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From patient characteristics to treatment patterns, these MET exon 14 jumping mutation related studies on WCLC are worth a look!

 Last Update: 2022-11-15
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These studies from the WCLC can provide many valuable reference information
for clinical diagnosis and treatment.

The World Lung Cancer Conference (WCLC) is one of the most concerned academic events in the field of lung malignant tumor diagnosis and treatment in the world every year, and the research that can appear at the conference often has important guiding significance for clinical diagnosis and treatment, and with the concept of precision targeted therapy deeply rooted in the hearts of the people, around the research on non-small cell lung cancer (NSCLC) that can target gene mutations, It has also become an indispensable and important content of WCLC every year, and the research heat of NSCLC "rare mutations" has heated up rapidly in recent years
.

As a "rare mutation" of NSCLC that has attracted much attention, MET14 exon skipping mutation (MET ex14) has also appeared in WCLC many related studies, a comprehensive analysis of such tumor biological behavior, gene mutation profile, patient characteristics and real-world current treatment models will help improve clinical management and improve patient prognosis, this article will introduce 3 MET ex14+NSCLC related studies at the 2022 WCLC conference.
The guiding value
of clinical treatment is discussed.

Characteristics and previous treatment of patients with MET ex14+NSCLC

MET ex14 has a mutation frequency of about 3-4% in all NSCLCs, which is a typical rare mutation, so the analysis of real-world patient characteristics and treatment status is often carried out in a single center or a small number of centers, and the number of patients included in the analysis is relatively limited
.
Collecting a wider range of patient data from electronic medical record systems can greatly complement this shortcoming, allowing clinicians to gain a deeper understanding
of MET ex14+NSCLC.

A poster study (abstract number P1.
09-02) ^[1] at this WCLC conference, on The data of 138 adult patients with MET ex14+ NSCLC (limited to having received at least one previous round of systemic therapy and follow-up for > 90 days) were analyzed from 2011 to 2020 by Flatiron Health's electronic medical record system, and compared with more than 5100 MET wild-type NSCLC patients to evaluate the clinical features and real-world treatment patterns
of MET ex14+ patients.

The baseline characteristics of MET ex14+ patients and MET wild-type patients are shown in Table 1, showing that MET ex14+ patients are older (median age 75/68 years), more women (59.
4%/46.
6%), more non-squamous cell carcinoma (83.
3%/69.
3%), and significantly fewer patients with a smoking history (64.
5%/91.
2%)
。 In addition, the proportion of patients with high PD-L1 expression (≥50%) was significantly higher in MET ex14+ patients (56.
7%/29.
8%), but significantly fewer patients with high tumor mutation burden (TMB-H, defined as TMB≥10 mt/Mb) (16.
3%/48.
5%)
.

Table 1.
Baseline characteristics of MET ex14+ patients and MET wild-type patients In terms of
treatment mode, the most commonly used first-line treatment regimen for MET ex14+ patients and MET wild-type patients was chemotherapy, followed by immunotherapy.
The protocol mode and proportion of each line of treatment in the two groups were similar, but multi-target tyrosine kinase inhibitors (Multi-TKIs) were used more in the first-line treatment of MET ex14+ patients (11.
6%/0.
3%), occupying the position of immunotherapy + chemotherapy (25.
0% utilization rate) in MET wild-type patients.
Multi-TKIs accounted for 12.
3% and 7.
2% of second- and third-line patients with MET ex14+ (see Table 2 and Figure 1).

Table 2.
The treatment regimens and proportions of MET ex14+ patients and MET wild-type patients 1.

Treatment options and proportions
of MET ex14+ patients and MET wild-type patients This study fully reflects the clinical characteristics of MET ex14+ patients with a large sample size, but because the electronic medical record data comes from 2011-2020, highly selective MET-TKI has not been widely used in the United States, so the patient's treatment mode is still dominated by non-targeted therapies such as chemotherapy and immunotherapy, and the impact of precision targeted therapy cannot be seen, and the value of MET-TKI in improving patient prognosis still needs to be evaluated
by more and more extensive studies.

The heterogeneity of MET ex14+ tumors is significant, and clinical features such as co-mutations need to be analyzed urgently

Previous studies have shown that MET ex14+NSCLC can be detected in patients with lung squamous cell carcinoma and adenocarcinoma, and patients with or without smoking history, which is very different from other driver gene mutations in NSCLC concentrated in adenocarcinoma and patients without smoking history, and although MET ex14 is a clear driver gene mutation, patients may still be combined with other co-mutations, which have a certain potential impact on targeted therapy drugs and patient prognosis, so MET ex14+ needs to be further clarified Patient features and co-mutations in
NSCLC.

A study conducted by a team of multiple U.
S.
institutions at this WCLC (abstract number MA05.
08) ^[2]. 440 tumor samples from MET ex14+NSCLC patients were analyzed in detail at the genomic level by next-generation sequencing (NGS), whole exome and whole transcriptome sequencing, and PD-L1 expression and tumor mutation burden (TMB) levels were evaluated by immunohistochemistry, and the relationship
between the above analysis results and the clinical, pathological characteristics and smoking history of patients was searched.

A total of 147 different types of MET ex14 mutations involving more than 11 protein changes were detected, of which the most common MET ex14 mutation types were: D1028H (8.
4%), D1028N (7.
0%), c.
3082+2T>C (5.
7%), D1028Y 5.
2%), and c.
3082+1G >A（4.
5%）
。 A total of 43.
9% of the samples detected a TP53 comutation, but the comutation frequency (21.
1%-53.
9%) varied between patients with different types of MET ex14 mutations (see Figure 2).

Figure 2.
Co-mutation in patients with different types of MET ex14 mutations
In terms of pathological types, 86.
6% (n=381) of MET ex14+ patients were non-adenocarcinoma, squamous cell carcinoma (n=49) and adenosquamous cell carcinoma (n=10) accounted for 11.
1% and 0.
2%, respectively, and patients with squamous cell carcinoma were more likely to detect TP53 co-mutations (90.
4% vs.
60.
7%, p<0.
001) than adenocarcinoma patients, and there was a relatively short trend of median overall survival (OS) (336 days vs.
1106 days, HR=1.
22, p=0.
47).

。 A total of 93 patients had an assessable smoking status, of which 79 (84.
9%) had a history of
smoking.

A total of 8.
6% of MET ex14+ samples belonged to TMB-H, and 82.
2% of patients expressed positive PD-L1 (defined as ≥1%), but there were significant differences in PD-L1 positivity rates between different types of MET ex14 mutations (0-97.
5%, q<0.
05).

。 In addition, the mRNA expression of human leukocyte antigen G (HLA-G) in non-smoking patients was significantly upregulated compared with that of smoking patients (0.
31 vs.
0.
09 TPM, q<0.
05), but there was no significant difference between
non-smoking and other gene expression and signaling pathway activation in non-smoking patients.

In summary, the above data suggest significant heterogeneity in co-mutations, TMB and PD-L1 expression levels within the MET ex14+NSCLC patient population, and the prognosis differences between squamous cell carcinoma and adenocarcinoma patients are also of concern, and these heterogeneities affect the existing highly selective MET tyrosine kinase inhibitors (MET-TKI) and other treatment methods such as immunotherapy and chemotherapy.
Further research evaluation
is needed.

The MET ex14+NSCLC was refined and typed to guide clinical precision medication

The approval of highly selective MET inhibitors has comprehensively rewritten the diagnosis and treatment pattern of MET ex14+NSCLC, taking the first phase II clinical study of MET-TKI targeting MET ex14+ patients approved in China as an example, the recently updated long-term follow-up data of the study shows that the median OS of patients treated with cevotenib can reach 12.
5 months, and the 2-year survival rate of patients exceeds 30% (31.
5%).
Among them, the median OS of first-line patients was as long as 19.
4 months, indicating a significant clinical benefit of sevotinib ^[3], in addition, the efficacy data of Capmatinib and Tepotinib MET-TKIs that have been approved abroad are also close
。 In the phase II VISION study, the overall ORR for Tepotinib treatment was 44.
7 percent in 152 patients with MET14 jumping mutation NSCLC whose efficacy was evaluable ^[⁵^].
。 GEOMETRY mono-1 study MET14 exon skipping mutation cohort data show that Capmatinib has an ORR of 67.
9 percent in treatment-naïve patients (n=28^{) [6].}

However, the available clinical research data also show that the objective response rate (ORR) of MET-TKI treatment is still only about 50%.

Given the significant heterogeneity of MET ex14+NSCLC in the first study, there is a need to further subdivide patients to maximize
the therapeutic effect of MET-TKI.
A study from the team of Professor Han Yuchen of Shanghai Chest Hospital ^[4] (abstract number MA05.
07) at this WCLC meeting initially attempted to type
patients with intratumoral heterogeneity.

A total of 126 patients with MET ex14+NSCLC admitted to Shanghai Chest Hospital from April 2017 to December 2020 were analyzed, and RNA-based sequencing large panels (containing a total of 2660 tumor-immunotherapy-related genes) were used to evaluate the patients' molecular typing, specific signaling pathways, tumor microenvironment and clinicopathological characteristics ex14+NSCLC is divided into four different molecular subtypes (see Figure 3), and the specific characteristics are as follows: Figure 3.
The molecular subtype and main feature
subtype A (n=35) of MET ex14+NSCLC proposed by the investigators:
MET-driven type, characterized by the activation of MET signaling pathway and the immunosuppressive state of the microenvironment, The latter includes PTK2 gene activation, glycolysis of cancer cells and hypoxia in the microenvironment, increased infiltration of regulatory T cells (T _reg), epithelial-mesenchymal conversion (EMT), etc.
, patients tend to have later clinical stage, larger tumor volume, and more aggressive tumor biological behavior, but at the same time, they are also more sensitive to MET-TKI treatment.
Subtype B(n=18): mixed, lacking distinct features; Subtype C(n=12): immune-activated type, manifested as a high proportion of T cell and macrophage infiltration in tumors, and a high expression level of MHC-II molecular features, such patients may be more sensitive to immunotherapy; Subtype D (n=41): bypass-activated type, the presence of activation of carcinogenic signaling pathways such as WNT, MAPK, NOTCH, ERBB, etc.
, speculated to lead to resistance to MET-TKI, or need to be combined with other bypass inhibitors to improve the efficacy

of four subtypes of patients with gene mutation characteristics, clinicopathological features and prognosis, respectively, as shown in Figure 4, Figure 5 shows:

Figure 4.
Characteristics of gene mutations in patients with four subtypes Figure 5.
Clinicopathological features and prognosis of

patients with four subtypes The researchers also provided the response of some subtype A (n=8) and subtype D (n=3) patients to MET-TKI treatment, which also reflects the difference in response to treatment by different molecular typing MET ex14+, indicating that patients with subtype A may be more sensitive to treatment, while patients with subtype D are more likely to develop drug resistance (see Figure 6).

All in all, the molecular typing proposed by Professor Han Yuchen's team in this analysis may be used to guide the clinical use of MET-TKI and optimize treatment options
.

Figure 6.
Differences in treatment response between patients with subtype A and subtype D

brief summary

With the continuous delivery of outstanding efficacy data of MET-TKIs such as cevotinib, Capmatinib, and Tepotinib in clinical research, helping some patients to achieve effective disease control and long-term survival, MET ex14 is still paying attention to it, and it is now a "mandatory inspection site"
for NSCLC generally recommended by domestic and foreign guidelines 。 Clinicians need to fully understand the characteristics and tumor biological behavior of MET ex14+NSCLC patients to optimize detection objects, detect as many patients as possible, and provide highly individualized treatment plans as much as possible, so that precision treatment can benefit more patients
.

References:
[1] Le X, Hampe M, Wu W H, et al.
P1.
09-02 Real-world Clinical Characteristics and Treatment Patterns of METExon 14 Skipping Mutation in Advanced/Metastatic NSCLC[J].
Journal of Thoracic Oncology, 2022, 17(9): S106.
[2]Marks J, Yin J, Halmos B, et al.
MA05.
08 MET Exon 14 Skipping Mutation in Non-Small Cell Lung Cancer (NSCLC) by Specific Mutation, Histology, and Smoking History[J].
Journal of Thoracic Oncology, 2022, 17(9): S61.
[3]Lu S, Fang J, Li X, et al.
Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations[J].
JTO Clinical and Research Reports, 2022, 3(10): 100407.
[4]Han Y, Chen S, Xiang C, et al.
MA05.
07 Intertumoral Molecular Heterogeneity of Non-small Cell Lung Cancer with MET Exon 14 Skipping[J].
Journal of Thoracic Oncology, 2022, 17(9): S60-S61.
[5] Xiuning Le，et,al.
Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice.
Clin Cancer Res (2022) 28 (6): 1117–1126.
[6]Wolf J, Garon EB, Harry JM, et al.
Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study.
J Clin Oncol 2021; 39(suppl_15):9020-9020.

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