Expert consensus on the diagnosis and treatment of non-small cell lung cancer with MET alteration

MET fusions (including exon 14 skipping mutations) and pathogenic mechanisms

MET exon 14 skipping mutations, also known as MET-MET fusions, represent a distinct subtype of MET fusions. These mutations occur primarily in the branch site (a single nucleotide), the poly-pyrimidine tract (16 nucleotides), the splice acceptor site (2 nucleotides upstream), and the splice donor site (2 nucleotides downstream)⁷.

During transcription, MET exon 14 skipping mutations affect conserved sequences at RNA splice donor or acceptor sites, resulting in improper splicing of exon 14. Consequently, the MET protein loses its juxtamembrane domain or exhibits alterations, such as deletions of the Y1003 amino acid site, which impairs ubiquitination, leading to increased protein stability, reduced degradation, and persistent activation of downstream signaling pathways⁸. These effects collectively promote tumor development⁹.

Public data have shown that MET exon 14 skipping mutations are the most prevalent MET gene alterations among the Chinese lung cancer population (Figure 1)¹⁰.

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Figure 1

Frequency and location of MET hotspots in NSCLC. Schematic diagram of MET mutation hotspots and locations of lung cancer in Chinese population¹⁰. SEMA, semaphorin; PSI, plexin-semaphorin-integrin domain; IPT, immunoglobulin-plexins-transcription domain; TK, tyrosine kinase domain.

In the absence of MET inhibitors, these mutations are associated with high tumor aggressiveness, resistance to anticancer therapy, and a poor prognosis^11,12.

Table S1 shows the locations of MET exon 14 skipping mutations. In addition to MET exon 14 skipping mutations, numerous other MET fusion types exist, although the incidence is relatively low with novel MET fusions occurring in 0.26%–0.29% of patients^13,14. Secondary resistant MET fusions, emerging after treatment with tyrosine kinase inhibitors (TKIs), can constitute up to 5% of the MET alterations, which includes amplifications, mutations, and fusions¹⁵. Several MET fusion partner genes have been identified in NSCLC¹⁶, including KIF5B, STARD3NL, HLA-DRB1, UBE2H¹⁷, SLC1A2, PTPRZ1, EPHB4, THAP5, TNPO3, and DST, often co-occurring with TP53 mutations¹⁴. Notably, MET fusion proteins retaining an intact kinase domain (excluding MET exon 14) are more prevalent with 85.7% (6/7) of such patients responding effectively to MET TKIs¹⁴.

In 2017 Davies et al.¹⁸ reported the first case involving the identification and treatment of a MET fusion in NSCLC. Using AMP-based next-generation sequencing (NGS) for fusion gene detection, Davies et al.¹⁸ identified the HLA-DRB1-MET fusion, which had not been previously described. The patient demonstrated a significant response to crizotinib, a small molecule tyrosine kinase inhibitor targeting HGFR activity. This case highlighted the role of MET fusion genes as oncogenic drivers.

In November 2017 Cho et al.¹⁹ reported the first case of a MET fusion-positive lung adenocarcinoma. Targeted NGS of the patient’s specimen revealed a KIF5B-MET fusion gene. Treatment with the MET inhibitor crizotinib resulted in a significant and sustained anti-tumor response, indicating the oncogenic potential of the KIF5B-MET fusion gene in lung adenocarcinoma.

In March 2018 Plenker et al.²⁰ published a study highlighting the clinical implications of MET structural alterations. Using hybrid-capture-based NGS Plenker et al.²⁰ analyzed specimens from two lung adenocarcinoma patients who tested negative for common lung cancer driver mutations. Two MET fusion transcripts were identified: the previously documented KIF5B-MET fusion; and a novel STARD3NL-MET fusion. The clinical response to crizotinib was assessed in both patients and a partial response was observed. Further functional studies in cellular models confirmed that crizotinib effectively inhibited MET, ALK among other kinases. These findings underscore the oncogenic role of MET structural alterations and the potential of MET structural alterations as actionable drug targets in lung cancer.

Wang et al.21 presented epidemiologic data on MET fusion genes in NSCLC among the Chinese population at the 2018 ASCO Annual Meeting. Among 2410 NSCLC specimens analyzed, a novel MET-ATXN7L1 fusion was identified in 1 patient (0.04%) with lung adenocarcinoma. This patient exhibited a partial response to crizotinib^16,21.

In 2018 Zhu et al.¹⁷ reported the first case of a lung adenocarcinoma patient harboring a MET-UBE2H fusion in the Journal of Thoracic Oncology. This MET-UBE2H fusion was identified as a resistance mechanism to EGFR TKIs. The patient demonstrated a significant and sustained anti-tumor response to crizotinib and achieved a prolonged partial remission. The MET-UBE2H fusion is considered a novel rearrangement that confers resistance to EGFR TKIs¹⁷.

Various MET fusion genes have been identified, including SLC1A2-MET, PTPRZ1-MET, KIF5B-MET, HLA-DRB1-MET, SPECC1L-MET, CAPZA2-MET, CD47-MET, TES-MET, CAV1-MET, ITGA9-MET, TFEC-MET, CTTNBP2-MET, ANK1-MET, SPECC1L-MET, CAV1-MET, and STARD3NL-MET (Table S2).

MET point mutations and the pathogenic mechanisms

MET point mutations occur in various regions of the gene, including the SEMA domain responsible for ligand binding, the juxtamembrane domain, and the kinase domain. In NSCLC clinically relevant MET mutations are predominantly concentrated in the kinase domain.

The known MET secondary mutation sites include V1003F, H1094Y, D1228A, D1228E, D1228G, D1228H, D1228N, D1228Y, D1228V, Y1230C, Y1230D, Y1230S, Y1230H, Y1230N, D1231Y, G1163R, G1090S, V1092L, V10921, L1195V, D1246N, and Y1248H, among others²² (Table S3).

Some kinase domain mutations, such as D1228N, M1250T, and H1094Y/L, exhibit resistance to type I MET inhibitors (e.g., crizotinib) and have limited preclinical sensitivity data for type II MET inhibitors, such as cabozantinib and volitinib²³. These mutations often contribute to acquired resistance. For example, Y1230C/H and D1228H/N, which are located in MET exon 14, mediate resistance following crizotinib therapy^24–28. In addition, the D1246H mutation has been detected in plasma from an NSCLC patient with MET amplification who experienced disease progression after combination with EGFR-TKI/MET inhibitor therapy²⁹.

Point mutations in the SEMA domain (L229F, N375S, E168D, S323G) and juxtamembrane domain (R988C, R988C + T1010I, S1058P) have also been identified³⁰. While the SEMA domain mutations have demonstrated oncogenic potential in cancers of unknown primary origin and renal cancer, their biological significance in lung cancer remains poorly understood^31,32.

MET amplification and its pathogenic mechanisms

MET gene amplification, which is characterized by an increase in the gene copy number (GCN), occurs in two forms (focal amplification and polysomy). Focal amplification involves an increase in the copy number of the MET gene or adjacent regions without a significant change in the copy number of other genes located on the same chromosome. Polysomy refers to the duplication of an entire chromosome, resulting in multiple copies of chromosome 7 within the cell. Both forms can lead to upregulation of MET mRNA levels and increased MET protein expression, which enhance activation of MET-related signaling pathways¹¹. Amplification increases the number of MET receptors on the cell surface, leading to constitutive kinase activation^33,34.

MET gene amplification is associated with a higher histologic grade, advanced clinical stages, and poor prognosis. MET gene amplification can be classified into two types (primary and secondary amplifications).

Primary amplification occurs as a primary tumor driver gene alteration and is observed in 1%–5% of lung adenocarcinoma cases^11,33. Low-level MET amplification often co-exists with other driver gene abnormalities (approximately 50%), while high-level amplification typically occurs without other driver mutations. Targeted drug efficacy rates vary significantly, with 0% for low-level amplification or low MET protein expression and up to 67% for high-level amplification or high protein expression³⁵.

Having at least five copies of the MET gene renders tumor cells dependent on the signaling pathway³⁶. In cases of high MET copy numbers, amplification serves as the primary oncogenic driver. Conversely, medium or low MET amplification levels are often accompanied by mutations in other oncogenic drivers, such as EGFR, RET, or BRAF³⁷. These findings provide a theoretical basis for targeted therapy in patients with high-level MET amplification. Such patients demonstrate a better response to MET inhibitors, resulting in a higher tumor response rate¹¹.

Secondary MET amplification occurs after targeted therapy in NSCLC patients with other driver gene mutations, such as EGFR or ALK. When the EGFR or ALK signaling pathway is inhibited by an EGFR- or ALK-TKI, secondary MET amplification activates alternative signaling pathways, bypassing the inhibited pathway and triggering downstream activation. This mechanism contributes to resistance to TKIs. After an average of 9 months of treatment with first-, second-, or third-generation EGFR-TKIs, 15%–20% of patients develop MET amplification^33,38. Similarly, MET amplification has been reported in ALK-rearranged NSCLC patients undergoing ALK-TKI treatment³⁹. The INSIGHT 2 study, which was led by Wu⁴⁰, demonstrated that combining a highly selective MET inhibitor (tepotinib) with osimertinib is effective and safe for NSCLC patients with EGFR mutations and secondary MET amplification who have developed resistance to targeted therapy. This oral targeted therapy regimen has the potential to replace chemotherapy and warrants further investigation.

Currently, limited research exists on the differences in response to MET-TKI treatment between primary and secondary MET amplification. A retrospective clinical trial suggested that MET-TKIs are more effective in treating primary MET amplification compared to secondary amplification⁴¹. This finding contrasts with the previous understanding and may be explained by primary MET amplification functioning as an independent driver mutation. However, due to the small sample size and the lack of prospective study evidence, the clinical significance of this observation in guiding clinical treatment decisions requires further validation through larger and more reobust clinical studies.

MET-kinase domain duplication (KDD)

KDD refers to the duplication of the gene segment encoding a protein kinase domain, which results in a protein with multiple kinase domains from a single gene. KDDs have been identified in tumor types that potentially contribute to acquired resistance and show sensitivity to matched targeted therapies.

In a large-scale clinical sequencing study by Gay et al.⁴², 114,200 patients with advanced tumors underwent CGP to test 184–406 tumor-related genes. Among these patients, 598 (0.62%) exhibited KDD with MET-KDD accounting for 3.18% (19/598). In 2019 the AACR reported the first data on MET-KDD in the Chinese lung cancer population; the incidence of MET-KDD was 0.09% (6/6837)⁴³.

Plenker et al.²⁰ reported a case of MET-KDD in a 60-year-old male diagnosed with ALK fusion-positive lung adenocarcinoma. After chemotherapy led to stable disease, treatment with ceritinib resulted in a partial response lasting 3 months before progression occurred. Subsequent NGS revealed a newly acquired MET-KDD, while the ALK fusion persisted. Treatment with crizotinib resulted in another partial response, which was sustained for 3 months.

MET overexpression and the pathogenic mechanisms

MET overexpression results from various MET gene alterations, such as MET amplification and exon 14 skipping mutations. These changes lead to overproduction or impaired degradation of the c-MET protein, leading to sustained abnormal activation of downstream pathways, such as HGF/MET. This process promotes increased cell proliferation, invasion, inhibition of apoptosis, and angiogenesis, driving tumor growth and metastasis.

It has been reported that MET protein overexpression occurs in 13.7%–63.7% of NSCLC cases^44–46. Among EGFR-mutant advanced NSCLC patients treated with EGFR-TKIs, the incidence ranges from 30.4%–37.0%⁴⁵.

MET protein overexpression has been incorporated into the inclusion criteria for several clinical trials of MET inhibitors, such as INSIGHT, TATTON, and SAVANNAH, due to its significance as a biomarker^47–49.

The correlation between MET protein overexpression and other MET alterations is low between MET protein expression, as measured by IHC staining, and exon 14 skipping mutations^50–52.

The relationship between MET overexpression and MET amplification remains an area of active investigation. Data from the TATTON study revealed that 80% of patients who developed MET protein overexpression (≥ 50% of tumor cells with a 3+ score) after acquiring resistance to EGFR-TKIs also exhibited MET gene amplification (MET GCN ≥ 5 or MET/CEP7 > 2)⁵³. In contrast, a study of 181 lung adenocarcinoma patients who had not received targeted therapy showed that only 1% of patients with MET protein overexpression (IHC score ≥ 200) had MET gene amplification⁵⁰. Patients without MET amplification may still have MET overexpression and could potentially benefit combining EGFR TKIs and MET inhibitors based on clinical studies^47,49.

Detection of MET fusion (MET exon 14 skipping mutation)

Methods for detecting MET exon 14 skipping mutations^54–57 include Sanger sequencing, FISH, RT-PCR, and NGS. Among these methods, Sanger sequencing is less commonly used due to low sensitivity and throughput. FISH is limited in detecting complex or novel fusion types⁵⁸. NGS is increasingly favored in clinical practice for the ability to detect a wide range of gene fusions. Given the diverse forms of MET exon 14 skipping mutations, special attention is needed in clinical testing and interpretation⁵⁹.

Detection of MET mutations

MET mutations can be detected using traditional methods that target specific gene regions or NGS, which enables the simultaneous detection of multiple gene mutations and is ideal for comprehensive genomic analysis.

DNA-based hybrid capture NGS is the preferred method for detecting MET gene point mutations. This method uses a stable DNA template, ensuring complete coverage of all exon sequences in the MET gene and enabling accurate identification of missense mutations. Hybrid capture probes are specially designed to amplify genomic regions comprehensively, eliminate duplicate sequences, and reduce analytical noise. Moreover, targeted coverage of intronic regions can prevent primer binding issues while simultaneously detecting genomic variations within these regions. The hybrid capture approach, which spans the entire genome, also corrects sequencing biases and minimize allele dropout. This method also provides superior accuracy for detecting missense mutations⁶⁴.

Detection of MET amplification

The primary methods for detecting MET gene amplification are FISH and NGS. FISH is considered the gold standard for detecting MET amplification. However, the criteria for defining MET gene amplification and the clinical benefit threshold remain unclear.

The MET gene is located on chromosome 7 and trisomy or polysomy of chromosome 7 is a common pan-cancer genetic marker that can be misinterpreted as MET amplification⁶⁵. FISH is particularly useful in distinguishing between these anomalies. In cases of chromosome 7 polysomy, the ratio of the MET gene-to-the centromere of chromosome 7 (MET/CEP7) remains unchanged. Converstly, a higher MET:CEP7 ratio indicates focal amplification of the MET gene.

FISH

FISH uses fluorescent probes to label the MET gene in situ, enabling direct observation of MET fluorescent signals in individual tumor cells under a microscope to calculate the MET gene copy number. FISH can also label the MET gene and CEP7 to determine the MET:CEP7 ratio in tumor cells.

Currently, no standardized interpretation guidelines exist for detecting MET amplification via FISH (Figure 2), but accurate patient stratification is crucial for effective MET-targeted therapies⁶⁶. The primary criteria used in clinical practice are the University of Colorado Cancer Center (UCCC) and Cappuzzo criteria. The inclusion criteria typically include MET GCN ≥ 5 or MET/CEP7 ≥ 2 in clinical trials investigating MET gene amplification as a resistance mechanism to EGFR-TKIs^47,67. A post-hoc subgroup analysis of a Ib/II trial combing capmatinib and gefitinib in NSCLC patients demonstrated that a MET GCN > 6 threshold, as detected by FISH, offered the best predictive performance for treatment efficacy⁶⁸. A retrospective study categorized the MET:CEP7 ratio into the following three amplification levels: low (≥ 1.8 to ≤ 2.2); intermediate (> 2.2 to < 5); and high (≥ 5)³⁷. However, the study evidence level was weaker than multicenter clinical trial findings. A phase I clinical study (NCT02896231) enrolled 17 advanced NSCLC patients with primary MET amplification, which was defined as a GCN ≥ 5 by FISH or a MET copy number ≥ 2.25 by NGS. Treatment with bozitinib yielded an objective response rate (ORR) of 41.2%⁶⁹, supporting the use of MET inhibitors in patients with MET GCN ≥ 5.

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Figure 2

Judgment criteria of MET dual probe in situ hybridization testing.

Detection of MET-KDD

The main methods for detecting KDD in genes are discussed below.

Detection of MET overexpression

IHC is the method used to detect MET protein overexpression. This technique relies on specific antigen-antibody binding, in which a labeled antibody is conjugated to a chromogenic agent, such as a fluorophore, enzyme, metal ion, or isotope. Upon reaction, the chromogenic agent produces a color change, which enables the identification of antigens (peptides and proteins) within tissue cells. This process allows for the localization, qualitative analysis, and relative quantification of the target proteins. Several antibodies used wordwide for MET detection have been approved as domestic medical device products in China involving various clone numbers. The staining performance of different antibodies varies and there is no standardized interpretation criterion (Table 1).

Current interpretation standards in clinical research combine the intensity of antibody expression with the percentage of tumor cells exhibiting that expression. In the TATTON and SAVANNAH studies, patients with MET IHC ≥ 50% strong tumor cell staining (3+) were enrolled using the SP44 antibody clone⁶⁷. The INSIGHT study enrolled patients with moderate (2+) or strong (3+) staining in ≥ 50% of tumor cells using the D1C1 antibody clone⁴⁷. The NCT01610336 study also enrolled patients with moderate (2+) or strong (3+) staining in ≥ 50% of tumor cells using the 3077 antibody clone⁶⁸. Given the diversity of antibodies and the lack of standardized interpretation criteria, comparative studies are needed to assess consistency among different antibodies. Moreover, further clinical research is required to validate the clinical significance of MET protein overexpression and refine interpretation criteria and benefit thresholds. Clinical studies currently recommend that IHC testing results should include at least the information on the antibodies used, the percentage of positive tumor cells, and the staining intensity. Comparison of MET alteration testing methods and recommendation level in NSCLC is listed in Table 2.

Reporting standards for MET exon 14 skipping mutation

The following should be included in DNA-based NGS reports: a clear description of the mutation (e.g., MET exon 14 skipping mutation); mutation site information; variant allele frequency; and reference transcript [commonly used MET gene transcripts are NM_000245 and NM_001127500 (attention should be given to the differences in sequence numbering between them)]. The report should clearly indicate whether the variation causes a MET exon 14 skipping mutation. If uncertain, whether the variation causes a MET exon 14 skipping mutation should be detailed in the variant interpretation section. The methods section should specify the coverage of MET exons and introns to enable physicians to fully assess the detection capability. For RNA-based tests, such as RT-PCR and RNA sequencing, the report should explicitly state if the mutation involves MET exon 14 skipping.

Reporting standards for MET gene amplification

The following should be included in FISH detection reports: the number of tumor cells assessed; the average MET copy number per cell; the average CEP7 copy number per cell; the ratio of average MET copy number-to-average CEP7 copy number; and the proportion of tumor cells exhibiting amplification. The MET gene amplification status should be determined based on applicable criteria with a clear differentiation between focal amplification and polysomy when positive. The NGS report should provide a clear description of the variant information, gene copy number details, and the positive threshold for MET gene copy number variation, as determined by the testing platform. For NGS reports of MET gene amplification using liquid samples, the report should include details on the higher false-negative rate caused by low sensitivity of liquid biopsy, the positive thresholds specific to liquid biopsy, and any limitations of the method, in addition to the standard information provided.

Reporting standards for MET overexpression

The IHC report for MET testing should include the following: patient details (including name, gender, age, and outpatient/inpatient ID); name of the responsible physician; date of specimen submission; pathology report identification number; specimen collection site; specimen type; antibody information; detection method; whether image analysis was used; control settings; whether the sample size is sufficient for evaluation; and result interpretation (i.e., 0, 1+, 2+, or 3+).

Sample selection and processing method

It is advisable to collect samples at one time to preserve tumor tissue specimens for molecular testing, which can meet the requirements for both pathologic and molecular diagnoses. NGS multi-gene testing is recommended for patients who develop treatment resistance and require furgher biopsies to detect genetic alterations or explore resistance mechanisms. This approach allows for comprehensive genetic information from limited specimens and reduces the need for additional invasive sampling and guiding subsequent treatment decisions.

All tissue and cytology specimens must undergo quality control by a pathologist to evaluate the tumor type, cell content, necrosis and hemorrhage rates, and stroma. It is necessary to select the appropriate type of histologic specimen for molecular testing and to ensure an adequate number of tumor cells for DNA or RNA extraction. If feasible, tumor enrichment procedures may also be performed to maximize tumor content in the specimen. After routine histologic diagnosis, sufficient tissue should be preserved for molecular biological testing to guide treatment based on molecular profiling^79,80. Adequate tissue must be retained to allow for molecular profiling for advanced NSCLC^79–86.

The primary sample types for MET detection include tumor tissue, cytology samples, and body fluid samples. MET exon 14 skipping mutations can be detected using RNA and it is important to ensure timely fixation and appropriate storage to prevent RNA degradation. Formalin-fixed paraffin-embedded samples, cell blocks, and cell smears are acceptable for molecular testing, while acid-treated specimens should be avoided^82,87,88.

When selecting an appropriate testing method, laboratory conditions, sample type, sample quantity, and quality control results should be considered. Liquid biopsy samples can serve as a supplementary testing option when tumor tissue and cytology samples are unavailable and the limitations of using such samples must be clearly stated in the test report.

Internal and external quality control of MET testing

A robust quality control system is crucial for ensuring the reliability of pathologic diagnosis and the accuracy of MET testing in clinical practice. Laboratories should establish standard operating procedures (SOPs) and quality control systems.

Capmatinib

Capmatinib is the first highly selective single-target MET inhibitor approved worldwide. It is administered at 400 mg BID under fasting conditions.

Capmatinib has shown good efficacy in both treatment-naïve and previously-treated NSCLC patients with MET exon 14 skipping mutation. Patients receiving capmatinib as a first-line treatment exhibit a higher ORR and disease control rate (DCR), as well as longer duration of response (DoR) and progression-free survival (PFS). Capmatinib approval was mainly based on results from a pivotal study for new drug registration (the prospective, non-randomized, open-label phase II GEOMETRY mono-1 study)⁷³. Ninety-severn patients with MET exon 14 were enrolled and the primary efficacy endpoint was the ORR assessed by the Blind Independent Review Committee (BIRC). The results showed that the ORR was 68% and 41%, the DCR was 96% and 78%, the DoR was 12.6 and 9.7 months, and the PFS was 12.4 and 5.4 months in treatment-naïve and previously-treated patients, respectively⁷³. A total of 14 patients in the study had brain metastases at baseline. Among the 14 patients, 13 (3 treatment-naïve and 10 previously-treated) were evaluable for tumor assessment. Seven patients achieved a partial response (including 4 complete responses), while 12 had stable disease.

Capmatinib demonstrates preliminary efficacy in NSCLC patients with MET primary amplification, especially among those NSCLC patients with a high GCN. In the OMETRY mono-1 study, 15 treatment-naïve patients had a MET GCN ≥ 10 and 69, 42, 54, and 30 previously-treated patients had a MET GCN ≥ 10, 6–9, 4–5, and < 4, respectively. The ORR was 40%, 29%, 12%, 9%, and 7%, the median DOR was 7.5, 8.3, 24.9, 9.7, and 4.2 months, and the median PFS was 4.2, 4.1, 2.7, 2.7, and 3.6 months among the corresponding cohorts, respectively.

Capmatinib has also been evaluated in combination with first- and third-generation EGFR-TKIs for NSCLC patients with acquired resistance to EGFR-TKIs and MET amplification or MET overexpression. In these patients, capmatinib combined with gefitinib preliminarily showed antitumor activity, especially in the high MET amplification group (GCN ≥ 6: ORR = 47%; mPFS = 5.5 months), whereas in MET-overexpressing patients (IHC 3+) the efficacy was slightly inferior (ORR = 32%, median PFS = 5.45 months)⁶⁸. When capmatinib was administrated in combination with nazartinib, the ORR was 43.5% and 27.9%, the DoR was 6.3 and 9.3 months, the PFS was 7.7 and 5.5 months, and the OS was 18.8 and 17.2 months in patients with EGFR-TKI resistance and MET amplification (GCN ≥ 4) or MET overexpression (IHC 3+) and in those with negative MET alterations, respectively⁹⁰.

Capmatinib has shown good overall safety and tolerability, with the most common adverse reactions being peripheral edema, nausea, vomiting, and increased blood creatinine, most of which were grade 1 or 2. The study enrolled 15 Chinese patients, who achieved an ORR of 53.3%. Although the DOR, PFS, and OS have not been reached, the safety profile was consistent compared to the overall population⁹¹. However, capmatinib caused interstitial pneumonia in 4.8% of patients, of which 1.9% was grade ≥ 3 and 1 death was reported⁹².

The overall ORR was 20% in NSCLC patients with MET alterations (IHC 2+/3+, H-score ≥ 150, or MET/CEP ≥ 2.0, GCN ≥ 5, or EGFR wild type and IHC 3+, n = 55) treated with capmatinib, reaching up to 47% in patients with a GCN ≥ 6 (n = 15). The median PFS was up to 9.3 months⁴⁷.

Tepotinib

Tepotinib is an oral, highly selective type IB MET-TKI.

The VISION study⁹³ was a phase II clinical study that investigated the efficacy and safety of tepotinib in metastatic NSCLC with MET exon 14. The VISION study⁹³ enrolled 152 MET exon 14-positive patients to receive tepotinib (500 mg PO QD), among whom 99 had a follow-up duration > 9 months and were included in the efficacy analysis. The overall ORR (IRC-assessed) was 46.5% (44.2%, 48.5%, and 47.8% as the first-, second-, and third or above-line therapy, respectively). The median DoR, PFS, and OS were 11.1, 8.5, and 17.1 months, respectively. In recently updated data⁹⁴, the VISION study enrolled 313 MET exon 14-positive patients in cohorts A and C, who were followed for > 35 and > 18 months, respectively. The overall efficacy was generally consistent with the efficacy reported for the first time. The median DoR, PFS, and OS increased with a prolonged duration of follow-up and the ORR (IRC-assessed) was 51.4% (44.2%, 48.5%, 48.2%, and 47.8% as the first-, second-, second or above-, and third or above-line therapy, respectively). The median DoR, PFS, and OS were 18, 11.2, and 19.6 months, respectively. The ORR was 57.3% and the median DoR, median PFS, and median OS were 46.4, 12.6, and 21.3 m, respectively, in treatment-naïve patients. The ORR was 45% and the median DoR, median PFS, and median OS were 12.6, 11, and 19.3 months, respectively, in previously-treated patients. The ORR in intracranial lesions was 66.7%, the overall ORR was 56.1%, and the median DoR, PFS, and OS were 9, 8.5, and 17.5 months, respectively, in 15 patients with brain metastases at baseline.

Tepotinib achieved an ORR of 41.7%, a median DoR of 14.3 months and a median PFS of 4.2 months in the 24 patients with MET amplification (MET GCN ≥ 2.5 by NGS) included in the VISION study. Tepotinib has also been investigated in multiple studies for populations with MET secondary amplifications. Tepotinib combined with gefitinib was significantly more effective than chemotherapy in patients with acquired resistance to EGFR-TKIs (ORR: 67% vs. 42.9%; PFS 16.6 vs. 4.2 months, HR = 0.13, 90% CI = 0.04–0.43; OS: 37.3 vs. 13.1 months, HR = 0.08, 90% CI = 0.01–0.51) in the randomized, controlled, phase II INSIGHT study⁹⁵. Forty-three patients achieved a PR, the ORR was 43.9%, and the median PFS was 5.4 months among 98 patients with positive FISH tests (MET GCN ≥ 5 and/or MET/CEP7 ≥ 2) in the INSIGHT2 study in which the efficacy and safety of tepotinib was assessed in the MET-amplified population with resistance to first-line osimertinib.

The most common adverse reactions to tepotinib were peripheral edema, nausea, diarrhoea, and increased blood creatinine, most of which were grade 1 or 2, demonstrating good overall safety and tolerability with manageable and controllable adverse reactions. One patient died of respiratory failure due to interstitial lung disease (ILD), which was considered related to tepotinib by the investigator.

Savolitinib

Savolitinib, a highly selective type IB MET-TKI, is the first approved type Ib MET inhibitor with independent intellectual property rights in China.

A Chinese multicenter, open-label, single-arm phase II clinical trial (HMPL-504) enrolled a total of 70 patients (including 25 patients with pulmonary sarcomatoid carcinoma) with unresectable or metastatic NSCLC with MET exon 14 to evaluate the efficacy, safety, and pharmacokinetics of savolitinib (600 mg po QD for patients with a body weight ≥ 50 kg and 400 mg po QD for patients with a body weight < 50 kg)^96,97. Among the 70 patients, 42 (60%) received at least 1 prior systemic treatment, 28 (40%) were naïve, 8 were treated with savolitinib (400 mg), and the remaining patients were treated with savolitinib (600 mg). The efficacy results showed that the overall ORR (IRC-assessed) was 42.9%, the DCR was 82.9%, and the median DoR, median PFS, and median OS were 8.3, 6.8, and 12.5 months, respectively. Savolitinib showed consistent benefits across subgroups. Specifically, the ORR was 40% and 44.4%, the median DoR was 17.9 and 8.3 months, the median PFS was 5.5 and 6.9 months, and the median OS was 10.6 and 17.3 months for pulmonary sarcomatoid carcinoma and other NSCLC histologic subtypes, respectively. The ORR was 46.4% and 40.5%, the median DoR was 5.6 and 9.7 months, the median PFS was 5.6 and 6.9 months, and the median OS was 10.9 and 19.4 months for treatment-naïve and previously-treated patients, respectively. Brain metastases were not selected as the target lesion in the efficacy assessment by IRC. Among the 3 patients in whom brain metastases were selected as the target lesion by the investigator, the intracranial lesions achieved a tumor response, and the median OS was up to 17.7 months in patients with brain metastases at baseline. The research team presented the data from a confirmatory, single-arm, multicenter, phase IIIb study at the 2023 World Conference on Lung Cancer⁹⁸. In this study 87 treatment-naïve NSCLC patients with MET exon 14 were enrolled and 84 patients were included in the efficacy assessment by IRC with an ORR of 59.5%, a DCR of 95.2%, and a median PFS of 12.6 months; the DoR and the median OS have not been reached.

The TATTON study was a multi-cohort, multicenter, phase Ib study to evaluate the efficacy and safety of savolitinib combined with osimertinib in patients with previously treated EGFR mutation-positive lung cancer with MET amplification. The combined treatment showed an ORR of 33%–67% and a PFS, DoR, and OS of 5.5–11.1, 9.5–11, and 18.8–30.3 months, respectively, across cohorts. In patients with third-generation EGFR-TKI resistance and MET amplification, the ORR was 30% and the PFS was 5.5 m⁵³. The SAVANNAH study is an ongoing, randomized, single-arm, global multicenter, phase II clinical trial to evaluate the efficacy of savolitinib combined with osimertinib in patients with locally advanced or metastatic NSCLC who have progressed on osimertinib. Partial data from the SAVANNAH study were published by Whampoa in 2022. The available results showed that among all patients with high MET levels (IHC 90+ and/or FISH 10+), the ORR was 49%. In patients with high MET levels who had not received chemotherapy, the highest ORR was 52%. In patients who did not have high MET levels, the ORR was 9%.

The most common adverse reactions to savolitinib were peripheral edema, nausea, and elevated hepatic enzymes; drug-induced ILD was not reported.

Glumetinib

Glumetinib (SCC244) is a potent and highly selective small molecule type Ib MET inhibitor. The pivotal phase II GLORY study was an open-label, international multicenter phase II clinical study to investigate the efficacy and safety in patients with locally advanced or metastatic NSCLC with MET exon 14 who had received ≤ 2 prior systemic treatments or no prior systemic treatment⁹⁹. In this study 84 Chinese and Japanese patients were enrolled and received glumetinib (300 mg po QD), of whom 79 were included in the efficacy analysis, including 44 treatment-naïve and 35 previously-treated patients. The efficacy results showed that the primary endpoint ORR assessed by BIRC was 66% (71% in the treatment-naïve population and 60% in the previously-treated population), the secondary endpoint DCR was 84% (89% in the treatment-naïve population and 77% in the previously-treated population), the median DoR was 8.3 months (15 months in the treatment-naïve population and 8.2 months in the previously-treated population), the median PFS was 8.5 months (11.7 months in the treatment-naïve population and 7.6 months in the previously-treated population), and the median OS was 17.3 months (not reached in the treatment-naïve population and 16.2 months in the previously-treated population). The efficacy benefit trends were consistent across preset subgroups. A total of 14 patients had brain metastases at baseline. Thirteen patients were evaluable for efficacy and the ORR assessed by BIRC (intracranial lesions were not selected as the target lesion) was 85%. Five patients with brain metastases were selected as the target lesion by the investigator and all achieved intracranial objective responses. A total of 98% of patients receiving glumetinib experienced adverse reactions, of which approximately half were grade > 3 in severity. The most common adverse reactions were edema, hypoproteinaemia, headache, and decreased appetite. Among the adverse reactions, headaches were a relatively specific adverse reaction.

Vebreltinib

Vebreltinib (formerly bozitinib APL-101/PLB-1001, CBT-101) is a highly selective type IB MET-TKI. The multicenter phase II KUNPENG study^100,101 enrolled a total of 52 patients with locally advanced or metastatic advanced NSCLC with MET exon 14 to receive vebreltinib (200 mg po BID). As of 9 August 2022 the efficacy results showed that the BIRC-assessed ORR was 75% (77.1% in the treatment-naïve population and 70.6% in the previously-treated population), the DCR was 96.2%, the median DoR was up to 15.9 months (16.5 months in the treatment-naïve population and 15.3 months in the previously-treated population), the median PFS was up to 14.1 months (14.5 months in the treatment-naïve population and 7.7 months in the previously-treated population), the overall median OS was 20.7 months (20.3 months in the treatment-naïve population and 20.7 months in the previously-treated population), and the median time-to-response (TTR) was 1.0 month. Subgroup analysis showed that lung cancer patients with baseline brain or liver metastases or old age (≥ 75 years) all benefited from treatment with vebreltinib with ORRs of 100.0%, 66.7%, and 85.7%, respectively. In 12 patients with MET amplification, the ORR was up to 100%¹⁰⁰.

In addition, vebreltinib was also investigated in populations with primary MET amplification. Cohorts 2 and 3 of the KUNPENG study included patients with primary MET amplification who had failed standard treatment and treatment-naïve patients with primary MET amplification, respectively. As of 14 May 2024, 33 and 53 patients were enrolled in cohorts 2 and 3, respectively, and a total of 80 patients were included in the efficacy-evaluable analysis set. The results showed a BIRC-assessed ORR up to 52.5% (53.3% in the previously-treated cohort and 52.0% in the treatment-naïve cohort), a DCR of 83.8% (86.7% in the previously-treated cohort and 82.0% in the treatment-naïve cohort), a median TTR of 0.95 months (1.05 months in the previously-treated cohort and 0.95 months in the treatment-naïve cohort), a median DoR of 11.1 months (11 months in the previously-treated cohort and 11.1 months in the treatment-naïve cohort), a median PFS of 8.3 months (7.4 months in the previously-treated cohort and 8.3 months in the treatment-naïve cohort), and a 12-month PFS rate of up to 35.8%. The FAS analysis showed a median OS of 13.2 months (11.2 months in the previously-treated cohort and 15.5 months in the treatment-naïve cohort). Vebreltinib had good overall safety with the most adverse reactions in grades 1 and 2 and the most common adverse reactions were peripheral edema, hypoproteinemia, and anemia.

Ensartinib

Both crizotinib and ensartinib are type Ia MET inhibitors that compete at the specific sites of multiple MET kinases, including Y1230 and G1163. Crizotinib has been investigated and demonstrated preliminary efficacy in populations with MET exon 14 and MET amplification.

In the PROFILE1001 study 65 patients in the cohort with MET exon 14 received crizotinib and were evaluable for efficacy. The results showed an ORR of 32%, including 3 patients with a complete response and a median PFS, median DoR, and median OS of 7.3, 9.1, and 20.5 months, respectively¹⁰².

In the PROFILE1001 study, 38 patients with a primary MET amplification and a MET:CEP7 ratio ≥ 1.8 received crizotinib and were tested by FISH¹⁰³. Twenty-one patients with high MET amplification (a MET:CEP7 ratio ≥ 4), 14 patients with moderate amplification (a MET:CEP7 ratio > 2.2 and a MET:CEP7 ratio < 4), and 3 patients with low amplification (a MET:CEP7 ratio ≥ 1.8 and a MET:CEP7 ratio ≤ 2.2) had ORRs of 8/21 (38.1%), 2/14 (14.3%), and 1/3 (33.3%), a median DOR of 5.2, 3.8, and 12.2 months, and a median PFS of 6.7, 1.9, and 1.8 months, respectively. In two other studies^104,105, after crizotinib treatment the ORR was only 27% in the population with moderate-to-high MET amplification (a MET:CEP ratio > 2.2) and only 16% in the population with high amplification (a MET:CEP ratio × 6.0).

Ensartinib is a second-generation ALK inhibitor that overcomes crizotinib-induced resistance mutations and has significant intracranial antitumor activity. Ensartinib also has some inhibitory effect on MET exon 14. In a study published by Xia et al.¹⁰⁶, 29 MET exon 14-positive patients treated with ensartinib achieved an ORR up to 69% and a median PFS and DoR of 6.1 and 6.8 months, respectively. A recent phase II trial further confirmed the activity of ensartinib in MET exon 14-positive NSCLC, showing an ORR of 53.3%, a DCR of 86.7%, an mPFS of 6.0 months, and a median DoR of 7.9 months¹⁰⁷. The toxicity profile differs from type Ib MET inhibitors, which is an essential addition to the MET field. However, neither crizotinib nor ensartinib has been approved for use in patients with MET-altered NSCLC. Efficacy of anti-MET agents in NSCLC with MET alterations is listed in Table 3.

Choice other than sMETi

In addition to MET-TKIs, bispecific antibodies and antibody-drug conjugates (ADCs) targeting MET have also made some breakthroughs in recent years.

Chemotherapy

Before the advent of targeted therapy and immunotherapy, chemotherapy was the standard treatment option for patients with advanced NSCLC. Platinum-based doublet chemotherapy achieved a 1-year survival rate of 30%–40%. Currently, first-line chemotherapy is mainly used in patients who are not candidates for targeted therapy or immunotherapy. A retrospective study¹¹⁴ showed that only 1 (9%) patient achieved a partial response after chemotherapy among 11 NSCLC patients with MET exon 14 and a median time-to-treatment discontinuation of 2.8 months. A systematic retrospective analysis of 39 studies involving 3989 NSCLC patients¹¹⁵ revealed that in NSCLC patients with MET exon 14, the ORR was 50.7%–68.8% in patients receiving targeted therapy (MET-TKIs) and 23.1%–27.0% in patients receiving chemotherapy. Patients receiving chemotherapy had a significantly lower ORR than patients receiving targeted therapy. In another report from Korea¹¹⁶, the median PFS and OS of first-line chemotherapy in NSCLC patients with MET exon 14 were 4.0 and 9.5 months, respectively, with an ORR of 33.3% in patients receiving pemetrexed-containing chemotherapy regimens (n = 12). The analysis of a study of 850 East Asian lung cancer patients¹¹⁷ showed that the median OS was only 6.7 months after conventional chemotherapy in 18 NSCLC patients with MET exon 14. A retrospective analysis of 148 NSCLC patients with MET exon 14 in the United States¹¹⁸ showed patients who did not receive MET inhibitors (87.5% receiving chemotherapy and 12.5% receiving immunotherapy) had a significantly lower OS than patients who received MET inhibitors (8.1 months vs. 24.6 months). To date there are few data on chemotherapy in NSCLC patients with MET gene mutations, most of which were small retrospective studies. Based on the available data, chemotherapy has limited efficacy in NSCLC patients with MET gene mutations compared to selective MET TKIs, although there is a reported tumor response.

Whether chemotherapy combined with PD-1/PD-L1 inhibitors is the best therapy for NSCLC with MET alterations

Targeted therapy is the preferred treatment option for driver gene-positive NSCLC compared to ICIs, which has been demonstrated in EGFR-mutated, ALK-positive NSCLC patients. Unlike the above targets, MET exon 14-altered patients usually have a history of cigarette smoking and a significant number of patients are positive for PD-L1 expression, which makes the correlation between MET exon 14 mutation status and immunotherapy effect more complex.

The results of multiple studies^119,120 showed that there is no clear correlation between ICI efficacy and PD-L1 expression status in MET-altered NSCLC patients.

Chemotherapy combined with immunotherapy is less effective than driven gene therapy in first-line studies of NSCLC with MET alterations. As reported by Furqan et al.¹²¹, a real-world study analysis of 287 advanced NSCLC patients with definite MET exon 14 showed that patients with MET exon 14 receiving capmatinib as first-line treatment had a higher real-world ORR (rwORR), longer real-world PFS (rwPFS), and OS compared to platinum-based chemotherapy, ICI monotherapy, or immunotherapy combined with chemotherapy; the rwORR was 73.4%, the rwPFS was 68% at 18 months, and the OS was 92.6% at 18 months.

Among first-line studies involving patients with NSCLC and MET alterations, ICI monotherapy was inferior to other first-line therapies. Leighl et al.¹²² conducted a real-world analysis of 138 advanced NSCLC patients with MET exon 14 divided into high, low, absent, and unknown PD-L1 expression groups according to the tumor proportion score (TPS). The most common first-line regimen was ICI monotherapy, immunotherapy combined with chemotherapy, and chemotherapy alone for the high, low, and negative PD-L1 expression groups, respectively. In the high PD-L1 expression group, ICI monotherapy was less effective with a shorter median PFS and median OS than other first-line regimens (median PFS: 4.1 months vs. 5.4 months; median OS: 11.4 months vs. 17.0 months). No PFS and OS data were reported for first-line METi therapy in patients with high PD-L1 expression.

A prospective exploratory analysis¹²³ showed no significant differences in the ORR, PFS, and OS in patients receiving nivolumab regardless of MET amplification. In contrast, patients with high-level MET gains had a better ORR than patients with low-level MET gains.

In a phase II, multicenter, open-label clinical trial¹²⁴ to investigate the therapeutic effect of capmatinib combined with PD-1, advanced lung cancer patients without EGFR gene mutations who progressed on the first systemic treatment received capmatinib combined with PD-1. Patients participating in the study were first assessed for MET mutations and divided into high- and low-MET groups. The results showed that patients benefited from the two drugs regardless of MET mutation status, even patients without MET mutations.

Treatment strategies for NSCLC with acquired MET alterations

Acquired MET alterations have emerged as an important resistance mechanism to EGFR-TKI therapy in NSCLC patients with EGFR-sensitive mutations through high affinity for RTKs and sustained activation of RTK signaling pathways¹²⁵. Acquired MET amplification is one of the most common acquired resistance alterations and is currently being investigated as a therapeutic target in some studies. Whereas targeted therapy for MET may also lead to acquired resistance by acquired point mutations in MET, this further increases the therapeutic and diagnostic challenges¹²⁶.

According to previous studies, MET-TKIs [tepotinib or capmatinib (INC280)] combined with gefitinib have achieved good responses and prolonged PFS in populations with acquired MET amplification. Sun et al.¹²⁷ compared the efficacy of chemotherapy combined with bevacizumab, MET-TKIs, and EGFR-TKIs in 9 NSCLC patients with acquired MET amplification and the results showed that chemotherapy combined with bevacizumab might benefit patients with EGFR-sensitive mutations and acquired MET amplification after EGFR-TKI failure and warranted further prospective studies with large samples.

Drug resistance and type II MET inhibitors

In addition to type I inhibitors, MET-TKIs include types II and III, depending on the mode of binding to MET kinase. Type II TKIs are also ATP-competitive and predominantly bind to the inactive conformations of MET kinases in a manner that may help overcome resistance caused by mutations in some MET kinase domains. Cabozantinib, merestinib, glesatinib, foretinib, and ANS014004 are all type II TKIs^128–130 that have been investigated in clinical trials in a variety of solid tumors and have shown some antitumor activity in patients with lung cancer and an ORR of 17.8% in NSCLC patients treated with foretinib¹³¹ and up to 30% in NSCLC patients with MET mutations treated with glesatinib¹³⁰. Unlike type I and II TKIs, type III TKIs bind to an allosteric site of MET kinase, induce conformational changes in the MET kinase, and thereby inhibit its activity¹³². To date no type II or III MET-TKIs have been approved for MET-altered NSCLC, but data suggest that the combination of type Ib and type II MET-TKIs can overcome the resistance produced by type Ib MET-TKIs.

Like other TKIs, patients receiving MET-TKIs may progress due to secondary resistance. The mechanisms of secondary resistance are generally divided into two categories (MET-dependent and -independent). MET-dependent resistance mainly includes secondary mutations in the MET kinase domain and amplification of the MET gene, which account for about one-third of all resistance cases. Mutations at positions H1094, G1163, L1195, D1228, and Y1230 of the MET gene and allelic amplification in exon 14 of MET have been shown to be associated with the resistance mechanisms to MET-TKIs, such as crizotinib and capmatinib. MET-independent resistance involves sustained activation of MET downstream signaling pathways, such as alterations associated with the RAS/MAPK and PI3K/AKT pathways and activation of bypass signaling pathways, including amplification or other mutations in genes, such as EGFR, BRAF, and KRAS¹³³.

Because type I/II MET-TKIs induce resistance by mutations at different loci, sequential or combined use of MET TKIs with different structures may become a therapeutic strategy to overcome MET-dependent resistance. Preclinical studies showed that glesatinib, a type II MET-TKI, overcame resistance caused by the Y1230H or Y1230S mutation. Foretinib, a type II MET-TKI, showed inhibitory effects on the capmatinib/tepotinib-induced Y1230X and D1228X mutations^134,135 and the combination of capmatinib and a type II MET-TKI (merestinib) inhibited the development of common resistance mutations¹³⁶. Type II MET TKI ANS014004 bound to the inactive conformation (DFG-out) of MET in the ATP pocket by extension into the hydrophobic back pocket. In vitro studies showed that ANS014004 had superior antitumor activity against the MET Y1230H mutation and the MET D1228A mutation to cabozantinib and merestinib, suggesting that ANS014004 holds promise to overcome acquired resistance to type I MET TKIs. Clinical data have also confirmed the feasibility of this strategy. A phase II study showed that capmatinib had some efficacy in crizotinib-resistant patients with MET exon 14 mutation with an ORR of 10%, DCR of 80%, and mPFS of 5.5 months in 20 patients¹³⁷. Several case reports have also suggested that cabozantinib can overcome resistance resulting from crizotinib-induced MET D1228N and D1246N mutations^138,139. The combination of drugs targeting corresponding pathways is a feasible strategy against MET-independent resistance. Preclinical studies have demonstrated the excellent efficacy of dual inhibition of MET and other pathways in cell lines and/or xenograft models^133,140,141. In the MET-2 cohort of the phase I CHRYSALIS study involving amivantamab, 19 patients with MET exon 14 mutations who progressed on MET-TKI therapy had an ORR of 21% on amivantamab¹⁰⁷. In addition, sintilimab (an ICI) combined with chemotherapy ± bevacizumab significantly improved PFS compared to chemotherapy in EGFR-TKI-failed EGFR-positive non-squamous NSCLC^142,143. This also provides some reference for MET-TKIs in the treatment of progressed NSCLC after resistance.

Toxicity management

MET TKIs have good overall tolerability with only a few patients discontinuing treatment due to adverse reactions. Common adverse reactions to MET-TKIs include peripheral edema, hypoalbuminemia, nausea, vomiting, and hepatic function abnormalities. However, each MET TKI currently marketed has a different spectrum of adverse reactions and for specific adverse reactions, targeted preventive, monitoring, and therapeutic measures should be taken. Given that MET exon 14 is more common in elderly patients who need more attention paid to adverse reaction management, we should properly manage adverse reactions caused by MET-TKIs by standardized diagnosis and treatment protocols and preventive measures.

It should be noted that MET-TKI-induced edema may not be immediately symptomatic and the onset of adverse reaction edema varies between drugs. We should measure body weight early and prevent edema by wearing support stockings, elevating the foot of the bed, reducing salt intake, and encouraging patients to maintain daily activities and appropriately increase exercise. Once edema occurs, we should closely monitor the skin, avoid injury, and if necessary, use diuretics and lymphatic drainage.

The pathogenesis of hypoalbuminemia is unknown. Given the potential mechanism underlying hypoalbuminemia in NSCLC patients treated with MET TKIs, a high-protein diet alone may not be sufficient for control and albumin infusion or diuretics may provide transient benefit and/or prevent disease progression. A high-protein diet is unlikely to resolve hypoalbuminemia until the underlying cause is resolved. For grade ≥ 3 hypoalbuminemia, dose reduction or MET TKI interruption should be considered.

Management of rashes includes pre-dose evaluation, using mild emollients, sunscreen agents, and cleansing solutions, and avoiding long-time bathing or bathing in hot water to effectively protect and repair the skin barrier function and reduce the occurrence of skin adverse reactions to a certain extent. After evaluation combined with the specific rash types, targeted therapy should be adopted, treatment should be discontinued in a timely fashion or the dose should be reduced, drug metabolism and excretion should be promoted, initiate anti-inflammatory therapy in a timely fashion, prevent and treat infections, and strengthen supportive treatment and wound care.

In addition, we should promptly identify and manage specific adverse drug reactions. Headaches are a common and specific adverse reaction of glumetinib. Among patients receiving monotherapy with glumetinib (≥ 300 mg QD), headaches (mostly grade 1 or 2) occur in approximately 30% of tumor patients, mainly within 1–2 days of dosing. Only a few patients reduced the dose or discontinued the drug due to headaches and most patients completely recovered. ILD is a specific adverse reaction of tepotinib and there was one fatal case. Severe hypersensitivity is a specific adverse reaction to savolitinib.

Overall, through patient education, timely identification and active management of these adverse events, and continuous monitoring, we can effectively reduce the incidence of adverse reactions, then reduce the incidence of drug dose adjustment to maximize the potential therapeutic effects of the drugs.