Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments

Abstract

Introduction:

Mesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC). We reviewed the epidemiology and disease characteristics associated with primary and secondary METamp, as well as the testing procedures used to identify METamp, in advanced NSCLC. Economic and humanistic burdens, and the practice patterns and treatments under investigation for METamp were also examined.

Methods:

Embase and Medline (via ProQuest), ClinicalTrials.gov, and Cochrane Controlled Register of Trials (2015–2022) were systematically searched. Conference abstracts were searched via Embase and conference proceedings websites (2020–2022). The review focused on evidence from the United States; global evidence was included for identified evidence gaps.

Results:

The median rate of primary METamp in NSCLC across the references was 4.8% (n=4 studies) and of secondary METamp (epidermal growth factor receptor [EGFR]-mutant NSCLC) was 15% (n=10). Next-generation sequencing (NGS; n=12) and/or fluorescence in situ hybridization (FISH; n=11) were most frequently used in real-world studies and FISH testing most frequently used in clinical trials (n=9/10). METamp definitions varied among clinical trials using ISH/FISH testing (MET to chromosome 7 centromere ratio of ≥1.8 to ≥3.0; or gene copy number [GCN] ≥5 to ≥10) and among trials using NGS (tissue testing: GCN ≥6; liquid biopsy: MET copy number ≥2.1 to >5). Limited to no data were identified on the economic and humanistic burdens, and real-world treatment of METamp NSCLC. Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines.

Conclusion:

Primary METamp occurs in approximately 5% of NSCLC cases, and secondary METamp in approximately 15% of cases previously treated with an EGFR inhibitor. Variability in testing methods (including ISH/FISH and NGS) and definitions were observed. Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

1 Introduction

Non-small cell lung cancer (NSCLC) is a heterogenous disease that is frequently diagnosed at an advanced stage due to variability of signs and symptoms at diagnosis (1, 2). The treatment of NSCLC is becoming more individualized as broad molecular testing for actionable driver alterations has transformed the diagnosis and treatment of advanced NSCLC (3). As of 2023, both national and international guidelines recommend molecular testing to help guide treatment decisions in advanced NSCLC (4–6).

Alterations in the transmembrane tyrosine kinase mesenchymal-epidermal transition factor (MET) receptor such as MET gene amplification (METamp) have been identified as actionable drivers in NSCLC (7). METamp in NSCLC may be a primary oncogenic driver, or a secondary driver which arises during or following treatment and commonly develops as an adaptive resistance mechanism to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment (7, 8). Although EGFR-TKIs have significantly improved outcomes in patients with EGFR-mutant advanced NSCLC, the development of METamp-driven resistance to EGFR-TKIs is a key obstacle to long-term disease control (4, 9). In patients with secondary METamp following treatment with an EGFR-TKI, concomitant inhibition of both EGFR and MET is thought to overcome resistance to EGFR inhibitors due to METamp (9).

This targeted review was undertaken to better understand the burden of METamp NSCLC in the United States (US) and to identify the available evidence on the epidemiology and disease characteristics associated with primary and secondary METamp. Other outcomes evaluated included evidence on METamp testing procedures, the economic and humanistic burdens of METamp NSCLC, and practice patterns and treatments under investigation for METamp advanced NSCLC.

2 Methods

A systematic search of studies published as journal articles or conference abstracts written in the English language was performed on June 14, 2022 using predefined search terms in Embase and Medline (via ProQuest; Supplementary Table 1). Journal articles were searched from January 1, 2015 onwards, and conference abstracts were searched from January 1, 2020 onwards. Abstracts from the following 2022 conferences that were not yet indexed in Embase by June 14, 2022 were also searched: the American Association for Cancer Research, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and NCCN. Searches using predefined search terms in ClinicalTrials.gov (Supplementary Table 2) and the Cochrane Controlled Register of Trials (Supplementary Table 3) were performed to identify completed and ongoing clinical trials; searches were performed on June 14, 2022.

The utilized search strategies were global in scope and included terms for NSCLC, METamp, and outcomes of interest. Whereas the focus of this literature review was US-based evidence, global, non-US-based evidence was included when gaps in US-based evidence for outcomes of interest were identified. Publications containing information on the following topics for either primary or secondary METamp were selected for inclusion (Table 1): US-based epidemiology and global evidence for disease characteristics, genomic testing procedures, economic and humanistic burden, real-world treatment patterns, ongoing clinical trials, and clinical trial outcomes. Real-world prospective or retrospective studies, clinical trials, and US-based guidelines were included.

An independent researcher completed title, abstract and full text screening, identified studies to be included based on the Population, Intervention, Comparison, Outcomes, Study Design (PICOS) selection criteria (Table 1), and extracted data. Another independent researcher performed standard quality checks on approximately 10% of randomly selected references during the abstract and full text screening to verify results. Results are descriptive in nature. No formal statistical analyses or comparisons among identified studies were made.

3 Results

A total of 1,004 references were screened; of these, 117 references met the inclusion criteria, including 79 publications from ProQuest and searched conference abstracts, and 38 webpage references from ClinicalTrials.gov (Figure 1). Of the 117 references meeting inclusion criteria, references commonly provided information on more than one topic of interest.

Figure 1

3.1 Epidemiology and disease characteristics

A total of 13 publications providing information on the epidemiology of primary or secondary METamp in the US were identified. The median incidence of primary METamp in all NSCLC in the US was 4.8% (range: 2.0–5.8%), based on four studies including 3,379 patients (10–13). In these studies, primary METamp was defined as METamp at NSCLC diagnosis and/or before receipt of targeted therapies; METamp was identified either by a single test or by a testing panel that included METamp and other driver alterations (10–13). The median incidence of secondary (acquired) METamp in EGFR-mutant NSCLC previously treated with an EGFR-TKI was 15% (range: 2.9–66.7%), based on a total of 10 studies including 389 patients (13–22).

A total of 29 publications providing information on disease characteristics of METamp NSCLC were identified (23–51). A summary of results from 16 US- or non-US based studies that evaluated demographic and clinical characteristics of patients with NSCLC with or without METamp is found in Supplementary Table 4 (24–27, 29, 32, 33, 35–37, 44–47, 50, 51). Results from the identified studies show that the following characteristics were consistently considered not associated with METamp (either primary, secondary, or not specified): age (11 studies), sex (11 studies), and NSCLC sub-type (adenocarcinoma vs non-adenocarcinoma, squamous cell carcinoma, or other; 6 studies) (24, 26, 27, 32, 33, 36, 44, 45, 47, 50, 51). Results from two studies demonstrated a significant statistical association between METamp and a higher proportion of programmed cell death protein 1 ligand (PD-L1) expression (25, 35). Overall, most studies (8/10) found no statistical association between METamp and a positive smoking history (24, 26, 27, 32, 33, 44, 45, 47, 50, 51). Among two studies that evaluated patients with EGFR-mutant NSCLC who experienced progression on an EGFR-TKI, one study found that history of smoking was associated with a high probability of secondary METamp (p=0.011), and one study found no association between smoking status and presence of METamp (p=0.45) (24, 27). No studies specifically looked at the association between demographics and clinical characteristics in patients with primary or secondary METamp.

Results for patients with stage I–III NSCLC (n=170) show that patients with METamp versus no METamp had a significantly shorter time to development of distant metastasis (11.6 vs 43.8 months; p=0.004), and results of a multivariate analysis confirmed that METamp was highly associated with earlier progression to distant metastases (hazard ratio: 4.86; 95% CI: 1.85, 12.75; p=0.001) (36). All patients in this study received standard of care therapy per their disease stage at diagnosis, such as surgery, chemotherapy, radiation therapy, or EGFR inhibitor therapy when applicable; rates of therapy and primary versus secondary METamp were not reported. A second study found that among primary lung adenocarcinoma and metastatic lung adenocarcinoma tumor samples, the identification of METamp was significantly higher in the metastatic than primary tumor samples (p<0.001) (46). Evidence regarding the association between brain metastases and METamp differed based on the enrolled populations. Results from two different studies evaluating NSCLC tumor samples found that METamp was identified in a significantly higher number of NSCLC brain metastases samples (including lung adenocarcinoma brain metastases) compared with samples from primary tumors (29, 37). Results from one study evaluating patients with advanced NSCLC with EGFR mutations found that rates of brain metastases did not significantly differ among patients with primary METamp versus no METamp (45).

Interpretation of survival results for patients with METamp versus no METamp is limited due to differences in follow-up times, treatments, and patient populations. Among all studies identified, no statistical association between METamp and overall survival for patients with advanced NSCLC was found in six studies (24, 26, 27, 35, 44, 51), and significantly worse overall survival among patients with METamp NSCLC versus non-METamp NSCLC was found in three studies (36, 45, 47). Results from two studies evaluating patients with secondary METamp who had EGFR-mutant NSCLC and progression on an EGFR-TKI found that there was no significant difference in overall survival from the time of initiation of EGFR-TKI therapy according to METamp status (24, 27). Median progression-free survival from the most recent EGFR-TKI treatment was significantly shorter among patients with METamp versus no METamp, based on a multivariate analysis in one study (hazard ratio, 0.898; 95% CI: 0.835, 0.965; p=0.004) (24).

3.2 Testing

A total of 39 publications providing testing data for METamp (including two US-based guidelines providing testing recommendations for METamp NSCLC) were identified. The US-based guidelines included the NCCN Guidelines and the joint guideline by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) (4, 5).

The NSCLC NCCN Guidelines consider high-level METamp to be an emerging biomarker, which should optimally be identified when broad molecular profiling is performed for the following actionable driver mutations: EGFR, anaplastic lymphoma kinase (ALK), Kristin rat sarcoma virus (KRAS), c-Ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), neurotrophic tyrosine receptor kinase (NTRK1/2/3), MET exon 14 skipping, RET proto-oncogene (RET), and human epidermal growth factor receptor 2 (ERBB2 [HER2]) (4). The CAP-IASLC-AMP guidelines (published in 2018) recommend that it is appropriate to include MET alterations as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative (5). Molecular testing for MET alterations including MET exon 14 mutation and METamp is not indicated as a routine stand-alone assay outside the context of a clinical trial per the CAP-IASLC-AMP guidelines.

The definition of high-level METamp is evolving and may differ according to the assay used for testing (4). Fluorescence in situ hybridization (FISH) is generally considered the gold standard to evaluate MET gene copy number (52, 53). Tissue-based next-generation sequencing (NGS) can also be used to simultaneously test for METamp and other actionable biomarkers (4). There are no clinically defined cut-off values for NGS. While the NCCN Guidelines recognize that the definition of high-level METamp is not established, a copy number greater than 10 is considered consistent with characterizing a result as high-level METamp (4). Of 10 identified clinical trials providing definitions for METamp, FISH testing was the most commonly used testing strategy (nine studies) (30, 54–62). The definition for METamp in clinical trials varied and ranged from a MET to chromosome 7 centromere (MET/CEP7) ratio of ≥1.8 to ≥3.0 (Table 2) (30, 54–62).

Most real-world studies that included data from the US (20 publications from the US and three publications from multi-country assessments including the US) used NGS (12 studies) and/or FISH (11 studies) to test for METamp; among these studies, tissue samples were used in 13 studies, tissue or liquid samples in seven studies, liquid samples in one study, and no sample information was provided for two studies (10–14, 17, 18, 20, 25, 28, 36–38, 40, 49, 63–70). There are limited real-world data comparing the reliability of using NGS versus FISH to identify patients with METamp (52, 53). Results from a study in Germany suggest that there is higher concordance between NGS and FISH when considering highly amplified MET (gene copy number >10); however, NGS may be less able to detect cases harboring lower levels of expression (i.e., low or intermediate METamp) (52).

No studies evaluating the economic impact of specifically testing for METamp were identified in the literature review; however, two studies evaluating the economic impact of using NGS versus single gene testing strategies to identify actionable genomic alterations among patients with advanced NSCLC in the US were identified (71, 72). Both studies demonstrated cost savings with NGS from both a Medicare and US commercial payer’s perspective when testing for actionable genomic alterations included in clinical guideline recommendations (EGFR, ALK, ROS1, BRAF, KRAS, MET, HER2, RET, and NTRK1) compared with single gene testing strategies (71, 72). NGS was associated with a faster mean time to appropriate targeted therapy initiation (2 weeks) compared with other testing strategies, including single gene sequential testing (8–9 weeks) or hotspot panel testing (3 weeks) (71).

3.3 Economic burden and patient-reported outcomes

No information on economic or humanistic burdens in METamp NSCLC was identified in the literature.

3.4 Real-world treatment patterns and outcomes data

A total of 18 publications providing information on the real-world treatment patterns and outcomes data for METamp NSCLC were identified. Results from several studies indicated that patients with EGFR-mutant NSCLC who received a variety of first-, second-, or third-generation EGFR-TKIs may have detection of secondary METamp following progression on EGFR-TKI treatment (13, 24, 27, 42, 73, 74). Evidence from real-world studies suggests that there is no association between the type of EGFR-TKI and risk of acquiring METamp (13, 24, 42).

There is a lack of US-based evidence on treatments used in real-world settings following diagnosis of METamp NSCLC. The majority of references evaluating real-world treatment patterns among patients who have secondary METamp NSCLC were from China and assessed crizotinib alone or in combination with EGFR-TKIs (such as gefitinib, erlotinib, osimertinib, and icotinib; Supplementary Table 5) (27, 39, 42, 73–75).

3.5 Investigational treatments in METamp NSCLC

Inhibition of MET signaling is being investigated as a promising therapeutic strategy in patients with METamp NSCLC; a total of 16 publications providing information on clinical trial evidence in METamp NSCLC were identified. Several agents alone or in combination with EGFR-TKIs are currently under investigation for the treatment of METamp NSCLC, including small molecule MET receptor inhibitors (e.g., crizotinib (30, 55), savolitinib (57, 76, 77), tepotinib (61, 62, 78, 79), and capmatinib (56, 60)), monoclonal or bispecific antibodies that can block MET activity (e.g., amivantamab (80)), and an anti-MET antibody–drug conjugate (e.g., telisotuzumab vedotin (81)).

Thirty-eight Phase I–III trials evaluating treatments for METamp NSCLC and registered on ClinicalTrials.gov were identified as of June 14, 2022 (80, 82–118). Many identified trials included patients with several different MET alterations (including MET exon 14 skipping, MET overexpression, and METamp), and some trials included patients with a variety of different actionable genomic alterations. Only results from trials that focus exclusively on METamp or include a subgroup of patients specifically with METamp are included in this review. Studies that only presented combined results for patients with METamp and another MET alteration are not described in this review.

3.5.1 MET tyrosine kinase inhibitors

There are two types of MET-TKIs, including type I MET-TKIs that bind to an active form of MET (e.g., tepotinib, capmatinib, crizotinib, savolitinib, and bozitinib), and type II MET-TKIs that bind to an inactive form of MET (e.g., cabozantinib and glesatinib). The majority of MET-TKIs are orally administered (e.g., tepotinib, capmatinib, savolitinib, crizotinib) (30, 55–57, 60–62, 76, 78, 79).

Published results identified at the time of this literature review from clinical trials evaluating MET-TKIs are summarized in the following sections and in Table 3.

3.5.1.1 MET-TKI combination therapy for the treatment of secondary METamp NSCLC

3.5.1.1.1 Capmatinib

Results from a single arm Phase Ib/II trial evaluating capmatinib plus gefitinib after failure of EGFR inhibitor therapy in patients with EGFR-mutated, METamp NSCLC (n=36) demonstrated that patients treated with capmatinib plus gefitinib had a median (95% CI) progression-free survival of 5.49 (4.21, 7.29) months and an objective response rate of 47% (56).

3.5.1.1.2 Savolitinib

Results from a Phase Ib trial evaluating savolitinib plus gefitinib after progression on an EGFR-TKI in patients with EGFR-mutated, METamp advanced NSCLC (n=51) demonstrated that patients treated with savolitinib plus gefitinib had a median (95% CI) progression-free survival of 4.0 (2.8, 5.5) months and an objective response rate of 31% (76).

Another Phase Ib trial (TATTON) evaluated savolitinib plus gefitinib after progression on an EGFR-TKI in patients with EGFR-mutated, METamp advanced NSCLC in two expansion cohorts (57). The TATTON trial was divided into four parts, A to D, and parts B and D were the two global expansion cohorts evaluating savolitinib plus gefitinib. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR-TKI and those who had not been previously treated with a third-generation EGFR-TKI who were either T790M negative or T790M positive; part D enrolled patients who had not previously received a third-generation EGFR-TKI and were T790M negative. Results from this study demonstrated that the median (95% CI) progression-free survival in cohort B (n=138) was 7.6 (5.5, 9.2) months and for cohort D (n=42) was 9.1 (5.4, 12.9) months. The objective response rate was 48% in cohort B and 64% in cohort D.

Savolitinib in combination with osimertinib is being evaluated in several Phase II and III ongoing trials (94, 100–103). Results from the Phase II ORCHARD study evaluating savolitinib plus osimertinib after progression on first-line osimertinib monotherapy among patients with locally advanced/metastatic EGFR-mutant NSCLC demonstrated that patients treated with savolitinib plus osimertinib (n=17) had an overall response rate of 41% after a follow-up of 13 weeks (77). Results for other Phase II and III studies evaluating savolitinib plus osimertinib were not identified at the time of this literature review.

3.5.1.1.3 Tepotinib

A total of 19 patients with EGFR-mutated, METamp advanced NSCLC who progressed on an EGFR-TKI were enrolled in a Phase Ib/II trial (INSIGHT) (61, 78). In this study evaluating tepotinib plus gefitinib (n=12) and chemotherapy (n=7), median (90% CI) progression-free survival was 16.6 (8.3, 22.1) and 4.2 (1.4, 7.0) months (hazard ratio: 0.13; 90% CI: 0.04, 0.43), and median (90% CI) overall survival was 37.3 (21.1, 52.1) and 13.1 (3.3, 22.6) months (hazard ratio: 0.10; 90% CI: 0.02, 0.36). The objective response rate was 67% in patients receiving tepotinib plus gefitinib and 43% in patients receiving chemotherapy (78).

Tepotinib in combination with osimertinib is also being evaluated among patients with EGFR-mutated NSCLC following progression on osimertinib in the Phase II INSIGHT-2 trial (99). Primary analysis results for INSIGHT-2 have been presented at the World Conference on Lung Cancer Congress in September 2023 but were not yet published at the time of this literature review (119).

3.5.1.2 MET-TKI monotherapy

3.5.1.2.1 Bozitinib

Preliminary results from a Phase I, open-label, multicenter study evaluating bozitinib in locally advanced or metastatic NSCLC with MET dysregulation demonstrated that bozitinib had a manageable safety profile at the recommended Phase II dose of 200 mg twice daily (120). Only eight patients had METamp NSCLC in this study, and it was not specified if patients had primary or secondary METamp.

3.5.1.2.2 Capmatinib

Two Phase II trials evaluated the use of capmatinib monotherapy in patients with METamp NSCLC (54, 60). In the first study, a Phase II trial evaluating capmatinib in MET exon 14-mutated or METamp NSCLC, patients did not have an EGFR mutation or ALK fusion (60). Patients with METamp NSCLC and a gene copy number ≥10 had a median (95% CI) progression-free survival of 4.1 (2.9, 4.8) months for patients who had received 1–2 previous lines of therapy (n=69) and 4.2 (1.4, 6.9) months for patients with no previous lines of therapy (n=15) (60). The objective response rate was 29% for patients with 1–2 previous lines of therapy and 40% for patients with no previous lines of therapy. Additional cohorts for patients with a gene copy number less than 10 (gene copy number 6–9, 4–5, or < 4) were initially planned and ultimately closed for futility at an interim analysis (60).

In the second study, a Phase II trial evaluating capmatinib in patients with advanced NSCLC harboring METamp or MET exon 14 skipping alterations, patients must have received treatment with a prior MET-TKI, and there was no restriction on the number of prior treatment regimens (54). Only five patients in this trial had METamp, and none of these five patients achieved an objective response (54). The authors noted that a limitation of this study was the limited number of patients enrolled with METamp NSCLC.

3.5.1.2.3 Crizotinib

In a Phase I study enrolling patients with advanced NSCLC who have not received previous hepatocyte growth factor- or MET-targeted therapy, METamp was defined as a MET/CEP7 ratio >1.8; low levels of METamp were defined as ≥1.8 to ≤2.2; medium levels as >2.2 to < 4.0; and high levels as ≥4.0 (the initial cut-off for the high versus medium threshold was changed from a ≥5 to ≥4 MET/CEP7 ratio based on a preliminary response analysis) (30). Results from this study demonstrated that patients with advanced METamp NSCLC had a median (95% CI) progression-free survival of 5.1 (1.9, 7.0) months for all patients (N=38), 6.7 (3.4, 9.2) months for patients with high METamp (n=21), 1.9 (1.3, 5.6) months for patients with medium METamp (n=14), and 1.8 (0.8, 14.0) months for patients with low METamp (n=3). The objective response rate (95% CI) was 28.9% (15.4, 45.9) for all patients, 38.1% (18.1, 61.6) in the high METamp group, 14.3% (1.8, 42.8) in the medium METamp group, and 33.3% (0.8, 90.6) in the low METamp group. Median overall survival (95% CI) with crizotinib was 11.0 (7.1, 15.9) months for all patients, 11.4 (7.2, 19.3) months for patients with high METamp, 9.2 (2.1, 18.1) months for patients with medium METamp, and 5.6 (1.1, not estimable) months for patients with low METamp.

In a Phase II trial, crizotinib monotherapy was evaluated in patients with pretreated NSCLC with MET dysregulation or evidence of ROS1 rearrangements; patients with EGFR or KRAS mutations were excluded (55). Patients with METamp NSCLC (n=16) had a median (95% CI) progression-free survival of 5.0 (2.7, 7.3) months, a median (95% CI) overall survival of 5.4 (3.4, 7.4) months, and an objective response rate of 31.3% (95% CI: 5.2, 71.4) (55).

3.5.1.2.4 SAR125844

Results from a first-in-human Phase I trial evaluating SAR125844 in advanced solid tumors and MET dysregulation found that patients with advanced METamp NSCLC (n=22) demonstrated a partial response rate of 18.2%; no patients achieved a complete response (58). Patients in this trial were allowed, but not required, to have EGFR mutations or prior EGFR inhibitor therapy.

3.5.1.2.5 Tepotinib

Results from a Phase II trial evaluating tepotinib in EGFR and ALK-wild type NSCLC with high-level METamp (VISION) demonstrated that tepotinib (n=24) showed clinical activity, especially in the first-line setting at the data cut-off (August 20, 2021) (62, 121). Among all patients, the objective response rate was 41.7% (95% CI: 22.1, 63.4) and the median duration of response was 14.3 months (95% CI: 2.8, not estimable). Among patients treated in the first-line setting (n=7), the objective response rate was 71.4% (95% CI: 29.0, 96.3) and the median duration of response was 14.3 months (95% CI: 2.8, not estimable). Results at the August 20, 2021 data cut-off, identified through this literature search, were initially presented as conference proceedings in 2022 (62) and subsequently published in November 2023 (121).

3.5.2 Anti-MET antibodies

3.5.2.1 Amivantamab

Amivantamab has a unique structure in that it is a bispecific antibody that blocks both epidermal growth factor and MET receptors (80). It is being investigated in multiple studies, including in a Phase I trial enrolling patients with metastatic or unresectable NSCLC that has progressed after prior standard of care therapy (CHRYSALIS-1). The objective of this study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of amivantamab (either alone or in combination with lazertinib), and to determine the recommended Phase II doses for expansion of amivantamab monotherapy and combination therapy. One of the cohorts includes patients with primary EGFR-mutated disease and documented METamp or MET mutation after progression on any EGFR-TKI. Published results for patients with METamp NSCLC from this trial were not identified at the time of the literature review.

3.5.2.2 Sym015

Sym015 is a mixture of two humanized antibodies targeting MET (59). Interim safety and efficacy results from a Phase I trial were reported for eight patients with advanced METamp NSCLC (including seven patients who were MET-TKI-naïve, and one patient previously treated with a MET-TKI). The objective response rate was 25%.

3.5.3 Anti-MET antibody–drug conjugates

3.5.3.1 Telisotuzumab vedotin

Telisotuzumab vedotin is a first-in-class antibody–drug conjugate consisting of a humanized MET-targeting antibody, ABT-700, coupled to a cytotoxic microtubule inhibitor, monomethyl auristatin E, through a valine–citrulline linker (81). It is currently being evaluated as monotherapy and in combination with osimertinib, erlotinib, and nivolumab in participants with advanced solid tumors, including METamp NSCLC (98).

4 Discussion

Results from this review indicate that primary METamp occurs in approximately 5% of NSCLC cases. Secondary METamp, which is an established mechanism of resistance for patients with EGFR mutation-positive NSCLC (3), occurs in approximately 15% of advanced NSCLC cases previously treated with an EGFR inhibitor in the US. METamp has also been identified as a mechanism of resistance in patients with NSCLC and other actionable genomic alterations, including ALK fusion, RET fusion, ROS1 fusion, and KRAS G12C mutation (38, 40, 122–127). An overview of the MET pathway and mechanisms of METamp-mediated resistance in NSCLC is not included in the scope of this literature review and has been previously described in several reviews (3, 128–130).

The higher rates of secondary METamp among patients with EGFR-mutant NSCLC compared with primary METamp in NSCLC indicate a need for testing at different time points of the treatment journey, including at diagnosis and upon progression on an EGFR-TKI. In real-world settings, FISH and NGS are both commonly used to test for METamp. Variability exists in how METamp is defined across clinical trials and real-world evidence studies. Further studies are needed to evaluate the use and reliability of different testing strategies (NGS vs FISH; and tumor vs liquid testing) for identification of patients with METamp, with potential advantage to improved standardization of definitions of METamp.

No studies evaluating the economic and humanistic burdens of METamp NSCLC were identified in this literature review, suggesting further studies evaluating these burdens are warranted. Furthermore, there is a lack of US-based evidence on treatments used in real-world settings following diagnosis of METamp NSCLC. Any interpretation of real-world evidence is limited as sample sizes were small in the few studies identified. Studies evaluating real-world practice patterns and outcomes among patients with METamp NSCLC in the US and other countries are needed.

As of March 2023, there were no US Food and Drug Administration approved therapies for METamp NSCLC. The NCCN Guidelines recommend capmatinib, crizotinib, and tepotinib as monotherapy for patients with metastatic NSCLC and high-level METamp (4). The NCCN Guidelines also note that the best management of any patient with cancer is in a clinical trial, and participation in clinical trials is especially encouraged (4). The European Society for Medical Oncology guidelines similarly note that while METamp is a promising therapeutic target, targeting METamp is not currently routinely recommended and recruitment into trials is encouraged (6).

Historically, trials aimed at targeting MET overexpression (e.g., onartuzumab) in NSCLC have failed (6). Onartuzumab (METmab), for example, is a MET-receptor monoclonal antibody that was evaluated in combination with erlotinib for the treatment of advanced NSCLC with MET diagnostic-positive status tested by immunohistochemistry; however, the Phase III trial evaluating onartuzumab combination therapy was stopped prematurely due to lack of clinically meaningful efficacy (131).

Instead of MET overexpression, the focus has shifted to targeting genomic variants, such as MET exon 14 skipping and METamp (6). Several agents alone or in combination with EGFR-TKIs were identified as under investigation for the treatment of METamp NSCLC. Information on ClinicalTrials.gov is evolving and additional trials evaluating therapies for METamp NSCLC have been indexed since the time of our literature search in June 2022, such as the Phase I trial evaluating the antibody-drug conjugate MYTX-011 (132) and a Phase I/II trial evaluating amivantamab and capmatinib combination therapy (133).

Concomitant inhibition of both EGFR and MET is thought to overcome resistance to EGFR inhibitors due to METamp (9, 134), and combination therapy with EGFR inhibitors and several type I MET-TKIs (tepotinib, savolitinib, and capmatinib) have shown promising results among patients with EGFR-mutated, METamp NSCLC who progressed on a prior EGFR-TKI (56, 76, 78, 119, 135). Final analysis of the Phase Ib/II INSIGHT trial demonstrated an objective response rate of 66.7% in patients treated with tepotinib plus gefitinib (78). Primary analysis results from the Phase II INSIGHT-2 trial (data cut-off: March 28, 2023; results were published in 2023 after our literature search was performed) demonstrated that treatment with tepotinib plus osimertinib demonstrated an objective response rate of 50.0% and a median progression-free survival of 5.6 months among patients with EGFR-mutant NSCLC and METamp who progressed on first-line osimertinib (119). Preliminary results from the SAVANNAH Phase II trial published in 2022 showed that savolitinib plus osimertinib demonstrated an objective response rate of 49% in patients with EGFR-mutated NSCLC with high levels of METamp, defined as FISH 10+, whose disease progressed on treatment with osimertinib (135). Results from a Phase Ib/II study showed that patients treated with capmatinib plus gefitinib had an objective response rate of 47% (56).

4.1 Limitations

The scope of the literature review search strategies included terms for NSCLC, METamp, and outcomes of interest. Due to inclusion of METamp terms in the search strategies, references describing rates of secondary METamp as a secondary or exploratory outcome among patients with EGFR-mutant NSCLC, references describing broad molecular testing patterns for all actionable driver mutations in NSCLC, or references describing treatments under investigation for patients with MET alterations generally (and not METamp specifically) may not have been captured. The included data were current as of our search date (June 14, 2022); data published or included in a database after that date were not captured. Treatments under investigation for METamp NSCLC are evolving rapidly, and ClinicalTrials.gov should be checked regularly for an up-to-date list of ongoing trials. Information available on ClinicalTrials.gov, however, is limited and not all actionable genomic alterations being evaluated in a clinical trial and included in a study protocol may be listed on ClinicalTrials.gov.

5 Conclusion

Results from this literature review demonstrate that primary METamp occurs in approximately 5% of NSCLC cases and secondary METamp occurs in approximately 15% of advanced NSCLC cases previously treated with an EGFR inhibitor in the US. NGS and FISH were commonly used to identify METamp in real-world studies; across clinical trials, variability existed in how METamp was defined. Future studies evaluating the economic and humanistic burden, as well as the real-world evidence on treatment for advanced METamp NSCLC are needed.

Several promising agents, including MET-TKIs in combination with EGFR-TKIs, are currently under investigation for secondary METamp NSCLC.

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