EGFR exon 20 insertion mutation and MET exon 14 skipping mutation in non-small cell lung cancer: a scoping review in the Chinese population

Introduction

Lung cancer is a leading cause of cancer deaths worldwide. In China, it accounted for approximately 710,000 deaths in 2020, with around 80% being non-small cell lung cancers (NSCLCs) (1). NSCLC is associated with a poor 5-year survival rate, with a large proportion of patients (67.5%) having advanced disease at diagnosis (2). Over the past decades, the discovery of targetable driver mutations in NSCLC has transformed the management of patients with these mutations (3).

The epidermal growth factor receptor (EGFR) gene aberrations lead to over-activation of various downstream oncogenic pathways (4), such as the phosphoinositide 3-kinase/AKT pathway. Mutations in EGFR are presented in a considerable proportion of patients with NSCLC, especially in Asian patients (30–35%) (5). There are several types of EGFR mutations, of which in-frame insertion mutations in EGFR exon 20 (EGFRexon20ins) account for 4–10%, making it the third-most frequent subtype of EGFR mutation after EGFR L858R point mutation or exon 19 deletions (6). EGFRexon20ins NSCLC has poor prognosis. It has been shown that patients carrying EGFRexon20ins have a 75% increased risk of death compared to patients who have common EGFR mutations (7).

The mesenchymal-epithelial transition (MET) mutations are another group of NSCLC driver mutations. The MET proto-oncogene can be activated by MET exon 14 skipping mutation (METex14) and is also involved in cell proliferation that plays a critical role in cancer development (8). They present in approximately 3% to 4% of Western patients with NSCLC (9). However, Western NSCLC patients with METex14 mutation exhibit molecular characteristics that differ from those of Asian patients, particularly in Chinese patients as reported by previous study (10).

The presence of these mutations enables the application of precision medicine through the use of targeted therapies, rather than basing treatment options on crude histological subtypes. Recently, new targeted therapies which have recently been approved include amivantamab (1) and mobocertinib (2) that target EGFRex20ins, and capmatinib (11), tepotinib (12), glumetinib (13), savolitinib (14,15), and vebreltinib (16) that target METex14 (9). Although EGFRex20ins and METex14 mutations in NSCLC have attracted considerable interest from the scientific community (5,9,17), there remains limited information on the clinical relevance and impact of these mutations in Chinese patients. Some studies investigated epidemiological and clinical burden of METex14 in lung cancer in Chinese population (9,10,18,19), but there is no systematic summary. Therefore, we conducted a scoping review to assess the currently available evidence of these two rare mutations of NSCLC in the Chinese population. The scoping review is a type of knowledge synthesis that uses a systematic and iterative approach to identify and synthesize an existing or emerging body of literature on a given topic. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-528/rc) (20).

Methods

Literature searches and identification

We identified relevant studies through systematic searches of eight databases from inception to 14 November 2023: PubMed, EMBASE, The Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM), Wanfang and Chinese Scientific Journals (VIP) databases. Search terms included those related to EGFRex20ins, METex14, NSCLC and Chinese (see Appendix 1). There were no restrictions on publication language or study design. After removing duplicates, two reviewers independently determined whether articles were eligible for inclusion based on their titles and abstracts. To avoid missing studies, studies that include at least one Chinese authors also were reconfirmed in the full text to ensure the reporting of data from the Chinese population. We included studies that met the eligibility criteria, which involved examining the therapeutic effectiveness in Chinese patients with NSCLC harbouring EGFRex20ins or METex14 mutations or reporting the prevalence of EGFRex20ins or METex14 mutations in Chinese NSCLC patients, including Chinese cohorts or arms reported in multi-national studies. Case reports, reviews and abstracts were excluded. Furthermore, we were interested in examining the proportion of mutations among Chinese patients with NSCLC in the subgroup analysis such as smoking statuses and age groups. Discrepancies in data collection were resolved through discussion with a third senior author.

Data extraction

We extracted data from each study in a standardized manner, including information on age, gender, diagnosis, disease stage, family history, smoking status, frequency of mutations, interventions (treatment regimens, description, frequency, dosage, duration, combination of drugs), and outcomes including mutation proportion as defined by the number of NSCLC patients harboring mutation within the total number of NSCLC patients, and therapeutic effectiveness as defined by original studies such as overall survival (OS), progression-free survival (PFS), disease control rate (DCR), complete response (CR), and partial response (PR). Additional information on study design, clinical, biochemical, and pathological parameters was also collected from identified articles. If appropriate, authors of included studies were contacted to request missing or additional data.

Statistical analyses

Data were narratively summarized and presented in text and tables. For categorical variables, we summarized data in proportions as reported in original studies. For continuous variables, we summarized data in different outcome measures as reported in original studies using such as median OS or PFS and their 95% confidence interval (CI).

Results

A total of 111 studies were identified (see the list of included studies in Appendix 2), reporting on EGFRex20ins and METex14 mutations in 159,993 NSCLC Chinese patients (Figure 1). One study was based in Northeast China, 41 in Eastern China, 22 in North China, 9 in South China, 6 in Southwest China, 5 in Northwest China, and 13 in mixed regions (Figure S1). Of the 111 studies, 78 studies were single-center, 24 studies were multi-center, and this information was not available for 9 studies (Table 1). Only 8 studies were known to be funded by industry.

Figure 1 The PRISMA flow diagram for studies included in the scoping review. NSCLC, non-small cell lung cancer.

Of the 111 studies included, 76 studies reported on EGFRex20ins and 45 studies reported on METex14. Thirty-two studies had sample sizes of more than 1,000 patients (28.8%; Table 1). The most common method to detect the mutations was next-generation sequencing (N=35 studies), followed by reverse transcription polymerase chain reaction (RT-PCR) (N=27 studies; Table S1). Stage IV was the most reported stage (34.2%) and adenocarcinoma was the most reported subtype (52.3%) among patients with NSCLC (Table S2). Seventy-five studies were written in English, whereas 36 studies were written in Chinese (Table 1). None of the included studies reported the presence of both EGFRex20ins and METex14 mutations concurrently in NSCLC patients. However, individually these mutations have been reported to co-occur with other uncommon mutations (Table S3).

EGFRex20ins

Among the 76 included studies (Table S4) that reported on EGFRex20ins, the frequency of EGFRex20ins ranged from 0.02–6.56% of all NSCLC patients and 0.56–100% of all EGFR mutations in China. When we evaluated the frequency from studies with at least 1,000 patients, there were 32 studies in China; and the frequency of EGFRex20ins ranged from 0.02–2.85% of all NSCLC patients and 0.56–6.90% of all EGFR mutations (Table 2). The frequency of EGFRex20ins varied between the different regions in China, where North China reported the highest frequency and South China reported the lowest (Table S5).

Twenty-eight studies reported smoking status (N=1,798 patients), in which 70.6% of patients were non-smokers (N=1,270 patients) (Table S6). Six studies perform subgroup analyses by age group (21-26). Compared to younger patients (age <60 years), the frequency of EGFRex20ins was slightly higher in older patients (age ≥60 years), with 0–14.29% versus 1.68–17.39% (Table S7).

Sixteen studies evaluated the first-line treatment regimens for NSCLC patients with EGFRex20ins (Table 3). Among these studies, fourteen (N=338 patients) investigated the effectiveness of tyrosine kinase inhibitors (TKIs), with median PFS ranged from 2.0 to 9.97 months. Seven studies (N=735 patients) examined chemotherapy, with median PFS ranged from 3.4 to 15.43 months. Three studies (N=21 patients) investigated immune checkpoint therapy, with median PFS ranged from 1.7 to 2.8 months. Two studies (N=104 patients) explored the use of chemotherapy and TKI but only one study report PFS and OS. Another study (N=55 patients) explored the use of platinum and TKIs but did not report PFS or OS. Additionally, one study (N=49 patients) did not specify the examined intervention but reported a median PFS of 7.6 months (95% CI: 5.7–9.6).

Nine studies evaluated the second-line treatment regimens (Table 3). Among them, eight studies (N=159 patients in total) examined TKIs, with a median PFS ranged from 2.0 to 6.77 months. Two studies (N=83 patients in total) examined chemotherapy, reporting median PFS ranged from 2.4 to 6.0 months. Two studies (N=6 patients in total) investigated immune checkpoint therapy, with one of them reporting a median PFS of 2.3 months. One study (N=4 patients) investigated the third-line treatment, reporting a median PFS of 8.5 months. Another study (N=1 patient) investigated the fourth-line treatment, with a PFS of 6.6 months.

The treatments used varied depending on the study, and there was limited evidence on whether any one treatment was superior compared to the rest in terms of clinical efficacy and safety for patients with EGFRex20ins. Patients were usually treated with EGFR TKIs and chemotherapy. Notably, the presence of EGFRex20ins was generally associated with a shorter PFS time. Eight studies involving 11,009 patients delved into prognostic factors to predict PFS or OS outcomes. Among these factors, histological type of NSCLC, patient age, and smoking status were identified as potential elements associated with PFS or OS outcomes (Table S8).

Additionally, seven studies (27-33) involving 673 patients reported adverse events (AEs). Any grade AE ranged from 41.5% to 99.1%. These studies predominantly detailed grade 1–2 AEs, with common occurrences such as rash (15.4–57.3%), diarrhea (12.5–54.7%), dry skin (54.00%), decreased appetite (54.00%), and paronychia (12.0–52.00%). Moreover, three studies (27, 28, 31) documented grade 3 AEs, with incidence rates ranging from 38.0% to 62.0%. Grade ≥3 events that occurred in ≥10% of patients were rash (21.3%) and diarrhea (10.7%).

MET exon 14 skipping mutation

Among the 45 studies reported on METex14, the frequency of METex14 ranged from 0–26.7% of all NSCLC patients and 0–100% of all MET mutations in China (Table S9). When we evaluated the frequency from studies with at least 1,000 patients, there were 8 studies in China. The frequency of METex14 ranged from 0.08–1.38% of all NSCLC patients and 8.33–56.6% of all MET mutations (Table 2). The frequency of METex14 varied between different regions in China (Table S5), where the highest and lowest frequencies of METex14 were typically in Eastern and South China, respectively.

Nineteen studies, involving 34,107 patients, reported smoking status (N=571 patients), of which 63.9% patients were non-smokers (N=365 patients) (Table S10). Nine studies perform subgroup analyses by age groups (31,34-41) (Table S11). In general, compared to younger patients (age <60 years), the frequency of METex14 was higher in older patients (age ≥60 years), with 0–4.35% versus 0.43–27.78% (Table S11). Thus far, no studies included in the scoping review evaluated treatment regimen for NSCLC patients with METex14 in China such as tepotinib and capmatinib.

Eight studies evaluated first-line treatment regimens or more for NSCLC patients with METex14 (Table 4). They investigated the effectiveness of TKIs, reporting median PFS ranging from 3.4 to 11.5 months and median OS ranging from 10.9 to 35.8 months. Additionally, one study explored the use of Amivantamab, reporting a PFS of 0.8 months and OS of 0.9 months. Furthermore, three studies (14,42,43) involving 137 patients reported AEs. The incidence of AEs of any grade ranged from 36.8% to 100.0%. These studies primarily documented grade 1–2 AEs, including nausea (52.9%), edema peripheral (48.6%), rash (37.9%), decreased appetite (34.3%), vomiting (32.9%), elevated alanine aminotransferase (ALT) (28.8–36.8%), and elevated aspartate aminotransferase (AST) (20.7–28.9%), and dysgeusia (21.1%). Moreover, they reported grade 3 AEs, with incidence rates ranging from 28.0% to 45.7%. Grade ≥3 events occurring in ≥10% of patients included elevated AST (12.9%), elevated ALT (10.0%), and palmar-plantar erythrodysesthesia (PPE) (10.5%).

Discussion

This scoping review consists of 111 studies that report on a total of 159,993 patients and provides the most comprehensive assessment of EGFRex20ins and METex14 mutations in Chinese NSCLC patients to date. Most of the studies were non-comparative studies. We found that the frequency of these two mutations varied between different regions in China, with the lowest frequency in the South. Forty-eight studies (76.2%) were published in the last five years since these two mutations have attracted more attention in China. Patients with these mutations were more likely to have advanced NSCLC compared to those without. The most common histological subtype was adenocarcinoma.

Findings of a previous systematic review indicated that the frequency of EGFRex20ins ranged from 0.1–4% of all NSCLC patients and 1.0–12% of all EGFR mutations globally (9). In the present review, the frequency of EGFRex20ins ranged from 0.02–2.85% of all NSCLC patients and 0.56–6.90% of all EGFR mutations when we focus on the larger studies with at least 1,000 Chinese patients. The frequency of EGFRex20ins found in our study is similar to the reported data among Caucasian patients with NSCLC, although the upper range is lower in Chinese patients. The frequency of METex14 is much lower in Chinese patients (0.08–1.38%) with NSCLC than in Caucasian patients (~3%). Both mutations also account for a smaller proportion of all EGFR and MET mutations in Chinese patients with NSCLC. Therefore, the frequency of these mutations may be relatively low in Chinese patients with NSCLC. However, the frequency of these two mutations may have been underestimated since various genotyping methods were used (Table S1). Among the methodologies employed, RT-PCR, utilized in 27 studies (24.32%), was an earlier-published genotyping technique. In contrast, a more recent trend, observed in 35 studies (31.5%), involved the use of next-generation sequencing for identifying both known and novel variants (Table S1). Therefore, further large-scale studies using the next-generation sequencing are warranted to understand the frequency of these mutations in Chinese patients.

The treatment regimens were assessed in NSCLC patients with EGFRex20ins mutation. The treatments used varied depending on the study, with the most common treatment regimens consisting of EGFR-specific TKIs and chemotherapy (Table 3). There was limited evidence on whether any one treatment was superior compared to the rest in terms of clinical efficacy and safety for NSCLC patients with these mutations. In general, the presence of these mutations was associated with a shorter PFS time. In recent years, emerging real-world studies are focusing on EGFR-TKIs in the treatment of EGFR-mutant NSCLC (23,44-50) in Chinese population. However, EGFR-TKIs show controversial effectiveness in EGFRex20ins. Furmonertinib has shown encouraging antitumor activity and a good safety profile in advanced NSCLC patients with EGFRex20ins and the 6-month PFS rate was 69.4% (95% CI: 53.7–85.1%) (29), whereas afatinib has not shown favorable efficacy and tolerability in the treatment of advanced lung adenocarcinomas with EGFRex20ins comparing to other EGFR mutations (23) (median PFS =2.4 months, 95% CI: 0.0–5.1 months). The similar situation was found in the treatment with Gefitinib and Erlotinib (median PFS =2.3 months, 95% CI: 1.5–3.1) (51). Moreover, the EGFR-MET bispecific antibody amivantamab showed effectiveness in the treatment of EGFRex20ins-positive NSCLC with osimertinib resistant, which is similar to the findings from other study populations (52,53).

Fewer studies have examined the efficacy and effectiveness of treatments for NSCLC with METex14 mutation in the Chinese population, as indicated in Table 4. It has been shown that the median PFS was 3.4–11.5 months, and the median OS was 10.9–35.8 months in NSCLC patients with METex14 mutation who received bozitinib, savolitinib, or crizotinib treatment. In addition, the median PFS and OS were 1.9 months (95% CI: 1.9–3.7) and 10.3 months [95% CI: 7.3–not evaluable (NE)] in all 38 NSCLC patients with c-MET overexpression (n=34) or METex14 mutation (n=4) (42).

The evidence on the prognostic effect of these mutations was little to assess the impact on OS time. In terms of age group and smoking status, limited evidence was available to give a clear picture for the EGFRex20ins and METex14 mutations in Chinese patients with NSCLC.

There was also some evidence to assess the treatment regimens in other ethnic groups with EGFRex20ins mutation or with METex14 mutation (5). For the first-line treatment, the most common treatment regimens were chemotherapy for patients with EGFRex20ins mutation. Median OS ranged from 6.3 to 28.0 months. Median PFS and objective response rates (ORRs) were 3.4–6.9 months and 23–29%, respectively (5). For METex14 mutation, the efficacy and safety of two MET-TKIs capmatinib and tepotinib, have been previously assessed (5). These drugs yielded PFS of 5.6–12.4 months in clinical trials. However, it has been reported that one-third to half of patients showed inherent resistance to MET-TKIs. Given the evidence indicating inherent resistance to MET-TKIs in up to half of patients with METex14 mutation, future clinical trials should prioritize investigating novel therapeutic approaches or combination therapies to address this challenge. Additionally, it would be crucial to explore the efficacy and safety of these treatment regimens specifically in diverse ethnic groups to ensure a comprehensive understanding of their impact across different populations. This will not only enhance the precision of treatment but also contribute valuable insights into optimizing therapeutic strategies for patients with METex14 mutation.

Our study has several strengths. We conducted systematic searches on eight databases and identified 111 studies with nearly 160,000 Chinese patients with NSCLC. The assessment of mutation frequency in larger studies should be less prone to selective reporting than in smaller studies. Furthermore, evaluation of the current literature has allowed the identification of gaps in our current knowledge, which may help direct future research in Chinese NSCLC patients. For example, there is limited evidence on which treatment option is more beneficial when considering clinical efficacy and the safety of NSCLC patients with these mutations. Additionally, the frequency of EGFRex20ins and METex14 mutations and their correlation with gender, smoking status, stage, and histological grade remains unclear, especially when considering the presence of other co-occurring genomic mutations in these patients.

Limitations of our study include the possible underestimation in the frequency of EGFRex20ins and METex14 mutations in Chinese NSCLC patients, as the earlier genotyping method to detect the mutations in the included studies was RT-PCR. Mutation detection using next-generation sequencing, which focuses on large-scale studies, could potentially improve this. Further large-scale studies, including epidemiological studies and real-world data, are required to identify the association between the presence of these mutations, clinical characteristics at baseline, and treatment efficacy. Due to limited data on NSCLC patients with these mutations, we are unable to perform a meta-analysis.

At present, the optimal treatment regimen for Chinese NSCLC patients with EGFRex20ins and METex14 remains unclear. In the present review, we focused on evaluating the efficacy and safety of treatment regimens for Chinese patients with EGFRex20ins or METex14 mutations, based on non-comparative studies. Among these studies, the treatment regimens of EGFRex20ins varied depending on the specific study. For NSCLC patients with MET exon 14 skipping mutations, targeted therapies such as capmatinib, tepotinib, glumetinib, savolitinib, and vebreltinib have shown efficacy and have been approved for use. In contrast, MET amplification represents a distinct alteration that may respond differently to treatment, typically requiring more comprehensive therapeutic approaches. While MET exon 14 skipping mutations directly confer sensitivity to MET inhibitors, further research is required to optimize treatment regimens, particularly for cases involving MET amplification.

Conclusions

Our review highlights that both EGFRex20ins and METex14 mutations account for a smaller proportion of all EGFR and MET mutations in Chinese patients with NSCLC; while several targeted therapies have been approved in China, there is still insufficient evidence regarding the optimal treatment and therapeutic efficacy for Chinese patients with NSCLC. Further large-scale studies are required to identify associations between the presence of these mutations and clinical characteristics at baseline and outcome following treatment.

Acknowledgments

We thank Ms Yang Zhang and Dr. Zheng Ye from Systematic Review Solutions Ltd. for their assistance in methodology.

Funding: This study was funded by Xi’an Janssen Pharmaceutical Ltd.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-528/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-528/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-528/coif). All authors report that this study was funded by Xi’an Janssen Pharmaceutical Ltd. X.G. and Y.W. were employees of Xi’an Janssen Pharmaceutical Ltd. during the study. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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