As an authoritative reference to guide the diagnosis and treatment of non-small cell lung cancer (NSCLC) in China, the Chinese Society of Clinical Oncology (CSCO) NSCLC The diagnosis and treatment guidelines can not only be used to guide clinical diagnosis and treatment, but also reflect the latest development trend of lung cancer treatment research. The majority of clinicians are highly concerned about the annual guideline update.
Recently, the 2022 edition of the CSCO guidelines for the diagnosis and treatment of primary NSCLC was officially released. In the molecular typing of NSCLC, the biggest highlights of the update are: Based on the approval of targeted drugs for MET mutations in China, the non-squamous cell carcinoma tissue samples of inoperable stage III and IV patients were tested for MET exon 14 skipping mutation, and the recommendation was raised from level II to level I ( Type 3 evidence).
This update of the CSCO guidelines not only combines the latest developments in the availability of MET inhibitors in my country, but also the recommendations of foreign guidelines and consensus. The basic integration highlights the rising status of MET exon 14 skipping mutation, a rare mutation in the targeted therapy of NSCLC. In the context of the update of the guideline, it is necessary to re-understand the detection method of MET exon 14 skipping mutation and the current status of domestic and foreign guideline recommendations, so as to choose the most suitable detection method for patients, and truly achieve “precision treatment and detection first”.
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Gradually become a “must-check gene”
MET exon 14 skipping mutation detection heats up
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In the 2021 edition of the CSCO guidelines, the recommended level of MET exon 14 skipping mutation detection is level II, which is the same as MET amplification and BRAF V600E Mutation, KRAS mutation and other gene variants are side-by-side, and belong to the gene variants recommended by the guideline that “can be detected in tumor tissue by single-gene detection technology or next-generation sequencing technology (NGS).” The 2022 version of the CSCO guideline was updated to increase the recommended level of detection for MET exon 14 skipping mutations to the same level as EGFR mutations, ALK fusions, ROS1 and RET fusions. Figure 1. 2022 CSCO Guidelines for Primary NSCLC Molecular Typing Recommendations
my country’s “Clinical Practice Guidelines for Molecular Pathology Detection of Non-Small Cell Lung Cancer” released in 2021 has taken the lead in listing MET exon 14 skipping mutation as one of the four “must-check gene mutations” for NSCLC patients (the other three are EGFR, ALK, ROS1), and proposed that NGS and other methods can be used in practice to simultaneously detect MET exon 14 skipping mutations and other driver gene variants, and to detect patients with negative other driver gene variants separately< span>[1].
The good efficacy of tyrosine kinase inhibitor (TKI) targeted drugs in patients with MET exon 14 skipping mutation is obviously an important factor to promote the update of the guideline. The latest research data recently announced at the European Lung Cancer Congress (ELCC) showed that the first MET-TKI innovative drug sivotinib approved in my country, the median overall survival (OS) of patients with MET exon 14 skipping mutations. ) up to 12.5 months, and the objective response rate (ORR) and disease control rate (DCR) were excellent, suggesting a significant clinical benefit[2] sup>. The content of targeted therapy for patients with MET exon 14 skipping mutations will also enter the CSCO guidelines for the first time in 2021. In addition, in the phase II VISION study, tepotinib has durable clinical activity in patients with MET exon 14 skipping mutation NSCLC, the overall population ORR is 44.7%, and the safety is good[3]. The GLORY study showed that the ORR of the total population of gumetinib was 60.9%, and the ORR of the newly treated patients was slightly better than that of the previously treated patients, 66.7% and 51.9%, respectively, showing good clinical benefits[4]. In contrast, the development of MET exon 14 skipping mutation detection and targeted therapy abroad is faster. As the so-called stone of other mountains can be used to attack jade, we can also obtain a lot of useful references from the recommendations of current foreign guides and consensus. Currently, there are clear recommendations for the detection of MET exon 14 skipping mutations, mainly the authoritative National Comprehensive Cancer Network (NCCN) NSCLC clinical practice guidelines and the Japanese Lung Cancer Society ( JLCS) related guidelines. Among them, the latest version of NCCN guidelines (2022.V3) in 2022 recommends that MET exon 14 skipping mutation is one of the biomarkers that should be “at least detected” in patients with metastatic non-squamous NSCLC, and its importance is similar to that of EGFR, ALK, ROS1 and other genes Mutation and PD-L1 expression levels are the same[5]; JLCS was developed by a specialized biomarker committee for MET exon 14 skipping mutation Detection guidelines, which comprehensively introduce multiple issues related to the detection and treatment of MET exon 14 skipping mutations[6]. The importance of detecting MET exon 14 skipping mutations is beyond doubt, but clinicians should not only keep in mind the range of patients to be tested, the advantages and disadvantages of different detection methods, It is also necessary to understand and learn to choose the appropriate detection method for the patient’s situation.
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Detecting MET exon 14 skipping How should mutations be performed in clinical practice?
Currently The clinical detection methods for MET exon 14 skipping mutations are mainly RNA-based NGS, RNA-based next-generation sequencing (NGS) or reverse transcription-polymerase chain reaction (RT-PCR)Two, they can detect exon 14-deleted mRNA at the RNA level; or DNA-based NGS, a DNA-based NGS method that detects genetic variants at the DNA level in tissue or cytology samples. When tissue or cytology samples are not timely, detection of ctDNA by plasma liquid biopsy can also be used as a supplement[1,7]. Different detection methods have their own advantages and disadvantages. For example, NGS can simultaneously detect MET exon 14 skipping mutations and other driver gene mutations, and is widely used in clinical applications[1], and since MET exon 14 skipping mutations are generally mutually exclusive with other driver genes, even if patients with MET exon 14 skipping mutations are detected The results are negative, and other genes that can be targeted are also expected to be detected and treated. However, some studies have shown that the accuracy and mutation detection rate of RNA-NGS detection are higher than DNA-NGS[8], which may be related to DNA-NGS. -Insufficient coverage of gene probes in NGS testing. The mutation frequency of MET exon 14 skipping mutations in NSCLC is about 3%-4%, and missed detection should be avoided as much as possible. In the case that NGS detection is not available, RT-PCR is used for single-gene detection of MET exon 14 skipping mutation, which also has good specificity and sensitivity , Some studies have specifically verified the consistency of two traditional detection methods, RT-PCR and Sanger sequencing, with DNA/RNA-NGS detection, and found that the consistency of RT-PCR detection is relatively higher.[9]. Even in the United States, where the medical level is relatively developed, according to the NCCN guidelines from 2013 to 2015, the proportion of NSCLC patients with comprehensive detection of various biomarkers may only account for only 8%< span>[10]. Precise treatment requires detection to pave the way first. Based on the above-mentioned MET exon 14 skipping mutation detection method, clinicians have sufficient selectivity, and can match the corresponding detection methods according to the needs of different patients, and try their best to achieve “everything that should be tested.” check”. Existing data show that MET exon 14 skipping mutations are more common in elderly, female, non-smoking, and histologically sarcomatoid lung cancer patients< sup>[7], this type of patient population should pay more attention to the detection of this gene, and do not miss the detection.
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Summary
MET exon 14 skipping mutation has become NSCLC Another hot “rare mutation” in targeted therapy, detection methods and drug treatments are developing rapidly, and Chinese patients already have drugs available, benefiting significantly from the treatment of innovative drugs such as sivotinib, and the CSCO guideline update also In line with this development trend, the recommended level of detection of MET exon 14 skipping mutations has been raised, which will help clinicians and patients to improve detection awareness and strive for more opportunities for targeted therapy. Combining patient characteristics and testing accessibility, further optimizing the testing strategy will also help to truly implement the concept of “precise treatment, testing first”.
References:[1] Chinese Medical Association Pathology Branch, National Center for Quality Control of Pathology, Lung Cancer Group of Oncology Branch of Chinese Medical Association, et al. Clinical Practice Guidelines for Molecular Pathology Detection of Non-Small Cell Lung Cancer (2021 Edition) [J]. Chinese Journal of Pathology, 2021, 50(4): 323-332.[2] Lu S, Fang J, Li X, et al. 2MO Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC [J]. Annals of Oncology, 2022, 33(S2): S27.[3] 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. [4] Shun Lu, Yongfeng Yu, Jianya Zhou, et al. Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study). 2022 AACR. Abs CT034.[5] NCCN Guidelines Version 3.2022, Non-Small Cell Lung Cancer.[6] Yatabe Y, Goto K, Matsumoto S, et al. METex14 Skipping Testing Guidance for Lung Cancer Patients: The Guidance from the Biomarker Committee, the Japan Lung C anxiety Society[J]. Haigan, 2021, 61(5): 361-370.[7] Socinski M A, Pennell N A, Davies K D. MET Exon 14 Skipping Mutations in Non–Small-Cell Lung Cancer: An Overview of Biology, Clinical Outcomes, and Testing Considerations[J]. JCO Precision Oncology, 2021, 5: 653-663.[8] Subramanian J, Tawfik O. Detection of MET exon 14 skipping mutations in non-small cell lung cancer: overview and community perspective[J]. Expert Review of Anticancer Therapy, 2021, 21(8): 877-886.[9] Kim E K, Kim K A, Lee C Y, et al. Molecular diagnostic assays and clinicopathologic implications of MET exon 14 skipping mutation in non–small-cell lung cancer[J]. Clinical Lung Cancer, 2019, 20(1): e123-e132.[10] Gutierrez M E, Choi K, Lanman R B, et al. Genomic profiling of advanced non–small cell lung cancer in community settings: gaps and opportunities[J]. Clinical Lung Cancer, 2017, 18(6): 651-659.Organized from China Medical Tribune Tumor Today