MET: A narrative review of exon 14 skipping mutation in non-small-cell lung carcinoma : Cancer Research, Statistics, and Treatment

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Review Article: Biomarker Series

MET

A narrative review of exon 14 skipping mutation in non-small-cell lung carcinoma

Nathany, Shrinidhi; Batra, Ullas1,

Author Information
Cancer Research, Statistics, and Treatment: Apr–Jun 2022 - Volume 5 - Issue 2 - p 284-292
doi: 10.4103/crst.crst_158_22
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Abstract

INTRODUCTION

Recent approvals of newer small molecules have led to a change in the pattern of molecular testing in non-small-cell lung cancer (NSCLC). According to the new National Comprehensive Cancer Network (NCCN) guidelines,[1] comprehensive genomic profiling has been recommended even in patients with squamous histology owing to a higher prevalence of targetable alterations such as BRAF (Raf murine sarcoma viral oncogene homolog B), KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), MET (mesenchymal epithelial transition factor), and rarely EGFR (epidermal growth factor receptor).[123]

MET dysregulation, that is, copy number gain/amplification and exon 14 skipping mutation (METex14), is known to be one of the secondary mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs).[234] However, currently, METex14 NSCLC can also be targeted using specific TKIs. The rapid approvals of newer MET-selective TKIs, such as capmatinib and tepotinib, mandate MET testing as a part of the first line molecular testing in NSCLC.[35] Although rare, when detected, it can be appropriately targeted, thus leading to the institution of optimal therapy and better patient outcomes.

The aim of this review article on MET in NSCLC is to describe the normal structure, function, dysregulation, clinical features, trials, and outcomes in MET-dysregulated NSCLC.

METHODS

For this narrative review, we identified articles by searching in PubMed, Embase, Scopus, and My Cancer Genome using the keywords “MET,” “exon 14 skipping,” “capmatinib,” “tepotinib,” and “MET TKI”. In total, 76 articles were included for preparing this review. There were no defined inclusion/exclusion criteria for the search strategy as this was not a meta-analysis or a systematic review. Additionally, we did not conduct any formal statistical analysis as our goal was a narrative and descriptive review, and we did not aim to address any analytical problem statement.

HISTORICAL PERSPECTIVE

MET dysregulation was first discovered in the mid-1980s in an osteosarcoma cell line.[6] Subsequently, MET and HGF (hepatocyte growth factor, which is the ligand for MET) were found to be over-expressed in lung cancer in the 1990s.[6] From the year 2000 onward, advancements in molecular biology and pharmacogenomics led to the discovery of METex14 and MET amplification in de novo lung cancer as well as a secondary resistance mechanism.[6]

MOLECULAR BIOLOGY

The MET proto-oncogene maps to the 7q31 locus of chromosome 7 and encodes for a receptor tyrosine kinase (RTK) for HGF, also known as scatter factor.[7] The name MET was conferred based on the first three letters of the chemical mutagen “N-methyl-N'-nitro-N-nitrosoguanidine.”[7]

STRUCTURE

The MET protein is a 190 kDa protein consisting of a 50 kDa alpha chain and a 145 kDa beta chain linked by disulfide bonds.[8] There are two domains in the MET protein: the extra-cellular domain which comprises the SEMA (semaphorin), PSI (plexin, semaphorin, and integrin), and IPT (immunoglobulin plexin transcription) domains and the intra-cellular domain which comprises the juxtamembrane tyrosine kinase domain and a multi-functional docking site domain. The HGF and its two splice isoforms are the only known ligands for MET [Figure 1a].[910]

F1-18
Figure 1:
(a) Schematic depiction of the MET receptor with its domain structure and important residues in regulatory, catalytic, and docking regions. (b) Signaling of the MET receptor. When the HGF ligand binds, the MET receptor dimerizes and auto-phosphorylation occurs. This results in recruitment of molecules such as GrB2, GAB1, SRC, and STAT3 which bind to the docking sites, ultimately leading to activation of downstream signaling pathways. (HGF: hepatocyte growth factor, GrB2: growth factor receptor bound protein 2, GAB1: GrB2 associated binder 1, STAT3: signal transducer and activator of transcription 3, PSI: plexin-semaphorin-integrin, JMD: juxtamembrane domain, IPT: immunoglobulin-plexin-transcription factors, TKD: tyrosine kinase domain, SEMA: semaphorin domain)

SIGNALING

HGF binds to the SEMA domain leading to receptor homo-dimerization and activation of the Y1234 and Y1235 residues by auto-phosphorylation.[1112] Subsequent auto-phosphorylation in the docking site domain leads to recruitment of molecules such as GrB2 (growth factor receptor bound protein 2), GAB1 (GrB2-associated binder 1), SRC, and STAT3 (signal transducer and activator of transcription 3). This results in activation of the downstream RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways [Figure 1b]. Physiologically, the MET protein is expressed on epithelial cells and is responsible for embryogenesis, proliferation, cell motility, liver regeneration, organogenesis, and wound healing.[1113]

MET ALTERATIONS IN LUNG CANCER

MET dysregulation in lung cancer can occur through various genomic alterations including mutations, re-arrangements, amplification, and over-expression.[14] The common re-arrangement and splicing mutation leading to the skipping of exon 14 of the MET gene as well as MET amplification have been emphasized here. The major difference in MET dysregulation in lung cancer versus sporadic/hereditary renal cell carcinoma and medullary thyroid carcinoma is the specific domain of the MET gene involved. In the lung, it is the extra-cellular and juxtamembrane domains, in contrast to the MET tyrosine kinase domain in the other two malignancies.[15]

EXON 14 SKIPPING MUTATION

Mutations leading to skipping of exon 14 in MET have been reported as the most commonly occurring MET alterations in lung cancer.[15] METex14 has been reported in 3–4% of NSCLC,[14] which is relatively similar in incidence to that of the other well-known oncogenic drivers such as ROS1 (1-2%),[16] BRAF V600E (1-5%),[17] and ALK (5-7%),[18] further underscoring the importance of testing and clinical consideration of this distinct entity.

BIOLOGY OF EXON 14 SKIPPING MUTATION

The exon 14 of the MET gene encodes for 47 amino acids,[1920] which constitute the juxtamembrane domain described in the section on Structure (given above), which is the key region responsible for the prevention of over-signaling of the MET receptor. Alterations in the intronic regions around exon 14, that is, intron 13 and intron 14, or within exon 14 itself or whole exon deletion of exon 14 result in disruption of the transcription process of the MET gene, resulting in unabated MET signaling and thus carcinogenesis. Several types of changes including missense alterations, deletions, splice site changes, and whole exon deletions may result in the skipping of exon 14 of the MET gene.[21] The schematic structure of exon 14 and its alterations are depicted in Figure 2a and b, respectively.[22] The biology of exon 14 skipping and the resultant signaling, in relation to the normal process, have been depicted in Figure 3a-d.[23]

F2-18
Figure 2:
(a) Sites and regions altered in MET exon 14 skipping mutation with commonly occurring alterations, including c. 2888, whole exon deletion, c. 3028, deletions at the 5' end, and missense mutations at Y1003, D1010, and the 3' end. (b) Frequency and type of alterations leading to exon 14 skipping as reported by Awad et al.[19] in 1387 samples
F3-18
Figure 3:
(a) This image depicts the portion of the MET gene including exons 13–15 and introns 13 and 14. DNA gets transcribed to pre-mRNA, and introns are spliced out (scissors) by normal splicing processes involving the recognition of specific regions along the intron. mRNA undergoes translation to form the MET receptor protein. (b) This figure depicts the trans-membrane MET receptor protein. HGF (hepatocyte growth factor) (inverted green triangle) binds to the receptor. The Y1003 juxtamembrane residue is the binding site for E3 ubiquitin ligase CBL (pink), which tags the MET protein for lysosomal degradation, preventing over-signaling. (c) In this figure, MET mutations (red) that interrupt the branch point and/or 3′ splice site of intron 13 and the 5′ splice site of intron 14 result in altered splicing mechanisms and exon 14 skipping. METex14 is omitted in mRNA that is later translated into a protein product lacking the Y1003 residue leading to (d) loss of ubiquitination by CBL and no lysosomal degradation resulting in unabated signaling and oncogenesis. (mRNA: messenger ribonucleic acid, CBL: Casitas B lineage Lymphoma)

CLINICOPATHOLOGIC FEATURES OF PATIENTS WITH NSCLC WITH MET EXON 14 SKIPPING MUTATION

METex14 has been reported to occur in 3–4% cases of NSCLC,[14] although the prevalence varies according to the histology with sarcomatoid carcinoma showing the highest number of cases (4.9–31%),[24] followed by adenosquamous (4–8%),[14] adenocarcinoma (3–4%),[6] and squamous histology in 2%[25] cases. There are no distinct clinical features predictive of METex14. With respect to the demographic and clinical profile, patients with METex14 are usually older (65–76 years), with metastases occurring commonly to the lymph nodes (67%), contralateral lung (53%), pleura/pericardium (51%), bone (49%), and brain (37%).[1425] METex14 is mutually exclusive of other known oncogenic drivers such as EGFR, ALK, ROS1, KRAS, and RET.[25]

DETECTION OF MET EXON 14 SKIPPING MUTATION

Several methods have been employed for the detection of METex14. Both deoxyribonucleic acid deoxyribonucleic (DNA)- and ribonucleic acid (RNA)-based assays are available, including Sanger sequencing, next-generation sequencing (NGS), and reverse transcriptase polymerase chain reaction (RT-PCR). The preferred method is NGS owing to the wider spectrum of mutations covered. However, NGS also suffers from certain limitations. Most of the commercially marketed assays do not cover the 5' end of exon 14 adequately, and hence, alterations in this region are often missed on DNA-based sequencing.[26] RNA sequencing may also suffer from sequencing errors; hence, simpler RT-PCR assays have been designed and validated, which exhibit ease of workflow processes, with adequate sensitivity and specificity. A detailed comparison of each assay with the attributes of each is depicted in Table 1.[2728] Of these described assays, only FoundationOne CDx has been approved as the companion diagnostic for administration of the targeted therapy, capmatinib.[29]

T1-18
Table 1:
Various assays available for the detection of MET exon 14 skipping mutation

THERAPEUTIC OPTIONS

Although studies have reported a high expression of programmed death ligand 1 (PD-L1) in METex14 tumors, the mutation burden in these tumors is low.[30] The following therapeutic approaches can be employed to target these tumors:

MET TKIs

Multikinase inhibitors

These are small molecule MET tyrosine kinase inhibitors which can be classified as type 1 inhibitors which bind to the adenosine triphosphate (ATP) pocket in the active conformation and type 2 inhibitors which bind to it in the inactive conformation. Type 3 are non-competitive inhibitors which bind to allosteric sites outside the ATP pocket.[31] Type 1 inhibitors are further sub-classified based on their interaction with the G1163 solvent front residue into type 1a which interact with the residue, examples of which include crizotinib, and type 1b inhibitors which do not interact with the residue. These include the selective MET TKIs (discussed later) such as tepotinib, capmatinib, and savolitinib. Examples of type 2 inhibitors include cabozantinib, merestinib, glesatinib, and forestinib.[3233]

This multi-kinase inhibitor group includes drugs such as crizotinib, cabozantinib, merestinib, glesatinib, and TPX-022, which target multiple tyrosine kinases, including MET, but are not selective for MET.

Crizotinib

Historically, crizotinib was developed as a MET inhibitor but was found to be active against ALK and ROS1[3435] and hence was approved for the therapy of ALK- and ROS1-rearranged NSCLC.[36] The phase I PROFILE 1001 study (NCT00585195)[37] evaluated the safety and efficacy of crizotinib in 69 patients with NSCLC harboring METex14. Among these, 5% had a complete response, 28% had a partial response, and 45% had stable disease; the reported median progression-free survival (PFS) was 7.4 months (95% CI, 5.4–9.1). Crizotinib was granted United States Food and Drug Administration (USFDA) approval in 2018 for use in METex14 NSCLC based on the initial data from this study.[38] The phase II “Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer” (METROS, NCT02499614)[39] study reported an objective response rate (ORR) of 27% (95% CI, 11–47) with a median PFS of 4.4 months (95% CI, 3–5.8). The AcSé (NCT02034981)[40] study also reported a low ORR of 10.7% (95% CI, 2.3–28.2). Based on the above data, it is evident that type 1a inhibitors are not the optimal agents for patients with METex14.

Cabozantinib

This is a multi-kinase inhibitor presently approved for the treatment of medullary thyroid, renal cell, and hepatocellular carcinomas.[41] It has also exhibited pre-clinical anti-tumor activity in mouse models of lung cancer. In a randomized phase II study in 37 patients evaluating the use of cabozantinib alone versus cabozantinib in combination with erlotinib, the ORR was 10% (95% CI, 0.3–21.3), and the median PFS was 4 months (95% CI, 2–5.6).[42] Paik et al.[36] reported that one of the four patients in their study had a complete response to cabozantinib. Subsequently, interesting reports of intra-cranial responses from cabozantinib have also been published.[43] The drug is currently being evaluated in a phase II trial in patients with lung cancer with MET amplification or METex14 (“CABozantinib in Non-Small Cell Lung Cancer Patients With MET Deregulation” [CABinMET], NCT03911193).[44]

Merestinib

Merestinib is another multi-kinase inhibitor which is ATP-competitive and has demonstrated a good safety profile in patients with pre-treated advanced tumors. In pre-clinical studies of NSCLC, it has demonstrated anti-tumor activity in tumor cell lines as well as in patient-derived xenograft models.[36] It has demonstrated potent activity both when used alone as a single agent or in combination with emibetuzumab (MET-targeting antibody) in a gastric cancer cell line.[45] A Phase II trial evaluating the role of “Merestinib In METex14 NSCLC And Solid Tumors with NTRK rearrangements” is currently ongoing (NCT02920996).[46]

Glesatinib

Analogous to merestinib, glesatinib is also a multi-kinase ATP-competitive MET inhibitor, with activity against the D1228 and Y1230 residues, which are known to cause resistance to type 1 inhibitors.[36] There have been anecdotal case reports of durable responses in some patients as well as in pre-clinical models. An ongoing trial is evaluating glesatinib in combination with the anti-programmed cell death protein 1 (PD1) antibody, nivolumab, in advanced NSCLC (NCT02954991).[47]

Selective MET TKIs

These are selective MET TKIs which specifically bind to the ATP-binding pocket of the MET kinase. The three well-known agents in this group are capmatinib, tepotinib, and savolitinib. Other agents include bozitinib and glumetinib, which are briefly discussed in Table 2.

T2-18
Table 2:
Newer agents in development for MET exon 14 skipping mutation

Capmatinib

This is an oral selective ATP-competitive inhibitor of MET. Capmatinib has demonstrated potent anti-tumor activity in pre-clinical tumor cell lines and xenograft models. In the initial study by Frampton et al.,[23] two patients with NSCLC attained partial responses to capmatinib. This phase I study also demonstrated an acceptable safety profile of the drug with grade 3 and 4 adverse events reported in 4% cases.[23] The non-randomized multi-center phase II GEOMETRY Mono-I study (NCT02414139)[53] showed that responses with capmatinib were higher in treatment-naive compared to pre-treated patients. Capmatinib also showed significant intra-cranial activity and an acceptable safety profile. The most common adverse events reported were grade I and included nausea, vomiting, peripheral edema, and increased serum creatinine. In 2020, the USFDA granted approval for the use of capmatinib in patients with advanced NSCLC with METex14[54] along with an approval of FoundationOne CDx as the companion diagnostic.[29] The final results from GEOMETRY Mono-I depicted an ORR of 41% (95% CI, 29–53) with a duration of response of 9.7 months (95% CI, 5.6–13) in pre-treated patients; the corresponding figures were 68% (95% CI, 48–64) and 12.6 months (95% CI, 5.6–NR), respectively, in treatment-naive patients.[53] The median PFS in pre-treated versus treatment-naive patients was 5.4 months (95% CI, 4.2–7) and 12.4 months (95% CI, 8.2–not estimated), respectively. Another ongoing phase II trial is the “Capmatinib in Patients With Non-small Cell Lung Cancer Harboring cMET exon14 Skipping Mutation” (NCT03693339[55] study. The study titled “Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations (NCT04323436)” is evaluating the combination of capmatinib with the anti-PD1 antibody, spartalizumab compared to single agent capmatinib.[56]

Tepotinib

Tepotinib is an oral ATP-competitive MET inhibitor. The efficacy and safety were evaluated in the phase II VISION study (NCT02864992)[5758] in 152 patients who received tepotinib. The reported ORR was 44.7% (95% CI, 36.7–53), with a median PFS of 8.9 months (95% CI, 8.2–11.2) and a median duration of response of 11.1 months (95% CI, 8.4–18.5). Grade 3 or higher adverse events occurred in 28% patients with peripheral edema being the most common adverse event seen in 7% cases.[5758] In September 2019, the USFDA granted the breakthrough therapy status to tepotinib for advanced NSCLC with METex14.[59] The phase II randomized INSIGHT study in EGFR-mutated NSCLC with MET overexpression/amplification demonstrated an ORR of 45.2% (95% CI, 29.7–61.3) for the combination of tepotinib and gefitinib versus 33.3% (95% CI, 17.8–52.1) in the platinum-combination chemotherapy arm with a reported median PFS of 16.6 months (95% CI, 8.3–not estimated) versus 4.2 months (95% CI, 1.4–7), respectively.[60]

Savolitinib

Savolitinib is a highly selective oral MET inhibitor, which has been used in various malignancies including gastric and papillary renal cell carcinoma and NSCLC.[6162] The Phase Ib TATTON study in patients with advanced EGFR-mutant NSCLC with MET amplification reported an ORR of 44% (95% CI, 22–69) in the 18 patients who received the combination of savolitinib and osimertinib.[63] Other ongoing trials evaluating this combination include SAVANNAH (NCT03778229)[64] and ORCHARD (NCT03944772).[65] A phase II study evaluating the safety and efficacy of savolitinib in METex14 showed an ORR of 49.2% (95% CI, 36.1–62.3) with a disease control rate of 93.4% and a duration of response of 6.9 months (95% CI, 4.9–12.5).[66] The median PFS was reported to be 6.8 months (95% CI, 4.2–9.6). With respect to safety, grade 3 and higher adverse events occurred in 41.4% of the patients, resulting in treatment discontinuation in 14.3%. The common adverse events noted were edema, nausea, hypoalbuminemia, de-ranged liver functions, hypersensitivity, and vomiting.[646566]

MET antibodies

This group includes agents such as emibetuzumab, onartuzumab, and newer agents such as Sym-015 and REGN5093.

Embetuzumab

Emibetuzumab is an IgG4 monoclonal bivalent anti-MET antibody,[67] which has demonstrated potent anti-tumor activity in mouse xenograft models and NSCLC models. Pre-clinical studies have revealed high potency in a gastric cancer model when used in combination with merestinib.[45]

Onartuzumab

This is another anti-MET monoclonal antibody. However, it has failed to show positive clinical outcomes in phase II studies.[68]

Antibody drug conjugates

Telisotuzumab vedotin

This is a conjugate of monomethyl auristatin E and a MET-targeted antibody.[69] The Phase I study has revealed anti-tumor activity in METex14 NSCLC. Telisotuzumab vedotin is currently under evaluation in a phase II study.

Immuno-oncology (IO) for METex14 NSCLC

Despite the high expression of PD-L1, limited clinical responses have been reported with immunotherapy in METex14 NSCLC.[70] In a retrospective study which evaluated single agent immunotherapy in 13 patients with METex14 NSCLC, an ORR of 16% was observed with a median PFS of 3.5 months (95% CI, 1.9–11.1).[71] In a large study in 60,495 patients with NSCLC, 1387 cases of METex14 (2.3%) were detected, and it was found that the mutation burden was low in these tumors when compared to their MET-wild type counterparts, even though 48% cases had a PD-L1 expression >50%.[22] A recent study in 13 patients treated with immunotherapy reported contrasting results, with an ORR of 46.2% with the responses maintained for 18–49 months.[7273] In a study by Mazieres et al.[74] in 24 patients, the PFS did not exceed 3.4 months (95% CI, 1.7–6.2) with immunotherapy.

RESISTANCE TO MET TKI

Similar to other targeted therapies, both on-target and off-target resistance mechanisms have been reported. The various resistance mechanisms are discussed in Table 3.[7576]

T3-18
Table 3:
Description of various resistance mechanisms to MET TKIs

MET EXON 14 IN OTHER MALIGNANCIES

METex14 alterations are reported in 2.7% patients with cancer overall.[76] Apart from NSCLC, METex14 has been rarely reported in other cancer types. These include papillary renal cell carcinoma (16.9%), malignant melanoma (6.7%), endometrial carcinoma (4.8%), gastro-esophageal junction/gastric adenocarcinoma (4.3%), urothelial carcinoma (2.8%), cervical carcinoma (2.3%), cholangiocarcinoma (1.7%), and soft tissue sarcoma (1.5%).[76] METex14 has been reported in <1% cases of adrenocortical carcinomas and other rare malignancies.[76]

CONCLUSION

METex14 has emerged as a promising target in the era of precision medicine. Several trials have reported superior outcomes, and many are still underway. Promising results from targeted therapies and an incidence similar to other major known oncogenic drivers warrant MET testing in the first line setting in all patients with NSCLC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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    Keywords:

    Capmatinib; exon 14 skipping; MET; NSCLC

    © 2022 Cancer Research, Statistics, and Treatment | Published by Wolters Kluwer – Medknow