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Mesenchymal–epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare (3%–4%) driver mutation in non‐small cell lung cancer (NSCLC). Tepotinib, a selective MET inhibitor, has shown promise in treating METex14 skipping‐mutated NSCLC. However, its feasibility for perioperative application remains unclear. This report describes a 60‐year‐old man with stage IIIA (cT2N2M0) lung adenocarcinoma harboring a METex14 skipping mutation. After initial treatment with savolitinib was discontinued due to grade 4 transaminitis, the patient was switched to tepotinib, resulting in significant tumor regression. Six months later, further shrinkage was observed, and surgery revealed remarkable pathological response with no residual tumor in lymph nodes (ypT2N0M0, IB). Postoperative tepotinib continued, with no relapse at 6‐month follow‐up. This case highlights the potential of tepotinib as neoadjuvant therapy for resectable METex14 skipping‐mutated NSCLC, warranting further clinical trials. [ABSTRACT FROM AUTHOR]

Background: MET exon 14 skipping mutations occur in 3–4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. Methods: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6–58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1–11.3), 9.1 (4.0–19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9–92.4). The safety signals were generally consistent with the known safety profile of crizotinib. Conclusions: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. Clinical trial information: UMIN000031623. [ABSTRACT FROM AUTHOR]

We report the case of an 87-year-old female patient who was diagnosed with metastatic non-small-cell lung cancer harboring MET exon 14 skipping mutation (MET ex14) and PD-L1 expression of 60%. A first-line treatment with atezolizumab was started with primary resistance. Then, a second-line treatment with capmatinib, a selective type Ib MET tyrosine kinase inhibitor, was started, achieving a partial response. The patient is still alive and on treatment with capmatinib 300 mg twice daily after 20 months, with a good tolerability and no evidence of disease progression. In summary, our patient experienced a long-lasting response (>18 months) with capmatinib as second-line treatment. Further analyses evaluating the efficacy and tolerability of MET tyrosine kinase inhibitors are warranted, especially in the elderly, a non-small-cell lung cancer population whose tumors could more frequently harbor MET ex14 mutation. Executive summary Lung cancer is the leading cause of cancer related death. Tyrosine kinase inhibitors targeting specific genetic alterations in non-small-cell lung cancer (NSCLC) significantly improved response rate and survival outcomes. MET exon 14 skipping mutations, found in 3–4% of NSCLC, are more frequent in elderly patients. Capmatinib and tepotinib demonstrated efficacy for MET ex14 skipping mutations. Our case report showed capmatinib effectiveness in elderly NSCLC patient, maintaining a good quality of life. [ABSTRACT FROM AUTHOR]

Madison Fraser,1 Nagashree Seetharamu,2 Matthew Diamond,2 Chung-Shien Lee2,3 1Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, USA; 2Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Lake Success, NY, USA; 3Department of Clinical Health Professions, St. John’s University, Queens, NY, USACorrespondence: Chung-Shien Lee, Email leec3@stjohns.eduAbstract: Aberrant c-MET (Mesenchymal–Epithelial Transition) signaling contributes to cancer cell development, proliferation, and metastases of non-small cell lung cancer (NSCLC). MET exon 14 (METex14) skipping mutation is noted in approximately 4% of NSCLC cases and is targetable with the recently approved tyrosine kinase inhibitors capmatinib and tepotinib. Capmatinib, the focus of this review article, is a highly selective MET inhibitor approved for use in patients with METex14 mutated NSCLC. In this review, we discuss cMET as a target, the pharmacology of capmatinib, key trials of capmatinib in MET-altered lung cancer, and toxicity profile. We highlight some ongoing capmatinib clinical trials that expand their role to other subsets of patients, especially those with EGFR mutations, who develop MET alterations as a resistance pathway. We further provide our perspective on the management of METex14 NSCLC, strategies for sequencing agents, and toxicity management.Keywords: non-small cell lung cancer, Mesenchymal–Epithelial Transition gene, MET exon 14 skipping mutation, tyrosine kinase inhibitor, capmatinib

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians.

Abstract Skeletal muscle metastasis of lung cancer is rare. However, clinicians should be aware that tumour‐induced nerve compression symptoms may develop.

The MET exon 14 skipping mutation is found in approximately 3–4% of non-small cell lung cancers (NSCLC). In 2020, the American Food and Drug Administration approved the first drug targeting this mutation. Capmatinib is a selective MET tyrosine kinase inhibitor. In the European Union, capmatinib is used when the patient needs further treatment after receiving immunotherapy or platinum-based chemotherapy, or both. In the described case, due to disease progression during treatment with pembrolizumab and then with platinum-based chemotherapy, next-generation sequencing was performed, which allowed for detection of the MET gene exon 14 skipping mutation. Targeted therapy with capmatinib was the only method of treatment resulting in a partial response to the disease and improvement of the patient’s quality of life. This case indicates the importance of detailed molecular diagnosis and selection of the optimal method of treatment to prolong survival of the patient with advanced NSCLC. Due to promising results of research conducted so far, in the future, selective MET tyrosine kinase inhibitors — capmatinib and tepotinib — may become the new standard of first-line treatment in NSCLC patients with the MET exon 14 skipping mutation. [ABSTRACT FROM AUTHOR]

Neoadjuvant targeted therapy is an alternative treatment for locally advanced non-small cell lung cancer (NSCLC) patients with driver gene mutation. MET ex14 mutation is considered a driver gene, and crizotinib is the first oral tyrosine kinase inhibitor (TKI) for metastatic MET ex14 mutation-positive NSCLC patients. Here, we reported a case of a locally advanced NSCLC patient harboring MET ex14 mutation who achieved pathological complete response following neoadjuvant crizotinib therapy but developed rapid metastasis due to discontinuation of short-term postoperative adjuvant crizotinib therapy. Although no driver gene mutation was found via next-generation sequencing (NGS) with blood samples before discontinuation of adjuvant crizotinib, the patient was given crizotinib rechallenge. Fortunately, the patient achieved durable complete response. This suggested that neither pathological complete response nor negative circulating tumor DNA (ctDNA) could be an effective predictor for discontinuation of adjuvant targeted therapy. This case report demonstrated the potential of crizotinib as neoadjuvant therapy in MET ex14 mutation-positive NSCLC patients as well as the importance of long-term postoperative therapy even with negative ctDNA in blood. [ABSTRACT FROM AUTHOR]

Simple Summary: A variety of MET aberrations that lead to the dysregulation of the MET oncogene and thus the activation of various signaling pathways have been described. These include MET overexpression, the activation of MET mutations comprising exon 14 skipping mutations, MET gene amplifications, and MET fusions. Patients with such aberrations can be treated using a targeted inhibitor such as crizotinib, cabozantinib, tepotinib, and capmatinib. Therefore, the implementation of high-quality and sensitive methods for the detection of the various MET aberrations is essential. MET tyrosine kinase receptor pathway activation has become an important actionable target in solid tumors. Aberrations in the MET proto-oncogene, including MET overexpression, the activation of MET mutations, MET mutations that lead to MET exon 14 skipping, MET gene amplifications, and MET fusions, are known to be primary and secondary oncogenic drivers in cancer; these aberrations have evolved as predictive biomarkers in clinical diagnostics. Thus, the detection of all known MET aberrations in daily clinical care is essential. In this review, current molecular technologies for the detection of the different MET aberrations are highlighted, including the benefits and drawbacks. In the future, another focus will be on the standardization of detection technologies for the delivery of reliable, quick, and affordable tests in clinical molecular diagnostics. [ABSTRACT FROM AUTHOR]

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians. [ABSTRACT FROM AUTHOR]

Purpose: The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. Methods: Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. Results: Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. Conclusions: Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management. [ABSTRACT FROM AUTHOR]

Non-small cell lung carcinomas (NSCLCs), especially lung adenocarcinomas (LUADs), harbor several driver mutations against which highly effective tyrosine kinase inhibitors (TKIs) are available. Although TKIs are generally effective against certain NSCLCs, primary or acquired resistance almost always develops. Driver mutations include RET fusion (∼1–2% of NSCLC cases) and MET exon 14 skipping mutation (MET Δex14; ∼3–4%). Surprisingly, the LUAD cell line LC-2/ad with CCDC6-RET fusion thrived independently of RET signaling, and Hs-746T cells harboring MET Δex14 plus amplification survived MET silencing. However, these two cell lines were highly sensitive to dual silencing of the representative anti-apoptotic BCL2 family members BCL2L1 and MCL1, undergoing extensive apoptosis in monolayer or 3D on-top culture systems. Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations. • Lung adenocarcinoma cell lines and tissues express high levels of BCL2L1 and MCL1. • LC-2/ad cells harboring CCDC6-RET fusion depend on BCL2L1 and MCL1 for survival. • Hs-746T cells positive for MET exon 14 skipping exhibit a similar dependency. • Silencing BCL2L1 plus MCL1 almost completely eradicates these cell lines. [ABSTRACT FROM AUTHOR]

Background: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification., Patients and Methods: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test., Results: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2., Conclusions: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several selective mesenchymal–epithelial transition (MET) inhibitors have recently demonstrated favorable systemic efficacy in MET exon 14 skipping mutation-positive non-small cell lung cancer. However, there are limited data on their efficacy against central nervous system (CNS) metastasis, especially leptomeningeal seeding. Recently, we encountered a case of a 65-year-old woman who was diagnosed with metastatic lung adenocarcinoma. As routine molecular testing showed no genomic alterations, including epidermal growth factor receptor mutation and anaplastic lymphoma kinase translocation, the patient received a frontline platinum-doublet followed by paclitaxel. However, the tumor did not respond to these therapies, and her condition became deleterious owing to extensive brain and leptomeningeal metastases. Plasma genotyping revealed that the tumor harbored a MET exon 14 skipping mutation, and we started capmatinib, a selective MET inhibitor. The CNS lesions markedly decreased and the performance status of the patient dramatically improved. Our report highlights the significant CNS activity of capmatinib, even in cases of leptomeningeal metastasis. In addition, this report emphasizes the importance of the active utilization of molecular profiling to detect rare but druggable genetic alterations for the better management of patients with lung cancer. [ABSTRACT FROM AUTHOR]

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting. [ABSTRACT FROM AUTHOR]

Simple Summary: MET is a receptor tyrosine kinase encoded by the MET proto-oncogene that has a significant role in cancer cell progression. Several drugs targeting MET are under development for the treatment of different cancers, including non-small-cell lung cancer (NSCLC). However, until now, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective biomarkers to select the right patients for treatment. In a number of clinical trials, different biomarkers have been studied, but so far, MET exon 14 skipping mutation is the only one that has shown sufficient predictive properties. Another interesting biomarker is MET amplification detected by fluorescence in situ hybridization (FISH), which has shown promising results in the treatment of patients with NSCLC. Future clinical research will show whether MET amplification by FISH is an effective predictive biomarker for MET-targeted therapy. Dysregulation of the MET tyrosine kinase receptor is a known oncogenic driver, and multiple genetic alterations can lead to a clinically relevant oncogenesis. Currently, a number of drugs targeting MET are under development as potential therapeutics for different cancer indications, including non-small cell lung cancer (NSCLC). However, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective predictive biomarkers to select the right patient populations for treatment. So far, capmatinib is the only MET-targeted drug approved with a companion diagnostic (CDx) assay, which is indicated for the treatment of metastatic NSCLC in patients having a mutation resulting in MET exon 14 skipping. An alternative predictive biomarker for MET therapy is MET amplification, which has been identified as a resistance mechanism in patients with EGFR-mutated NSCLC. Results obtained from different clinical trials seem to indicate that the MET/CEP7 ratio detected by FISH possesses the best predictive properties, likely because this method excludes MET amplification caused by polysomy. In this article, the concept of CDx assays will be discussed, with a focus on the currently FDA-approved MET targeted therapies for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor ( EGFR ) L858R and mesenchymal-to-epithelial transition ( MET ) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S 1 and another nodule in the left S 1+2 . Bronchoscopic biopsy diagnosed the right S 1 nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S 1 adenocarcinoma detected EGFR L858R mutation. The 18 F -fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S 1 and the left S 1+2 nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT 1b N 2 M 0 ) of adenocarcinoma in the right S 1 and suspected another primary lung cancer in the left S 1+2 . Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S 1 cancer achieved partial response (PR), while the left S 1+2 nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne ® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S 1+2 nodule (cT 1b N 3 M 0 , c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S 1+2 cancer achieved and maintained PR by capmatinib, the right S 1 cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered., Competing Interests: All authors have no conflict of interest to declare., (Copyright 2024, Ando et al.)

Mesenchymal-epithelial transition (MET) exon 14-skipping mutation (METex14) is rare in pulmonary invasive mucinous adenocarcinomas (IMAs), and the clinical impact of MET-tyrosine kinase inhibitors (TKIs) remains unknown. We herein report a 75-year-old woman with IMA harboring METex14 who was treated with the MET-TKI tepotinib. The lung tumor regressed over six months; however, the patient ultimately died of exacerbated interstitial lung disease (ILD), possibly associated with tepotinib. An autopsy revealed diffuse alveolar damage in pre-existing chronic fibrosis. We discuss how to pre-evaluate ILD deterioration risks and monitor TKI-induced lung toxicity during treatment.

Skeletal muscle metastasis of lung cancer is rare. However, clinicians should be aware that tumour‐induced nerve compression symptoms may develop.We present a rare case of posterior interosseous nerve (PIN) palsy secondary to lung cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a major health concern worldwide because of its increasing incidence and mortality. This study aimed to clarify the association between mesenchymal-epithelial transition (MET) genomic alterations and clinical characteristics of lung cancer. Method: We collected data from 5,008 patients with lung cancer diagnosed and treated between January 2017 and July 2021 at the Affiliated Hospital of Qingdao University. Genomic alterations in the MET gene, including the exon 14 skipping mutation and amplification, were detected using amplification refractory mutation system-polymerase chain reaction (2,057 cases) and next-generation sequencing (2,951 cases). Clinical characteristics such as age, sex, tumor location, tumor stage, smoking, pleural invasion, and histology were statistically analyzed for MET exon 14 skipping mutation and amplification. The DNA splicing sites causing the MET exon 14 skipping mutation at the mRNA level were also investigated. Results: The incidence of the MET exon 14 skipping mutation was 0.90% (41/4,564) in adenocarcinoma, 1.02% (3/294) in squamous cell carcinoma, and 8.33% (1/12) in sarcomatoid carcinoma specimens. It was more frequently observed in patients over 60 years of age than the MET exon 14 skipping mutation wildtype. The MET exon 14 skipping mutation co-occurred with epidermal growth factor receptor (EGFR) L858R, EGFR 19-Del, and BRAF V600E mutations. At the DNA level, single nucleotide mutation and small fragment deletion (1–38 base pairs) upstream and downstream of MET exon 14 led to MET exon 14 skipping mutation at the mRNA level. MET amplification occurred in 0.78% (21/2,676) adenocarcinoma and 1.07% (2/187) squamous cell carcinoma specimens and was significantly associated with advanced tumor stages (III + IV) compared to the MET amplification wildtype. MET amplification primarily co-occurred with the EGFR mutation. Conclusions: Our study found that MET genomic alterations were statistically related to age and tumor stage and co-existed with mutations of other oncogenic driver genes, such as EGFR and BRAF. Moreover, various splicing site changes at the DNA level led to the exon 14 skipping mutation at the mRNA level. Further studies are required to clarify the association between MET genomic alterations and prognosis. [ABSTRACT FROM AUTHOR]

BackgroundLung cancer is a major health concern worldwide because of its increasing incidence and mortality. This study aimed to clarify the association between mesenchymal-epithelial transition (MET) genomic alterations and clinical characteristics of lung cancer.MethodWe collected data from 5,008 patients with lung cancer diagnosed and treated between January 2017 and July 2021 at the Affiliated Hospital of Qingdao University. Genomic alterations in the MET gene, including the exon 14 skipping mutation and amplification, were detected using amplification refractory mutation system-polymerase chain reaction (2,057 cases) and next-generation sequencing (2,951 cases). Clinical characteristics such as age, sex, tumor location, tumor stage, smoking, pleural invasion, and histology were statistically analyzed for MET exon 14 skipping mutation and amplification. The DNA splicing sites causing the MET exon 14 skipping mutation at the mRNA level were also investigated.ResultsThe incidence of the MET exon 14 skipping mutation was 0.90% (41/4,564) in adenocarcinoma, 1.02% (3/294) in squamous cell carcinoma, and 8.33% (1/12) in sarcomatoid carcinoma specimens. It was more frequently observed in patients over 60 years of age than the MET exon 14 skipping mutation wildtype. The MET exon 14 skipping mutation co-occurred with epidermal growth factor receptor (EGFR) L858R, EGFR 19-Del, and BRAF V600E mutations. At the DNA level, single nucleotide mutation and small fragment deletion (1–38 base pairs) upstream and downstream of MET exon 14 led to MET exon 14 skipping mutation at the mRNA level. MET amplification occurred in 0.78% (21/2,676) adenocarcinoma and 1.07% (2/187) squamous cell carcinoma specimens and was significantly associated with advanced tumor stages (III + IV) compared to the MET amplification wildtype. MET amplification primarily co-occurred with the EGFR mutation.ConclusionsOur study found that MET genomic alterations were statistically related to age and tumor stage and co-existed with mutations of other oncogenic driver genes, such as EGFR and BRAF. Moreover, various splicing site changes at the DNA level led to the exon 14 skipping mutation at the mRNA level. Further studies are required to clarify the association between MET genomic alterations and prognosis.

BackgroundMET amplification or METex14 skipping mutations are uncommon oncogenic events in NSCLC patients. Clinicopathological characteristics, concurrent gene alterations, and prognosis of MET TKIs in these patients are yet to be elucidated.MethodsWe retrospectively analyzed the genomic profiles of 43 MET amplifications or 31 METex14 skipping mutations in NSCLC patients with no previous treatment with EGFR TKIs. Survival outcomes were analyzed in evaluable patients receiving MET TKI treatment: MET amplification cohort (n = 29) and METex14 skipping mutation cohort (n = 29).ResultsAmong evaluable patients, a shorter PFS was observed in the MET amplification cohort than in the METex14 skipping mutation cohort (7.0 months vs. 11.0 months, P = 0.043). Concurrent mutations in both cohorts resulted in a statistically significant shorter PFS (MET amplification: 3.5 months versus 8.0 months, P = 0.038, METex14 skipping mutation: 7.0 versus NR months, P = 0.022). However, a statistically significant OS (17.0 months versus 20.0 months, P = 0.044) was only observed in the MET amplification cohort. TP53, the most common concurrent mutation in both cohorts, was associated with worse survival outcomes as compared to the wild type. The MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%).ConclusionMET TKIs could be a better treatment option for patients with METex14 skipping mutations. Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. PIK3CA mutations may confer primary resistance to MET TKIs in patients with MET amplification.

Background: MET amplification or METex14 skipping mutations are uncommon oncogenic events in NSCLC patients. Clinicopathological characteristics, concurrent gene alterations, and prognosis of MET TKIs in these patients are yet to be elucidated. Methods: We retrospectively analyzed the genomic profiles of 43 MET amplifications or 31 METex14 skipping mutations in NSCLC patients with no previous treatment with EGFR TKIs. Survival outcomes were analyzed in evaluable patients receiving MET TKI treatment: MET amplification cohort (n = 29) and METex14 skipping mutation cohort (n = 29). Results: Among evaluable patients, a shorter PFS was observed in the MET amplification cohort than in the METex14 skipping mutation cohort (7.0 months vs. 11.0 months, P = 0.043). Concurrent mutations in both cohorts resulted in a statistically significant shorter PFS (MET amplification: 3.5 months versus 8.0 months, P = 0.038, METex14 skipping mutation: 7.0 versus NR months, P = 0.022). However, a statistically significant OS (17.0 months versus 20.0 months, P = 0.044) was only observed in the MET amplification cohort. TP53, the most common concurrent mutation in both cohorts, was associated with worse survival outcomes as compared to the wild type. The MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%). Conclusion: MET TKIs could be a better treatment option for patients with METex14 skipping mutations. Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. PIK3CA mutations may confer primary resistance to MET TKIs in patients with MET amplification. [ABSTRACT FROM AUTHOR]

Introduction: MET exon 14 skipping mutation, observed in 3–4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. Methods: Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. Results: Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73 years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7 months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. Conclusion: Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response. [ABSTRACT FROM AUTHOR]

Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients. [ABSTRACT FROM AUTHOR]

Pembrolizumab has become the standard first‐line treatment for non‐small cell lung cancer (NSCLC) patients with high PD‐L1expression. MET exon 14 skipping is a rare mutation typically found in older, female, and non‐smoking patients with NSCLC. Herein, we report the case of a 71‐year‐old non‐smoking woman who was diagnosed with NSCLC in the left lung. EGFR mutation and ALK fusion were not detected. Because the biopsy specimen showed high PD‐L1 expression with a tumor proportion score of 95%, pembrolizumab was introduced as first‐line therapy, but resulted in no clinical benefit. The patient was subsequently administered chemotherapy with carboplatin and pemetrexed, leading to remarkable tumor shrinkage. A next‐generation sequencing panel analysis revealed a MET exon 14 skipping mutation. Thus, pembrolizumab might not be effective for NSCLC patients with MET exon 14 skipping mutations, even if PD‐L1 expression is high.

The spread of next-generation sequencing enables clinicians to identify rare oncogene alterations, including MET exon 14 skipping mutation, in clinical practice for NSCLC. Several tyrosine kinase inhibitors for MET exon 14 skipping mutation such as capmatinib and tepotinib have elucidated their effectiveness. Only a few reports have suggested their efficacy against central nervous system lesions, especially leptomeningeal metastases. We here report a case of a patient with NSCLC with MET exon 14 skipping mutation and poor performance status salvaged by marked leptomeningeal metastases response to tepotinib. We further provide measures of plasma/cerebrospinal fluid concentrations of tepotinib and its cerebrospinal fluid penetration rate.

Introduction: Selective tyrosine kinase inhibitors are proven effective in patients with non-small lung cancer (NSCLC) with a MET exon 14 skipping mutation., Case Presentation: The patient developed a metastatic lung adenocarcinoma with a MET exon 14 skipping mutation. She was treated with a first 1b MET inhibitor, Capmatinib, but had to stop the drug because of major hepatotoxicity. A few months later, she started Tepotinib, another 1b MET inhibitor with this time, no sign of hepatotoxicity., Discussion: Adverse events are frequent with 1b MET inhibitors. However, there is a wide interpatient variability. Absence of cross-toxicity between Capmatinib and Tepotinib is misunderstood but can be explained by slight differences in phamarcodynamics and pharmacokinetics. Practitionners have to be warned about severe adverse events to stop or change the drug if necessary., Conclusion: This is the first case showing the absence of cross-toxicity between 1b MET inhibitors.

Opinion Statement: The MET exon 14 skipping mutation is found in approximately 3% of lung adenocarcinomas and slightly more than 2% of lung squamous cell carcinomas. In recent years, more and more evidence has shown that MET inhibitors have achieved good anti-tumor effect in patients with MET exon 14 skipping mutation, suggesting that MET exon 14 skipping mutation may be a new target for NSCLC patients. Patients with positive MET exon 14 skipping mutation are recommended to be administered MET inhibitors, and crizotinib is recommended by the NCCN guideline. Due to the presence of gene amplification, second site mutation, bypass activation, and pathological type transformation, one of the inevitable problems of targeted therapy is drug resistance. If type I MET inhibitors (crizotinib, capmatinib, tepotinib, savolitinib) drug resistance is developed, type II MET inhibitors (cabozantinib, glesatinib, merestinib) can be considered. [ABSTRACT FROM AUTHOR]

Pembrolizumab has become the standard first‐line treatment for non‐small cell lung cancer (NSCLC) patients with high PD‐L1expression. MET exon 14 skipping is a rare mutation typically found in older, female, and non‐smoking patients with NSCLC. Herein, we report the case of a 71‐year‐old non‐smoking woman who was diagnosed with NSCLC in the left lung. EGFR mutation and ALK fusion were not detected. Because the biopsy specimen showed high PD‐L1 expression with a tumor proportion score of 95%, pembrolizumab was introduced as first‐line therapy, but resulted in no clinical benefit. The patient was subsequently administered chemotherapy with carboplatin and pemetrexed, leading to remarkable tumor shrinkage. A next‐generation sequencing panel analysis revealed a MET exon 14 skipping mutation. Thus, pembrolizumab might not be effective for NSCLC patients with MET exon 14 skipping mutations, even if PD‐L1 expression is high. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non-small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported., Materials and Methods: Data of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harboring novel driver alterations (m-cohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test., Results: m-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months (P= .846) and overall survival (OS) was 25.1 vs. 9.37 months, (P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent (P = .0160 and P = .0152). In the PD-L1≥50% group, first line IO single agent resulted in inferior ORR (P = .027) and PFS (P = .022) in m-cohort compared to wt-cohort., Conclusion: IO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required., Competing Interests: Disclosure Diego Signorelli declares personal fees from AstraZeneca, Merck Sharp and Dohme, Boehringer Ingelheim, BMS, Roche and Sanofy. Arsela Prelaj declares personal fees from AstraZeneca, Italfarmaco, F. Hoffmann-La Roche, BMS. Roberto Ferrara declares advisory role from Merck Sharp and Dohme. Claudia Proto declares personal fees from Italfarmaco, AstraZeneca, BMS and Merck Sharp and Dohme. Giuseppe Lo Russo provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Merck Sharp and Dohme, Takeda, Amgen, Eli Lilly, B.M.S., F. Hoffmann-La Roche, Italfarmaco, Novartis, Sanofi, Pfizer, G.S.K. and AstraZeneca. Marina Chiara Garassino declares personal financial interests with the following organizations: AstraZeneca, Merck Sharp and Dohm, International GmbH, BMS, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, F. Hoffmann-La Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Ose Immuno Therapeutics, Blueprint, Jansenn, Sanofi; she also declares Institutional financial interests with the following organizations: Eli Lilly, Merck Sharp and Dohm, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, Glaxo Smith Kline GSK, Spectrum pharmaceuticals. Paolo Marchetti provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: F. Hoffmann-La Roche, Merck Sharp and Dohme, BMS, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novartis and Pfizer. Filippo de Braud provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Ignyta, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. Sara Manglaviti: advisory board for Italpharma; travel accommodation by MSD and Sanofi outside the submitted work. Mario Occhipinti: advosry board for BMS and personal fee by MSD. Laura Mazzeo: travel accomodation by Sanofi. Marta Brambilla: travel accomodation by Lilli and Leo Pharma, Teresa Beninato: travel accomodation by Lilli, MSD, BMS and Sanofi. The other authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Met proto-oncogene exon 14 skipping (MET ex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK -positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with MET ex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of ensartinib were 67% and 94% in cohort 1, and 73% and 91% in cohort 2. The median DoR was 6.8 months and median PFS was 6.1 months in the total population. Rash was the most common drug-related adverse event, and peripheral edema of any grade was reported in only 9% patients. Molecular simulations indicated favorable binding of ensartinib to c-MET. The kinase assay demonstrated an IC 50 of 7.9 nM of ensartinib against MET ex14 protein. In vitro , Hs746T (MET ex14 mutation) and EBC-1 (MET amplification) cells were sensitive to ensartinib, with IC 50 values of 31 and 44 nM, respectively. Ensartinib exhibited comparable inhibitory effects on cell migration as crizotinib and tepotinib in both cell types. In vivo , ensartinib suppressed the growth of Hs746T cells. Ensartinib also potently inhibited the viability of PDOs. Overall, Ensartinib exhibited substantial antitumor effects against MET ex14 mutant NSCLCs in preclinical and clinical trials, with relatively low peripheral edema rates. • Ensartinib confers potent efficacy against MET exon 14 skipping mutant NSCLC. • Rash rather than peripheral edema emerges as the most common AE for ensartinib. • Ensartinib exhibits strong anti-MET effects both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Mesenchymal-epithelial transition exon 14 (METex14) skipping mutations occur in about 3%-4% of patients with non-small cell lung cancer (NSCLC). This is an aggressive subtype associated with poor prognosis. METex14 skipping is a potentially targetable mutation. Targeted therapy is a promising treatment modality for patients with advanced/metastatic METex14-mutant NSCLC. Performing systematic molecular testing to detect the driver mutation is essential for initiating targeted therapy. However, there is a lack of guidelines on molecular testing for assessing the eligibility of patients for targeted therapy. Therefore, a multidisciplinary panel consisting of experts from the Middle East, Africa, and Russia convened via a virtual advisory board meeting to provide their insights on various molecular testing techniques for the diagnosis of METex14 skipping mutation, management of patients with targeted therapies, and developing consensus recommendations for improving the processes. The expert panel emphasized performing molecular testing and liquid biopsy before treatment initiation and tissue re-biopsy for patients with failed molecular testing. Liquid biopsy was recommended as complementary to tissue biopsy for disease monitoring and prognosis. Selective MET inhibitors were recommended as the first and subsequent lines of therapy. These consensus recommendations will facilitate the management of METex14 skipping NSCLC in routine practice and warrant optimum outcomes for these patients., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Mahrous et al.)

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians.
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