Research progress on resistance and mechanisms of c-Met inhibitors in treating MET exon 14 skipping mutant non-small cell lung cancer: a narrative review

Introduction

According to global cancer statistics for 2022, lung cancer accounted for 12.4% of all new cancer cases and 18.7% of all cancer-related deaths, ranking first in both incidence and mortality (1). Non-small cell lung cancer (NSCLC) is the most prevalent histological subtype, comprising approximately 85% of all lung cancer cases (2). Currently, there is growing evidence that specific gene alterations can drive NSCLC (3,4), such as mutations in epidermal growth factor receptor (EGFR) (5), Kirsten rat sarcoma viral oncogene homolog (KRAS) (6), v-raf murine sarcoma viral oncogene homolog B (BRAF) (7), MET (8), and anaplastic lymphoma kinase (ALK) (9). Consequently, targeted therapies against these driver genes play a crucial role in NSCLC treatment. MET gene abnormalities include MET amplification, MET protein overexpression, MET exon 14 skipping mutations, and MET fusions. Among these, MET exon 14 skipping mutations occur in approximately 2–4% of the NSCLC population (10). A study in Chinese patients with pulmonary sarcomatoid carcinoma (PSC) demonstrated that those with MET exon 14 skipping mutations had a higher risk of recurrence compared to others [hazard ratio (HR) =2.954; 95% confidence interval (CI): 1.318–6.619; P=0.009] (11). Previous research has also shown that NSCLC patients with MET exon 14 skipping mutations have lower overall survival (OS) than those without this mutation (12). In a study of 20 Korean NSCLC patients with MET exon 14 skipping mutations receiving first-line chemotherapy, the median progression-free survival (PFS) was only 4.0 months (95% CI: 2.8–14.1), and the median OS was 9.5 months (95% CI: 6.5–23.1) (13). Studies on immunotherapy for lung cancer patients with MET exon 14 skipping mutations reported an objective response rate (ORR) of 17% (95% CI: 6–36%), a median PFS of 1.9 months (95% CI: 1.7–2.7), and a median OS of 18.2 months (95% CI: 12.9–not reached) (14). Although NSCLC harboring MET exon 14 skipping is associated with a high degree of malignancy, responds poorly to conventional therapies, and leads to a poor prognosis, c-Met inhibitors targeting MET have demonstrated remarkable efficacy in treatment (15). A meta-analysis included 9 publications comprising a total of 473 patients with locally advanced or metastatic NSCLC harboring MET exon 14 skipping mutations who were treated with c-Met inhibitors, and the results demonstrated that c-Met inhibitors achieved an ORR of 39.3% (95% CI: 29.6–52.2%) and a disease control rate of 77.8% (95% CI: 71.4–84.7%), indicating favorable efficacy (16). However, with the widespread application of c-Met inhibitors in clinical treatment, resistance to these agents has inevitably emerged and is being increasingly reported. The development of resistance not only limits the durability of the therapeutic efficacy of existing c-Met inhibitors but also poses significant challenges for the selection of subsequent treatment strategies. Therefore, in-depth investigation into the mechanisms of resistance to c-Met inhibitors and exploration of therapeutic strategies to overcome this resistance have become urgent issues in the clinical management of NSCLC patients with MET exon 14 skipping mutations. This review aims to summarize the current landscape of c-Met inhibitors, including their efficacy and the emerging challenge of resistance, and to elucidate the potential mechanisms of resistance in NSCLC with MET exon 14 skipping mutations, based on the latest research evidence. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0949/rc).

Methods

PubMed, CNKI, Web of Science, ClinicalTrials.gov, U.S. Food and Drug Administration (FDA) Drug Approvals and Databases were searched using terms related to c-Met inhibitor, immunotherapy, MET tyrosine kinase inhibitor, MET TKI, non-small cell lung cancer, NSCLC, MET exon 14 skipping, and mechanism of resistance, with the timeframe extending through May 31, 2026. Although predefined inclusion or exclusion criteria were not employed, this study included clinical trials, retrospective studies, in vitro experiments, reviews and meta-analyses published in English mainly within the last 10 years. Table 1 provides a summary of the search strategy.

MET signaling pathway and exon 14 skipping mutation

The MET gene, originally identified as a novel transforming gene (the MNNG-HOS transforming gene) upon chemical transformation of human osteosarcoma (HOS) cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (17), is located on human chromosome 7q21-31 and encodes the protein c-Met, a receptor tyrosine kinase (RTK) primarily expressed in epithelial cells (18). c-Met is a transmembrane protein whose extracellular region contains the semaphorin (SEMA) domain, the PSI (plexins, SEMAs, and integrins) domain, and the immunoglobulin-plexin-transcription (IPT) domain. Its intracellular segment includes the juxtamembrane (JM) domain, the tyrosine kinase catalytic domain, and the carboxyl-terminal tail featuring a multifunctional docking site (19) (Figure 1).

Figure 1 Structure of the c-Met transmembrane protein. IPT, immunoglobulin-plexin-transcription; JM, juxtamembrane; PSI, plexins, SEMAs, and integrins; SEMA, semaphorin.

Hepatocyte growth factor (HGF), expressed by mesenchymal cells, is the ligand for c-Met. The binding of HGF to the extracellular SEMA domain of c-Met (20) induces c-Met homodimerization (18). This leads to trans-phosphorylation of two tyrosine residues, Tyr1234 and Tyr1235, followed by phosphorylation of two additional docking tyrosines (Tyr1349 and Tyr1356) on the carboxyl-terminal tail (21). These phosphorylated residues recruit downstream signaling effectors such as growth factor receptor-bound protein 2 (GRB2), GRB2-associated binding protein 1 (GAB1), and SH2 domain-containing transforming protein (SHC), thereby activating key downstream pathways including RAS-MAPK, PI3K-AKT, and JAK-STAT. This cascade ultimately promotes cell growth, proliferation, invasion, metastasis, survival, and inhibits apoptosis (19) (Figure 2).

Figure 2 Schematic diagram of the MET signaling pathway. HGF, hepatocyte growth factor.

The JM domain contains three key regulatory sites—S985, D1002, and Y1003—which exert negative regulatory functions. A study has shown that phosphorylation of S985 inhibits tyrosine phosphorylation of c-Met and its subsequent biological effects in hepatocytes (22). Caspase-mediated cleavage of c-Met at D1002 generates a 40 kDa fragment that promotes apoptosis (23). The binding of HGF to c-Met leads to the phosphorylation of Y1003, which recruits the c-Cbl E3 ubiquitin ligase. This results in the ubiquitination of c-Met and its subsequent degradation via the proteasome (24,25). Introns contain key splicing elements, including the 5' splice site, branch site, and 3' splice site. Point mutations or small deletions within these regions can lead to aberrant intron removal, resulting in exon skipping mutations (26). Onozato et al. sequenced the MET gene in lung cancer patients and identified that patients with MET exon 14 skipping mutations harbored deletions affecting the branch site, polypyrimidine tract, and 3' splice site in intron 13, as well as point mutations in the 5' splice site of intron 14 (27). MET exon 14 skipping leads to the loss of the Y1003 residue in the translated MET protein receptor. This loss impairs the c-Cbl degradation pathway for c-Met, consequently increasing MET receptor activation levels. Phosphorylation of S985 is a critical negative regulatory mechanism (28). When MET exon 14 skipping causes the loss of the S985 site, MET receptor activity is further enhanced. Consistent with this, cell-based experiments have demonstrated that cells with MET exon 14 skipping exhibit increased levels of MAPK phosphorylation (29).

Efficacy of c-Met inhibitors

c-Met tyrosine kinase inhibitors (TKIs) are categorized into Type I, Type II, and Type III. Type I inhibitors competitively block ATP binding and are further subdivided into Type Ia and Type Ib (30). Type Ia inhibitors bind to multiple sites on c-Met (including Tyr1230 and G1163), whereas Type Ib inhibitors exhibit stronger interactions with Y1230, resulting in higher selectivity (31). Type II inhibitors (ATP-competitive inhibitors) occupy not only the ATP-binding pocket but also an adjacent hydrophobic pocket. Type III inhibitors are non-ATP-competitive and act on an allosteric site (32). Table 2 presents the efficacy of commonly used c-Met inhibitors for treating NSCLC with MET exon 14 skipping mutations.

The Type Ia inhibitor crizotinib (PF-2341066) inhibits the activity of ALK (42), MET (43), and ROS1 (44) RTKs. In vitro cell experiments demonstrate that crizotinib suppresses c-Met-mediated PI3K/AKT and RAS/MAPK pathways, revealing its antitumor effects (45,46). In the PROFILE 1001 clinical trial involving 65 patients with advanced NSCLC harboring MET exon 14 alterations, the ORR was 32% (95% CI: 21–45%), median duration of response (DOR) was 9.1 months (95% CI: 6.4–12.7), and median PFS was 7.3 months (95% CI: 5.4–9.1) (33). A phase II trial (Co-Met study) enrolled 23 patients with advanced NSCLC and MET exon 14 skipping mutations, administering crizotinib at a standard oral dose of 250 mg twice daily. The ORR was 38.1% (95% CI: 20.6–58.3%), with median DOR, PFS, and OS of 7.6 months [95% CI: 1.9–not estimable (NE)], 5.7 months (95% CI: 2.1–11.3), and 9.1 months (95% CI: 4.0–19.9), respectively (34). However, crizotinib exhibits poor blood-brain barrier penetration, often resulting in poor efficacy for patients with brain metastases (47,48).

Capmatinib (formerly INCB28060) is a potent and highly selective Type Ib c-Met inhibitor. It interacts with residues D1228 and Y1230 of c-Met, stabilizing a specific conformation (49). Capmatinib not only inhibits phosphorylation at Tyr1234 and Tyr1235 in the MET receptor and downstream signaling but also reduces ligand levels and phosphorylation of EGFR and human epidermal growth factor receptor 3 (HER3), thereby suppressing tumor cell proliferation, migration, and anti-apoptotic capacity (50). GEOMETRY mono-1 (NCT02414139), a multi-cohort phase 2 study, administered capmatinib at 400 mg twice daily to patients with MET exon 14 skipping mutation NSCLC. The results showed an ORR of 41% (95% CI: 29–53%) in previously treated patients and 68% (95% CI: 48–84%) in treatment-naive patients, with median DOR of 9.7 months (95% CI: 5.6–13.0) and 12.6 months (95% CI: 5.6–NE), respectively. Intracranial responses were also observed (35). Based on the demonstrated efficacy, the FDA approved capmatinib on May 6, 2020, for metastatic MET exon 14 skipping-mutant NSCLC (51).

Tepotinib (EMD 1214063) is a potent, highly selective, and reversible Type Ib c-Met inhibitor. Studies show that tepotinib inhibits phosphorylation of c-Met (Y1234/Y1235), Akt, GAB1 (52), and suppresses PI3K and MAPK signaling pathways (53), thereby interfering with tumor cell proliferation and migration. The phase II multicenter VISION trial (NCT02864992) enrolled 313 patients with MET exon 14 skipping-mutant NSCLC who received tepotinib 450 mg (active ingredient) once daily. The ORR was 51.4% (95% CI: 45.8–57.1%), with a median DOR of 18.0 months (95% CI: 12.4–46.4). Among the 164 treatment-naive patients, the ORR was 57.3% (95% CI: 49.4%-65.0%) with a median DOR of 46.4 months (95% CI: 13.8–NE). In the 149 pretreated patients, the ORR was 45.0% (95% CI: 36.8–53.3%) with a median DOR of 12.6 months (95% CI: 9.5–18.5). Regarding safety, adverse events occurred in 287 patients (91.7%), with 109 patients (34.8%) experiencing grade ≥3 adverse events (36). The U.S. FDA granted accelerated approval to tepotinib on February 3, 2021, and granted full approval on February 15, 2024, for the treatment of metastatic MET exon 14 skipping-mutant NSCLC (54,55).

Savolitinib (AZD6094 or HMPL-504) is a Type Ib c-Met inhibitor. Cellular experiments indicate it inhibits phosphorylation of c-Met and AKT, suppressing tumor growth (56). In a Chinese multicenter phase II trial, 70 NSCLC patients with MET exon 14 skipping mutations received oral savolitinib. The ORR was 42.9% (95% CI: 31.1–55.3%), median DOR was 8.3 months (95% CI: 5.3–16.6), and median PFS was 6.8 months (95% CI: 4.2–9.6) (37). A Chinese phase IIIb confirmatory study enrolled 87 NSCLC patients with MET exon 14 skipping mutations treated with oral savolitinib, reporting an ORR of 62% (95% CI: 51–72%) and a median DOR of 12.5 months (95% CI: 8.3–15.2) (38).

Gumarontinib (also known as Glumetinib or SCC244) is a Type Ib c-Met inhibitor. Experiments demonstrate that SCC244 potently inhibits c-Met phosphorylation in c-Met-driven cancer cells, blocking downstream signaling and exerting potent anti-proliferative effects (57). A phase Ib/II clinical study (GLORY study) conducted across 42 centers in China and Japan enrolled 79 NSCLC patients with laboratory-confirmed MET exon 14 skipping mutations. Patients received gumarontinib 300 mg orally once daily. The results showed an ORR of 66% (95% CI: 54–76%) and a median PFS of 8.5 months (95% CI: 7.6–9.7) (39). The National Medical Products Administration (NMPA) of China approved gumarontinib on March 8, 2023. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) approved it on June 24, 2024, for treating NSCLC patients with MET exon 14 skipping mutations (58).

Vebreltinib (also known as bozitinib) is a highly selective Type Ib c-Met inhibitor (59). The phase II KUNPENG study (NCT04258033) enrolled 52 NSCLC patients with MET exon 14 skipping mutations (Cohort 1) who received vebreltinib 200 mg twice daily. The results demonstrated an ORR of 75% (95% CI: 61.1–86%), median DOR of 15.9 months (95% CI: 9.2–17.8), median PFS of 14.1 months (95% CI: 6.4–17.9), and a median OS of 20.7 months (95% CI: 16.2–NE) after a median follow-up of 19.4 months (40). A case report described a patient with lung adenocarcinoma harboring a MET Asp1010Tyr mutation who experienced disease progression after 7.6 months of tepotinib treatment, without new resistance mutations identified. This patient was subsequently enrolled in the KUNPENG trial (NCT04258033) and treated with vebreltinib (200 mg twice daily), achieving a partial response after 6.8 months, with a DOR exceeding 13 months and PFS exceeding 20 months (60).

The Type II c-Met inhibitor cabozantinib can serve as a salvage option in sequential therapy for NSCLC patients with MET exon 14 skipping mutations (61). A phase II study (NCT01639508) enrolled 28 patients with advanced NSCLC harboring MET alterations (23 with MET exon 14 alterations only), treating them with cabozantinib 60 mg daily. Among 25 assessable patients, the ORR was 20% (95% CI: 8.9–39.1%). For all patients, median PFS was 4.5 months (95% CI: 3.3–5.7) and median OS was 7.2 months (95% CI: 2.9–11.5) (41). Notably, although this study enrolled patients with advanced NSCLC, and 24 (86%) patients had received prior MET TKI therapy, cabozantinib still provided clinical benefit.

Current landscape of resistance

Figure 3 illustrates the mechanisms of primary and acquired resistance to c-Met inhibitors in MET exon 14 skipping-mutant NSCLC discussed in this review.

Figure 3 The main mechanisms of resistance to c-Met inhibitors in MET exon 14 skipping-mutant NSCLC. NSCLC, non-small cell lung cancer.

Primary resistance mechanism

Some patients exhibit a poor initial response to targeted therapy, characterized by disease progression and the absence of objective response, which may be associated with molecular abnormalities such as point mutations, signaling pathway dysregulation, or alterations in the expression levels of certain proteins. A study reported a case of MET exon 14 skipping mutation NSCLC in which the patient harbored a D1010H mutation and Y1230C mutation at a very low frequency prior to treatment. The investigators suggested that the low-abundance Y1230C did not confer upfront resistance but may have accelerated the patient’s disease progression (62). In a patient with lung adenocarcinoma harboring a MET exon 14 skipping mutation (Phe1007fs), brain metastases increased after 8 weeks of crizotinib treatment, with no additional genetic mutations detected, suggesting primary resistance (63). Phosphatase and tensin homolog (PTEN) is a specific phosphatase that dephosphorylates PIP3 to PIP2 (64), thereby regulating cell growth, proliferation, and migration (65). It acts as a crucial negative regulator of the PI3K/AKT signaling pathway (66), and its loss leads to constitutive PI3K pathway activation. Three NSCLC patients with MET exon 14 skipping mutations developed resistance to MET TKIs. PTEN immunohistochemistry indicated loss of PTEN expression in two patients, and next-generation sequencing (NGS) revealed a PIK3CA mutation (N1044K) in one patient (67).
One case involving adenosquamous lung cancer with a MET exon 14 skipping mutation (D1028N) and high programmed cell death ligand 1 (PD-L1) expression showed disease progression following crizotinib therapy, however, the cause of resistance may be unclear (68).

Acquired resistance mechanism

Some studies have demonstrated that acquired resistance to MET TKIs inevitably developed after several months of treatment in patients with MET exon 14 skipping-mutant NSCLC, with underlying mechanisms including secondary mutations and activation of bypass signaling pathways. Several studies have also revealed that resistance to c-Met inhibitors can result from the combined effects of secondary mutations and bypass activation. One reported case of lung adenocarcinoma with a MET exon 14 skipping mutation developed resistance after crizotinib treatment, with genetic analysis revealing both a D1246H mutation and KRAS amplification (69). Sequencing analysis of cell-free circulating tumor DNA from NSCLC patients with MET exon 14 skipping mutations identified the emergence of secondary mutations—including D1228H/N, Y1230H/S, L1195V, and F1200I—along with KRAS amplification and KRAS G12D mutation following MET TKI treatment (70) (Table 3).

Activation of bypass signaling (off-target resistance)

Bypass signaling represents a key mechanism of drug resistance. In one case, disease progression occurred in a NSCLC patient with a MET exon 14 skipping mutation after 5 months of crizotinib treatment and subsequent biological specimens identified HER2 gene amplification (75). HER2/ErbB2, a member of the EGFR family, can form heterodimers with other EGFR family members such as HER1 and HER3 (84). This activation initiates downstream signaling cascades including the RAS/RAF/MEK/ERK and PI3K/AKT pathways, driving cell proliferation and conferring resistance to apoptosis (85). Cellular experiments have demonstrated that combining c-Met inhibitors with the MEK1/2 inhibitor trametinib or the EGFR inhibitor afatinib can suppress tumor growth in MET exon 14 mutant tumors with concurrent KRAS mutations (86). Another NSCLC patient with a MET exon 14 skipping mutation developed resistance following crizotinib treatment, and EGFR amplification was detected in the drug-resistance sample. A patient-derived xenograft model established from this resistant case showed significant tumor growth inhibition when treated with an EGFR-MET bispecific antibody (87). In a case of PSC with a MET exon 14 skipping mutation, disease progression occurred after 36 weeks of savolitinib therapy. Tumor biopsy revealed amplifications of FGFR1, EGFR, and KRAS genes (76). Additionally, a patient with MET exon 14 skipping mutant lung adenocarcinoma experienced metastatic progression after capmatinib treatment, and a biopsy detected HER2 amplification (68). Following MET TKI treatment, NGS detected EGFR and HER3 amplification, indicating bypass activation resistance (78) (Table 3).

Secondary mutations (on-target resistance)

A salt bridge formed between D1228 and K1110 stabilizes the π-π interaction between Type I c-Met inhibitors, such as Savolitinib, and Y1230, facilitating drug binding to the MET receptor (88). One study demonstrated that cells expressing the MET Y1230H mutation maintained MET phosphorylation and downstream signaling activation, conferring resistance to the c-Met inhibitor PHA-665752 (89). Research has identified the emergence of D1228H/N and Y1230C mutations in the MET receptor of NSCLC patients with MET exon 14 splicing alterations following MET TKI treatment. These mutations hinder c-Met inhibitor binding, leading to resistance (78). Cellular experiments indicate that Y1230C/D/S/H/N or D1228E/G/H/N mutations confer resistance to Type I inhibitors but remain sensitive to Type II inhibitors, whereas L1195F/V and F1200I/L mutations confer resistance to Type II inhibitors but retain sensitivity to Type Ib inhibitors (90). A study utilizing the c-Met inhibitor NVP-BVU972 for resistance screening in cells identified clones with MET D1228 and Y1230 mutations. Subsequent secondary screening with the c-Met inhibitor AMG 458 detected additional mutations including MET D1228A, F1200I/L, L1195I/V, and G1163V/E (91). In two patients with MET exon 14 skipping mutation NSCLC who developed acquired resistance to crizotinib, G1163R, D1228A/H, and Y1230H mutations were identified in one case (74), while the other case harbored a Y1230H mutation (73). In a lung cancer patient with a MET exon 14 splice site mutation, pulmonary nodules enlarged after one month of crizotinib treatment, and NGS identified a newly acquired MET exon 19 D1246N mutation (77). Plasma analysis from a patient in a phase II study with MET exon 14 skipping mutation lung cancer revealed the emergence of a MET Y1230C mutation upon disease progression after capmatinib treatment. Furthermore, plasma specimens from two other crizotinib-resistant MET exon 14 skipping mutation patients showed secondary MET mutations: D1228H and D1228N + Y1230H, respectively (80). A patient with squamous cell carcinoma harboring a MET exon 14 D1010H mutation initially achieved a partial response to crizotinib but developed new liver metastases after 8 months, and a biopsy detected a MET exon 19 D1228N mutation (72). Another study reported multiple NSCLC patients with MET exon 14 skipping mutations who developed resistance after MET TKI therapy. This included one patient with a D1228N missense mutation co-occurring with MET amplification after crizotinib, others with D1228N/H/Y and Y1230C/H/N missense mutations post-crizotinib, one with a D1228H mutation after sequential crizotinib and savolitinib, one with a Y1230S mutation after savolitinib, another with D1228N/H/Y and Y1230C/H mutations after savolitinib, and one with a D1228H mutation after capmatinib treatment (82). A patient with a MET exon 14 skipping mutation experienced disease progression with new bone metastases after 4 months of crizotinib. Subsequent NGS detected MET D1228N/H and Y1230H mutations (71). In a case of MET exon 14 skipping mutant lung adenocarcinoma, the primary lesion progressed after 12 months of capmatinib. NGS identified a MET exon 19 p.D1228H c.3682G>C missense mutation. The patient was then switched to savolitinib, which maintained a response for 19 months before additional metastatic lesions appeared, and subsequent NGS showed the disappearance of the D1228H mutation but the emergence of a MET Y1230N mutation (83). A pulmonary adenocarcinoma patient with a Y1003H c-Cbl binding site mutation and MET exon 14 skipping mutation progressed after 10.6 months of crizotinib. NGS detected a D1246N mutation and an FGFR2 mutation (79). Another pulmonary adenocarcinoma patient with a MET exon 14 skipping mutation progressed after 6 months of crizotinib; analysis of lymph node DNA identified a D1228N mutation (81). Finally, a lung adenocarcinoma patient with a MET D1028H mutation, in whom digital droplet PCR later detected a D1228N mutation, experienced stable primary lesions but new tissue metastases on crizotinib, and the disease progressed 7 weeks after switching to cabozantinib (68) (Table 3).

Discussion

Currently, resistance to c-Met inhibitors is characterized by its universality and high heterogeneity, and in-depth research on its underlying mechanisms remains insufficient. Given the complexity of resistance mechanisms and the limitations of current understanding, clinical strategies to overcome resistance are still in the exploratory stage. The current strategies to overcome resistance are as follows.

• Immune checkpoint inhibitors (ICI) plus chemotherapy. A recent study comparing the efficacy of first-line MET TKIs versus ICI ± chemotherapy in MET exon 14 skipping mutation NSCLC patients found no significant difference in median OS (MET TKI: 19.4 months; ICI ± chemotherapy: 22.1 months; HR =0.97, 95% CI: 0.65–1.45, P=0.9). However, this study revealed that in patients with PD-L1 tumor proportion score (TPS) ≥80%, first-line ICI ± chemotherapy was associated with a longer real-world PFS (rwPFS) (ICI ± chemotherapy: 9.4 months; MET TKI: 5.0 months; HR =0.50, 95% CI: 0.27–0.92, P=0.03). For patients with PD-L1 TPS between 50% and 79%, no significant differences were observed in efficacy [real-world ORR (rwORR), rwPFS, and OS] between the two treatment strategies. In patients with PD-L1 TPS <50%, first-line MET TKI therapy resulted in higher rwORR [MET TKI: 60%; ICI ± chemotherapy: 34.6%; odds ratio (OR) = 2.83, 95% CI: 0.97–8.71, P=0.06], longer median rwPFS (MET TKI: 12.2 months; ICI ± chemotherapy: 5.7 months; HR =0.40, 95% CI: 0.21–0.76, P=0.005), and longer median OS (MET TKI: 27.4 months; ICI ± chemotherapy: 15.0 months; HR =0.49, 95% CI: 0.26–0.95, P=0.03) compared to ICI ± chemotherapy (92). Therefore, ICI are a therapeutic option for patients with high PD-L1 expression.
• Consider switching to a different type of c-Met inhibitors. Patients who develop resistance due to acquired D1228 or Y1230 mutations following treatment with Type I c-Met inhibitors may benefit from subsequent therapy with Type II c-Met inhibitors. Conversely, tumors resistant to Type II inhibitors may exhibit sensitivity to Type I c-Met inhibitors (90).
• Combination strategies with downstream signaling pathway inhibitors. A study in vitro has demonstrated that concurrent inhibition of c-Met and PI3K can overcome resistance to MET TKI in MET exon 14 skipping NSCLC patients harboring PI3K pathway alterations (67).
• Anti-MET antibody drugs. EGFR-MET bispecific antibody amivantamab targets the extracellular domains of MET, leading to inhibition of downstream signaling (93). The CHRYSALIS trial (NCT02609776) enrolled MET exon 14 skipping NSCLC patients, who received intravenous amivantamab treatment. In a cohort of 53 patients with prior c-Met inhibitor therapies, the ORR was 19% (95% CI: 9–32%), the median PFS was 5.3 months (95% CI: 4.0–7.2), and the median OS was 15.8 months (95% CI: 13.9–NE). Amivantamab activity was observed in this study. This indicates that anti-MET antibody-drug therapy is effective in treating tumors that have developed acquired resistance to MET TKIs, such as those with MET D1228 and Y1230 mutations, and the exploration in this area represents a promising field (94). These approaches may contribute to addressing drug resistance to c-Met inhibitors in MET exon 14 skipping-mutant NSCLC and thereby improving patient outcomes.

In tumors without MET exon 14 skipping, acquired resistance mutations at sites such as D1228 and Y1230 have also been observed following treatment with crizotinib or other MET TKIs. A patient with lung adenocarcinoma harboring KIF5B-MET fusion received crizotinib for one month, followed by the addition of bevacizumab for more than three months, after which the disease had progressed. Targeted sequencing of blood samples revealed an acquired MET Y1230H mutation (95). In another case, a pretreated triple-negative breast cancer patient with MET amplification developed resistance to crizotinib, and NGS identified a somatic MET D1228N mutation (96). According to a study, a patient with MET amplified gastric cancer experienced rapid disease progression after 3.5 months of savolitinib therapy. Analysis of circulating tumor DNA identified MET resistance mutations within the kinase domain, including D1228H (31%), D1228N (12%), D1228V (1%), and Y1230C (1%) (97). A NSCLC patient harboring a MET Y1003H mutation was treated with crizotinib, and the PFS was 22.4 months. After disease progression, NGS analysis of pleural effusion tissue identified a D1228N mutation (98). Therefore, these kinase domain mutations can be observed across diverse MET-driven alterations and may represent a common resistance mechanism to MET TKI therapy. Nonetheless, research on the nature of MET TKI resistance is still limited, and further studies are warranted to elucidate these mechanisms.

Several limitations are inherent to this review: (I) selection bias may have been introduced due to the non-systematic nature of the literature review; (II) a systematic search approach was not employed, so potentially relevant data could have been missed; (III) no formal assessment of the quality of the included literature was undertaken.

Conclusions

The application of c-Met inhibitors represents a breakthrough in the treatment of NSCLC with MET exon 14 skipping mutations, significantly improving patient prognosis. However, the emergence of drug resistance poses a formidable challenge to current clinical strategies, as it not only limits the long-term efficacy, but also leads to poor treatment response or rapid disease progression after therapy. This review comprehensively discusses drug resistance, with the core mechanisms including primary resistance and acquired resistance (including secondary mutations and bypass signaling activation). Nevertheless, research elucidating these resistance mechanisms remains relatively limited. We look forward to more research in the future to further elucidate resistance mechanisms, and based on this, optimize treatment strategies so as to bring better efficacy and longer survival benefits to NSCLC patients with MET exon 14 skipping mutations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0949/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0949/prf

Funding: This work was supported by “Qimingxing” Research Fund for Young Talents of West China Hospital, Sichuan University (No. HXQMX0071), Beijing CSCO Clinical Oncology Research Foundation (No. Y-2022METAZQN-0116), Wu Jieping Medical Foundation, and the Natural Science Foundation of Sichuan Province (No. 2024NSFSC1928).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0949/coif). The authors have no 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.

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