinib (36), and bozitinib (4,37,39). Results from a sample of notable trials are included in Table 3.

Type II MET TKIs

Cabozantinib, glesatinib, merestinib, and foretinib are notable type II MET TKIs presently in different stages of investigation and clinical development for use in patients with MET-altered NSCLC (4,39). Until very recently, data has primarily been limited to the pre-clinical and early phase settings, and none of these agents has yet to demonstrate sufficient efficacy to receive regulatory approval in the US for this indication.

Cabozantinib, an oral type II multikinase inhibitor with MET activity, very recently became the first type II MET TKI to demonstrate antitumor activity in a phase II trial evaluating MET-altered NSCLC, including patients previously treated with a MET TKI. In this phase II, single arm study, 28 patients with advanced/metastatic NSCLC harboring various MET alterations [METex14 (82%), MET AMP (7%), and concurrent METex14 and MET AMP (11%)] were enrolled (Table 4) (40); 86% of patients were previously treated with a MET TKI. Among 25 evaluable patients, the ORR was 20% (95% CI: 8.9–39.1%), meeting the study’s primary endpoint. Notably, however, PD was the best response in 12% of patients and 0 patients had CR. All patients with PR had METex14, and one had concurrent MET AMP. Side effects were consistent with previous reports for cabozantinib in other tumor types, including fatigue (39%), diarrhea (39%), palmar-plantar erythrodysesthesia (35%), anorexia (36%), and hypophosphatemia (32%). While the ORR was modest and lower than what we have seen with type I MET TKIs, this represents progress in an area of unmet need, particularly given the efficacy in previously treated patients. Next generation MET TKIs and other agents with distinct mechanisms of action are necessary to overcome emerging resistance mechanisms and offer options after progression on available type I TKIs.

Glesatinib is an investigational, oral, competitive ATP-inhibitor of MET in addition to AXL, VEGFR1-3, RON, and TIE2 (6,41). In an open label phase II study evaluating glesatinib in patients with advanced/metastatic, previously treated NSCLC with MET alterations, only modest clinical activity was demonstrated, resulting in early study termination (Table 4) (41). Patients included those with MET activating mutations identified either in tumor tissue or via circulating tumor DNA [ctDNA; determined by NGS or polymerase chain reaction (PCR), included mutations causing exon 14 skipping or certain recurrent missense mutations in MET] as well as those with MET AMP (identified in either tumor tissue or via ctDNA, defined by MET/CEP7 ratio >5.0 or ≥10 copies of MET per nucleus by MET 2-color FISH, or >8 copies by DNA sequencing). Across all patients (n=68), ORR was 11.8% (95% CI: 5.22–21.87%), mDOR was 4.3 months (range, 2.5–9.4 months), mPFS was 4.0 months, and mOS was 7.0 months. Among patients with activating MET mutations, ORR was 10.7% (95% CI: 2.27–28.23%) by tissue testing and 25.0% (95% CI: 3.19–65.09%) by ctDNA. Among patients with MET AMP, ORR was 15.0% (95% CI: 3.21–37.89%) by tumor tissue testing, with no responses observed by ctDNA. The most frequent AEs were diarrhea (82.4%) and nausea (50%), with a lower-than-expected incidence of peripheral edema (14.7%). Investigators pointed to possible suboptimal bioavailability and target inhibition with glesatinib in this trial, which could explain both the lack of MET TKI class effect AEs (notably peripheral edema) in addition to inferior clinical outcomes when compared to approved MET-targeting agents. Another phase II trial evaluating glesatinib in combination with nivolumab in NSCLC (NCT 02954991) was terminated. There is currently no definitive clinical data to suggest efficacy in METex14 or MET AMP (39).

Merestinib and foretinib are two additional oral, competitive ATP-inhibitors with multikinase inhibitory activity, including type II action against MET. Preclinical and early studies have demonstrated promising results, however the efficacy of these drugs has not yet been demonstrated in robust clinical trials among patients with MET altered NSCLC (4,6,39).

Type III MET TKIs

No type III MET TKIs have been approved for clinical use, and there is only one drug (tivantinib) that has been in clinical development for use in MET-altered NSCLC. Tivantinib is an oral, allosteric METi, though its exact mechanism of action against MET and efficacy in MET-altered NSCLC remains controversial and uncertain (39). The phase III MARQUEE trial set out to evaluate the safety and efficacy of tivantinib plus erlotinib vs. erlotinib plus placebo in previously treated patients with locally advanced/metastatic nonsquamous NSCLC (Table 5) (42). The study was discontinued for futility at the interim analysis, as OS did not improve with combination therapy compared to erlotinib alone. Notably, exploratory analysis suggested a non-significant trend toward OS improvement among patients with high MET expression (mOS 9.3 vs. 5.9 months, HR 0.70, 95% CI: 0.49–1.01; evaluated using IHC with expression defined as high if membranous staining intensity was ≥2 in ≥50% of tumor cells). There was also an improvement in PFS in patients with high MET expression (mPFS 3.7 vs. 1.9 months, HR 0.72, 95% CI: 0.52–0.99). A non-significant trend toward longer OS was seen among those with MET GCN >4 (HR 0.83, 95% CI: 0.43–1.61; evaluated by FISH), though sample sizes were small. The phase III ATTENTION trial, evaluating erlotinib with or without tivantinib in Asian patients with previously treated stage IIIB/IV non-squamous NSCLC with WT EGFR (including stratification by MET expression and GCN), was terminated early due to higher levels of interstitial lung disease in the tivantinib group (43).

Monoclonal antibodies

Anti-HGF antibodies

Monoclonal antibodies targeting HGF have largely been ineffective in NSCLC. Rilotumumab, an IgG2 antibody that targets and neutralizes HGF thereby preventing MET activation, was evaluated in a phase I/II trial in combination with erlotinib in 45 individuals with previously treated NSCLC (44). Patients received a combination of rilotumumab 15 mg/kg and erlotinib 150 mg daily. The study found a mPFS of only 2.6 months (90% CI: 1.4–2.7) and a mOS of 6.6 months (90% CI: 5.6–8.9). The safety profile was acceptable; however, the survival rates were comparable to standardized published reports for erlotinib monotherapy. Rilotumumab has largely been abandoned for future analysis in this setting.

Ficlatuzumab is a humanized anti-HGF antibody that was initially evaluated in patients with various solid malignancies. In a phase II study evaluating 188 previously untreated individuals with NSCLC (not selected for EGFR or MET mutational status), patients were randomized to receive gefitinib or gefitinib plus ficlatuzumab (45). Unfortunately, the study demonstrated minimal efficacy, with no significant difference in ORR or PFS between treatment arms. Interestingly, the results showed some efficacy of combination therapy in the c-MET low expressor subset with concomitant EGFRm. This is theorized to be due to a potential delay in EGFR TKI resistance through HGF inhibition in this subgroup (46). Further research is needed to understand HGF inhibition in this setting.

Anti-MET antibodies

Anti-MET antibodies have been largely ineffective in NSCLC as well. Onartuzumab is a monovalent antibody produced with Fab fragments that block the high-affinity binding of the HGF alpha chain to c-MET (47). In a phase II trial evaluating previously untreated patients with advanced/metastatic squamous NSCLC, individuals were randomized to receive platinum-based chemotherapy plus onartuzumab or placebo (48). Randomization was stratified based on MET status (IHC positive: 2+ or 3+; IHC negative: 0 or 1+). ORR and OS were not significantly different between treatment arms in the intention-to-treat (ITT) or the MET positive populations. Four patients in the combination arm had grade 5 trAEs consisting of pneumonitis, pneumonia, cardiac failure, and unexplained death, though only 1 (unexplained death) was felt to be related to onartuzumab. Overall, the safety profile of the combination was assessed to be manageable, and no new safety signals were observed. However, in the setting of overall lack of clinical benefit, these results contributed to the termination of further development efforts of onartuzumab for squamous cell NSCLC.

Onartuzumab was also evaluated in the randomized phase III METLung study, where the addition of onartuzumab to erlotinib did not improve outcomes compared to erlotinib alone. This study evaluated 499 previously treated individuals with locally advanced/metastatic NSCLC selected by positive MET IHC (IHC 2+ or 3+ in ≥50% of tumor cells) (49). Individuals were randomized to receive onartuzumab 15 mg/kg every three weeks plus erlotinib 150 mg daily or erlotinib monotherapy. Notably, prior treatment with an EGFR TKI was not permitted. Approximately 11% of patients in each group had a concomitant EGFRm and there was no significant association between EGFR mutational status and treatment outcomes. mOS was 6.8 months for combination therapy vs. 9.1 months for erlotinib monotherapy, with a greater number of deaths in the onartuzumab arm, contributing further to evidence against the use of onartuzumab among patients with MET-altered NSCLC.

Emibetuzumab is a bivalent, humanized, anti-MET IgG4 monoclonal antibody that promotes internalization and c-MET degradation (50). In a phase II trial evaluating 141 previously untreated patients with metastatic, EGFRm NSCLC, participants were randomized to receive erlotinib with or without emibetuzumab after demonstrating disease control after an 8-week lead-in with erlotinib monotherapy (51). Patients were stratified by MET expression for a preplanned exploratory analysis (IHC ≥2+ in ≥60% or <60% of cells). No significant PFS or OS benefit was observed when comparing treatment arms in the ITT population or among those above or below the 60% MET expression cutoff. In an exploratory analysis of those with highest MET expression (IHC 3+ in ≥90% of tumor cells), a clinically meaningful improvement in mPFS was observed with the addition of emibetuzumab (20.7 vs. 5.4 months, HR 0.39, 90% CI: 0.17–0.91). This was hypothesized to be due to high MET expression acting as a co-stimulatory driver mutation, with these patients benefiting from concurrent targeting of MET and EGFR signaling. Patients with the previously defined highest level of MET expression treated with erlotinib alone had shorter PFS compared to those below this MET expression threshold, indicating that high MET expression is a negative prognostic biomarker in EGFRm NSCLC. While the study did not meet its primary endpoint to support the use of emibetuzumab in combination with erlotinib to improve PFS among those with advanced/metastatic EGFRm NSCLC, this data contributes to a growing field of knowledge regarding the prognostic and therapeutic significance of MET expression.

Sym015 is a balanced 1:1 mixture of two MET-targeting monoclonal antibodies (Hu9006 and Hu9338) that has shown promising outcomes in the pre-clinical and early clinical settings. The compound triggers MET degradation and demonstrated preclinical efficacy and safety data in xenograft models (52). Sym015 was evaluated in a phase IIa trial including 20 patients with NSCLC harboring either METex14 or MET AMP, and demonstrated a response rate similar to some type II MET TKIs (53). Five patients demonstrated PR (ORR 25%), 11 had SD (DCR 80%), 2 had PD, and 2 were not evaluable. mPFS was 5.5 months (95% CI: 3.5–9.7), with slightly greater benefit among TKI naïve patients (mPFS 6.5 vs. 5.4 months, respectively). Grade 3 or greater trAEs occurred in 13.3% of patients with the most common being fatigue (13.3%) and peripheral edema (11.1%). Larger scale clinical studies are necessary to further investigate the use of this compound both alone and in combination with MET TKIs.

B-Abs

B-Abs are designed to target two antigens or epitopes simultaneously (54). Amivantamab, a fully human B-Ab targeting both EGFR and MET, was initially FDA approved in the U.S. in May 2021 for the treatment of patients with advanced/metastatic NSCLC harboring EGFR exon 20 insertions after progression on or after platinum-based chemotherapy. It has subsequently been approved for this population in combination with chemotherapy in the 1L setting, in combination with lazertinib for 1L treatment of advanced/metastatic NSCLC harboring EGFR exon 19 deletion (ex19del) or L858R mutations, as well as in combination with chemotherapy among those harboring EGFR ex19del or L858R after progression on an EGFR TKI.

Given its bispecific nature, amivantamab is also under investigation and has demonstrated anti-tumor activity in MET-driven NSCLC (55). The CHRYSALIS trial is an ongoing phase I study of amivantamab in advanced/metastatic NSCLC (Table 6). Two cohorts in this trial, MET-1 and MET-2, were designed to evaluate the use of amivantamab among those with primary EGFRm disease with documented MET alteration after progression on an EGFR TKI (MET-1), as well as those with primary METex14 (MET-2) (56,60,61). In an updated, final analysis of data from the MET-2 cohort, durable and clinically meaningful antitumor activity was observed (56). In this cohort, 97 patients with primary METex14 were treated with amivantamab monotherapy. Sixteen were treatment naïve, 28 were previously treated with no prior exposure to a METi, and 53 had a prior METi. ORR was 32% in the whole population. ORR was higher among treatment naïve patients (50%) and those with no prior METi (46%), compared to those with prior METi exposure (19%). AE profile was consistent with prior studies of amivantamab, with the most common events including rash (79%), infusion reaction (72%), and paronychia (45%), and with 48% of patients experiencing grade 3 or higher trAEs. Amivantamab has been approved for the treatment of advanced/metastatic EGFRm NSCLC despite the known toxicity profile, and efforts are underway to improve the safety and tolerability of this drug (62-64). Considering the robust efficacy outcomes seen in this trial among those without prior exposure to METi, as well as similar or improved outcomes compared to standard of care subsequent line therapies recommended after failure of a MET TKI (chemotherapy, IO), updated results from the CHRYSALIS trial contribute to building evidence supporting the use of amivantamab in the front- and subsequent lines for the treatment of NSCLC harboring METex14. If approved, the toxicity profile will certainly play a role in treatment decisions, emphasizing the importance of current efforts to prevent and mitigate AEs.

The ongoing phase I/II METalmark trial aims to investigate the use of amivantamab plus capmatinib among patients with METex14 and MET AMP, with the goal of achieving more potent inhibitory action by targeting both intra- and extra-cellular regions on MET. Currently, there is phase I dose selection data available and only very early evidence of antitumor activity in small numbers of patients with METex14 and MET AMP (Table 6) (57,58). Davutamig (REGN5093), a MET-MET B-Ab that binds two distinct epitopes of MET, is also in clinical development. A phase I/II first-in-human trial (NCT04077099) evaluating davutamig among patients with advanced/metastatic NSCLC harboring METex14, MET AMP, or MET OE has demonstrated early signs of safety and efficacy (Table 6) (59). Work is ongoing in this area.

ADCs

ADCs work by identifying the c-Met receptor with precision and then deploying highly cytotoxic payloads selectively to targeted cells (65). This induces tumor cell apoptosis irrespective of downstream signaling, while providing additional diffusion to neighboring cells generating a bystander effect.

Teliso-V is a first-in-class c-MET-directed ADC composed of telisotuzumab coupled with a cytotoxic payload, monomethyl arustatin E (MMAE), through a valine-citrulline linker (66). After binding to c-MET, Teliso-V is internalized. MMAE then binds to tubulin and prevents polymerization, ultimately resulting in cell-cycle arrest and apoptosis. On May 14, 2025, Teliso-V was granted accelerated approval by the U.S. FDA for the subsequent line treatment of adults with advanced/metastatic, non-squamous NSCLC with high MET OE, becoming only the third approved therapy for MET-altered NSCLC and the first drug specifically targeting MET OE, significantly expanding the landscape and addressing a previously unmet need. As discussed, prior to this approval there were only two type Ib MET TKIs approved for the treatment of NSCLC harboring METex14, limiting targeted treatment options to only a small cohort of MET-altered NSCLC, and all within a single drug class.

Approval of Teliso-V was based on LUMINOSITY trial, a phase II study evaluating the ADC in patients with advanced/metastatic NSCLC with c-MET protein OE defined by IHC: ≥25% of tumor cells with 3+ membrane staining (high: ≥50% 3+; intermediate: ≥25–<50% 3+) (67,68). Patients with ≤2 lines of prior systemic therapy were enrolled into one of three cohorts defined by histology and EGFR mutational status: non-squamous EGFR WT; non-squamous EGFRm; and squamous. Individuals in the non-squamous cohorts were further stratified by degree of MET OE (high vs. intermediate). Notably, the squamous and non-squamous EGFRm cohorts met criteria for futility at interim analyses. In an updated analysis of patients with non-squamous, EGFR-WT NSCLC with a median follow-up time of 24.9 months, durable responses and no new safety signals were observed. Among 168 patients in this cohort, ORR was 29.2% (Table 7) (68). The benefit was heightened among those with high MET OE (ORR 34.5%) compared to intermediate (ORR 23.8%). Across all levels of MET OE, mPFS was 5.6 months (95% CI: 4.6–6.8) and mOS was 14.2 months (95% CI: 9.9–16.4). The most common any-grade trAEs were peripheral neuropathy (31%), peripheral edema (16%), and fatigue (14%).

TeliMet NSCLC-01 is an ongoing, phase III trial comparing Teliso-V to docetaxel in patients with non-squamous, EGFR WT NSCLC with MET OE as defined by IHC (3+ intensity in ≥25% tumor cells) (69). Finally, several cohorts of a phase I/Ib trial (NCT02099058) have investigated and continue to investigate Teliso-V alone and in combination with nivolumab, erlotinib, and osimertinib among patients with advanced/metastatic NSCLC that express c-MET (70-72).

There are several other ADCs targeting MET in various stages of clinical development (Table 8) (73-78).

IO

The role of IO among patients with NSCLC with actionable oncogenic driver mutations, including MET alterations, remains controversial. Unfortunately, much of the data in this space is derived from small subgroup analyses, non-controlled trials, and/or retrospective studies (79). While it is well established that high programmed death ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) are factors associated with superior response to immune checkpoint blockade (ICB) in NSCLC (80), the presence and interplay of oncogene addiction is an area that has warranted further investigation and has complicated the treatment landscape. For example, driver mutations in EGFR and ALK have been associated with a “cold” immune microenvironment based on lack of CD8⁺ tumor-infiltrating lymphocytes (TILs), and resultantly, inferior response to ICB (79,80). Further, some actionable driver mutations are more common among non-smokers in NSCLC, a population that has been associated with tumors with lower TMB, potentially resulting in decreased sensitivity to ICB compared to the smoking population (79). In clinical practice, the use of IO may be avoided among patients with some actionable drivers (namely EGFR and ALK), given historically poor response rates, significantly more robust response to targeted therapy, as well as concern for increased risk of immune-mediated toxicities when used together with or in close temporal proximity to a TKI (79). This space is complex and evolving, however, with the development of new agents, increasing understanding of unique biomarkers, and an expanding role for IO. For MET specifically, work is ongoing to understand the ideal treatment paradigm and sequencing of therapies in different patient populations.

Response to IO was evaluated retrospectively in a study of 147 patients with lung cancer of any stage harboring METex14 and demonstrated low response rates and PFS regardless of PD-L1 expression and TMB (81). Among 111 evaluable tumors, 37%, 22%, and 41% of patients were observed to have PD-L1 expression of 0%, 1–49%, and ≥50%, respectively, highlighting that MET-altered tumors may still express PD-L1 at intermediate and high levels. TMB analysis of tumors from 140 patients demonstrated a lower median TMB among patients with METex14 compared to unselected NSCLC, and no correlation between PD-L1 and TMB. Twenty-four patients who received IO were evaluable for response, with 22 receiving anti-programmed cell death protein 1 (PD-1)/PD-L1 monotherapy and 2 receiving combination anti-PD-1 and anti-Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy. Eleven patients received IO in the 1L, 6 in the 2L, and 7 in the third-line (3L). ORR was 17% (95% CI: 6–46%) and mPFS was 1.9 months (95% CI: 1.7–2.7). Outcomes were not improved among those with higher PD-L1 expression or TMB, suggesting possibly a stronger role of METex14 in the lack of robust response to therapy.

In a retrospective evaluation of patients included in the global IMMUNOTARGET registry, 551 patients with at least one oncogenic driver mutation received ICI monotherapy in the first (5%), or subsequent line (82). Thirty-six patients had MET AMP or METex14. ORR among those with MET alterations was again low at only 16% (compared to: KRAS 26%, BRAF 24%, ROS1 17%, EGFR 12%, HER2 7%, RET 6%, ALK 0%), reemphasizing that patients with certain actionable drivers, including MET, may demonstrate inferior response to ICI monotherapy and would therefore benefit from exhaustion of more effective strategies first, including targeted and/or possibly combination therapies.

A more recent retrospective real-world (rw) analysis evaluated 1L treatment with MET TKI vs. ICI +/− chemotherapy among patients with advanced/metastatic, MET-altered NSCLC. Results of subgroup analyses suggest that there is in fact a role for IO in this population and that personalization of therapy to unique patient groups is critical (83). In this study, 1L treatment choices included capmatinib or tepotinib in 33.5% of patients, ICI monotherapy in 25.9%, chemoimmunotherapy in 23.4%, crizotinib in 13.9%, and “other” MET TKI in 3.3%. Overall results demonstrated no significant difference in rwPFS or OS between those receiving 1L TKI compared to those receiving 1L ICI +/− chemotherapy. rwORR was noted to be higher among those receiving capmatinib or tepotinib (57.7%) and crizotinib (63.6%) compared to ICI monotherapy (41.0%) and chemoimmunotherapy (38.9%), however there were no significant differences in median rwPFS or OS across these treatment groups. Other key subgroup analyses demonstrated higher rwPFS in the group receiving ICI +/− chemotherapy compared to MET TKI for those with PD-L1 ≥80% (HR 0.50, P=0.03). Conversely, rwPFS and OS were higher in the group receiving TKI therapy for those with PD-L1 <50% (PFS: HR 0.40, P=0.005; OS: HR 0.49, P=0.03) and among those with BM (PFS: HR 0.39, P=0.02; OS: HR 0.36, P=0.03). rwPFS was also higher in the group receiving TKI therapy for patients with bone metastases (HR 0.55, P=0.01).

The role of IO in the treatment of patients with NSCLC harboring oncogenic drivers is highly nuanced. In MET-altered NSCLC, certain subgroups, including those with PD-L1 expression <50% and patients with brain and/or bone metastases, appear to derive greater benefit from 1L MET-targeted therapy. However, there is likely still a role for IO, particularly among those with very high PD-L1 expression, emphasizing the need for personalized treatment selection. Additionally, further investigation regarding how treatment modifies the immune microenvironment and whether the immune landscape differs between type of MET alteration would be valuable to inform 1L and sequential treatment choices. Higher-quality, prospective data would be beneficial in this space.

MET alterations as a mechanism of resistance to EGFR TKIs

The FLAURA trial shifted the standard of care from first- and second-generation EGFR TKIs to 3rd generation osimertinib for 1L treatment of advanced/metastatic NSCLC harboring activating mutations in EGFR. This is based on osimertinib’s selective inhibition of both EGFR TKI-sensitizing mutations and the common T790M resistance mutation. While data has shown very effective disease control with osimertinib in these populations, most patients will still develop resistance after about 18–19 months (84,85). Aside from histologic transformation, acquired resistance to EGFR targeted therapy may develop via EGFR-dependent (“on target”) or EGFR-independent (“off target”) mechanisms. EGFR-dependent mechanisms refer to secondary alterations in EGFR that prevent the inhibitory action of the EGFR-targeted drug, while EGFR-independent mechanisms refer to the activation of a “bypass” pathway allowing activation of downstream signaling despite inhibitory action against EGFR. MET AMP has emerged as the most common mechanism of EGFR-independent resistance to 1L osimertinib, accounting for nearly 20% of cases (86,87).

Much of the work in this space has focused on determining subsequent line treatment options targeting on- and off- target acquired resistance mechanisms once progression on a 1L EGFR TKI has occurred. In the setting of widespread, systemic progression requiring change in therapy, several strategies are under investigation, including a personalized approach, aimed at targeting known acquired resistance mechanisms, as well as an unselected approach, aimed at targeting the most frequent resistance mechanisms for patients in whom a clear secondary target is not known. Often, the strategy involves continuing the 1L EGFR TKI with the addition of other agents, with the goal of continuing to target any population of cells still sensitive to EGFR inhibition while also targeting cells harboring acquired resistance mutations (86). In patients with acquired MET AMP, concurrent inhibition of EGFR and MET is a proposed subsequent line strategy to overcome resistance to EGFR TKs that is under intensive investigation (Table 9).

In up to 40–50% of cases of disease progression on osimertinib, there is no known or detectable secondary driver mutation that can be targeted in the subsequent line. An evolving area of research has focused on a shift in the treatment paradigm to try to prevent and/or overcome the development of resistance through combination 1L therapies (Table 10). The phase 3 FLAURA-2 trial set out to evaluate whether the addition of chemotherapy in the 1L setting could potentially decrease persister cell populations that may lead to acquired resistance. In February 2024, the FDA approved osimertinib plus platinum-based chemotherapy for 1L treatment of patients with advanced/metastatic NSCLC harboring EGFR ex19del or L858R mutations based on statistically significant improvement in PFS as demonstrated by FLAURA-2 (91). The observed PFS benefit was greater among those with poor prognostic factors, including CNS disease and L858R mutation. Further, updated data presented at the World Conference on Lung Cancer in September 2025 demonstrated durable PFS benefit as well as an OS benefit (HR 0.77, 95% CI: 0.61–0.96) with osimertinib and chemotherapy compared to osimertinib alone, providing even stronger evidence for its use in the front line setting (88).

With a similar goal but slightly different approach, the phase 3 MARIPOSA trial was designed to evaluate whether 1L combination therapy with activity against common mechanisms of acquired resistance could delay progression and improve survival outcomes. In this study, patients with previously untreated, advanced/metastatic NSCLC harboring EGFR ex19del or L858R mutations were randomized to receive combination amivantamab plus lazertinib or either osimertinib or lazertinib monotherapy. Because secondary EGFR alterations and MET AMP are the most common mechanisms of resistance to 1L EGFR TKI therapy, combining an EGFR-MET B-Ab (amivantamab) with a highly selective 3rd generation EGFR TKI (lazertinib) could serve to proactively address and delay development of resistance. In August 2024, the FDA approved the combination of amivantamab and lazertinib for 1L treatment of patients with advanced/metastatic, EGFRm NSCLC based on statistically significant improvement in PFS compared to osimertinib monotherapy as demonstrated by MARIPOSA (89). Similarly to FLAURA-2, updated data from the MARIPOSA trial published in September 2025 demonstrated an OS benefit with amivantamab and lazertinib compared to osimertinib monotherapy (HR 0.75, 95% CI: 0.61–0.92) (90). With both MARIPOSA and FLAURA-2 demonstrating an OS benefit and overall similar efficacy outcomes in the 1L setting for EGFRm NSCLC, clinical decision making is challenging. Clinicians should have focused discussions with patients regarding toxicity profiles, patient comorbidities, quality of life, and patient preference when choosing a 1L regimen in this setting. Further data characterizing clinical and biological features that may drive differential response to each of these regimens will be beneficial.

Other front-line combinations are under investigation, including combination of EGFR TKIs plus chemotherapy, antiangiogenic drugs, or ICIs, as well as TKI combinations (86).

Mechanisms of resistance to MET-TKIs

Both primary and secondary resistance mechanisms ultimately limit the long-term efficacy of MET-targeted agents, and acquired resistance may arise via on- or off-target pathways. In a study of 20 patients with metastatic NSCLC with METex14 who had achieved a response to therapy with a MET TKI followed by progression, 15 patients (75%) demonstrated a known or suspected mechanism of resistance. Seven patients (35%) demonstrated an on-target mechanism (MET kinase domain mutation or high-level amplification of the METex14 mutant allele), while 9 patients (45%) demonstrated an off-target mechanism (mutation or amplification in KRAS, EGFR, HER3, BRAF). One patient demonstrated both on-and off-target mechanisms (92). Preclinical models suggest that specific on-target resistance mutations may be driven by the type of METi used, with secondary mutations arising specifically at codons with which the initial METi interacted (6). For example, because type IA TKIs interact with MET via the solvent front residue G1163 and type IB TKIs have no interaction with G1163, one study demonstrated that secondary mutations at this location were found almost exclusively after cell lines were exposed to type IA MET TKIs (93). Further, secondary mutations in F1200, a codon with direct interaction with type II inhibitors, was commonly seen after exposure to type II TKIs (93). Off-target resistance to MET-targeted therapy arises in genes such as EGFR and KRAS, which allow bypass of MET and activation of down-stream signaling cascades. Understanding these on- and off-target patterns opens doors for possible therapeutic solutions, including the sequential use of different classes of MET TKIs, the use of drugs targeting the extracellular domain of MET, and/or the combination of drugs with different targets (6).

Discussion and future directions

A growing understanding of unique mechanisms of MET-axis dysregulation in NSCLC has provided insight into known and potential therapeutic targets, though unmet needs remain. Identifying which biomarkers are both predictive and actionable, standardizing analytic modalities and diagnostic thresholds for biomarker identification, expanding treatment options through novel mechanisms, managing emerging treatment resistance, and determining how to best select patients who will benefit from MET-targeted therapy are critical areas of ongoing investigation.

We have reviewed here the pathophysiology and epidemiology of METex14, MET AMP, MET OE, and MET FUS. We have also reviewed the landscape of established therapies and those in development to target MET in advanced/metastatic NSCLC. Numerous agents and strategies have been and continue to be investigated with the goal of targeting MET in both the front- and subsequent line settings, including TKIs, monoclonal Abs, B-Abs, ADCs, and IO. However, approved targeted therapies for NSCLC harboring MET alterations remain shockingly limited. Until 2025, only two type Ib MET TKIs (capmatinib and tepotinib) were approved in the U.S. for this indication, and response rates and survival outcomes have lagged behind what we have observed with EGFR- and ALK-targeted TKIs.

More recently, there have been promising investigations surrounding ADCs and B-Abs, drug classes that offer unique mechanisms of action, have the potential for efficacy in a boarder population of patients (i.e., MET OE, TKI resistant tumors, secondary drivers), and harbor distinct toxicity profiles. Notably, the 2025 approval of Teliso-V, an ADC targeting MET that is now approved for NSCLC with high MET OE, represents the first expansion of the MET treatment landscape beyond TKIs directed at METex14 since the approvals of capmatinib and tepotinib in 2020 and 2021, respectively.

While no B-Abs have yet to be FDA approved for use in patients with NSCLC harboring primary MET alterations, building evidence may result in future approvals. Robust data for amivantamab, a B-Ab that targets both MET and EGFR, has supported approvals for its use in patients with advanced/metastatic EGFRm NSCLC, with benefit possibly driven by mitigation of acquired resistance to EGFR inhibition through MET AMP. For patients with primary METex14, the ongoing CHRYSALIS study has demonstrated clinically meaningful efficacy of amivantamab monotherapy in the front- and subsequent-lines, including modest benefit among those with prior exposure to METi. The toxicity profile of amivantamab has demanded ongoing work to improve tolerability, with implementation of prophylactic and supportive protocols and ongoing investigation of subcutaneous administration.

Aside from drug development, work focused on uniformly defining clinically meaningful and actionable MET alterations in NSCLC is critical. Methodology for detection and thresholds for characterization, particularly for continuous variables (MET AMP and MET OE), have varied significantly between studies, contributing to a lack of clear understanding regarding the predictive value of these biomarkers, efficacy of targeted drugs, and practical use in the clinical setting. For example, Teliso-V is approved for NSCLC with “high” c-MET OE as defined by IHC (≥50% of tumor cells with 3+ staining) based on methodology and findings in the LUMINOSITY trial. However, other studies have used different thresholds in terms of both percent of cells and intensity on IHC to define MET OE. MET AMP is also variably defined, with some studies using FISH (MET/CEP7 or GCN per cell) and others using NGS, with further variability in diagnostic thresholds across these methodologies. The NCCN recommends an NGS GCN ≥10% to define high-level MET AMP, though acknowledges that the definition is evolving. For detection of METex14 in tumor tissue, RNA based sequencing methods may be more sensitive than DNA, though with practical challenges related to quantity of tissue needed for RNA extraction (94). ctDNA from plasma samples can also be used, providing an option for molecular testing in those with inadequate or unavailable tissue, though with lower sensitivity compared to tissue testing. Overall, given the diversity of mechanisms of MET dysregulation, lack of standardized diagnostic thresholds, and requirement for distinct methods of detection depending on mechanism and other clinical factors, a multi-omics approach is currently necessary. This is true particularly for detection of MET alterations in the face of the challenges described, but also applies to NSCLC in general, where comprehensive characterization of the genomic and immune landscape of each tumor is critical to guide clinical treatment decisions and trial eligibility.

There are several limitations to this work. While we have attempted to comprehensively review the current landscape of MET alterations in NSCLC, this is a non-systematic review, and therefore literature included was subject to selection bias. Further, without a systematic approach to literature review, all relevant data may not have been included. Finally, the quality of included data was not formally assessed.

Conclusions

The treatment landscape in MET-altered NSCLC is rapidly evolving. Work is ongoing to optimize outcomes via novel therapeutic developments as well as though investigation of combination and sequential approaches. Standardization of diagnostic methodology and well-defined thresholds predictive of benefit from MET-targeted therapy will contribute to more successful biomarker-driven patient selection, help refine diagnostic and therapeutic decision making, and improve outcomes in a challenging subset of patients for whom treatment options are limited.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1007/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1007/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1007/coif). L.B. serves as an unpaid editorial board member of Translational Cancer Research from June 2023 to May 2025. A.H. reports that she has received support for attending meetings and/or honoraria for educational events from MJH Life Sciences, Omni Health Media, Open Health Communications, MD Outlook, and IDEOlogy health. She has participated in data safety monitoring or advisory boards for Johnson & Johnson. C.G. reports that he has received honoraria for participation in the International Lung Cancer Congress (2025) as well as an institutional grant for wellness initiatives at UCSD. L.B. reports that she has received consulting fees from Pfizer, Neuvogen Scientific Advisory, and Daichi. She has participated in data safety monitoring or advisory boards for Pfizer, Bayer, Bristol Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, Genentech, Natera, Merck, Abbvie, Revolution Medicine, Anheart, AstraZeneca, Regeneron, Janssen, Novocure, Daichi, Sanofi, Gilead, Teligene, Neuvogen, Bioalta, and Summit. She has served on the Board of Directors for Alliance Clinical Trials in Oncology and is now the Executive Officer of the Respiratory Committee for Alliance. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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