UNASSIGNED: The distant metastasis of lung cancer primarily occurs in the bones, liver, brain, and lungs, while the breast is an extremely rare site of metastasis. There is very limited literature on the occurrence of breast metastasis from lung cancer, and metastatic lesions in the breast are prone to being misdiagnosed as primary breast cancer, requiring careful attention and differentiation in the clinical diagnostic and treatment process.
UNASSIGNED: The patient, a 63-year-old female, initially presented with an EGFR exon 21 L858R mutated left lung adenocarcinoma in 2017, treated successfully with surgical resection and subsequent monitoring. The relapse of disease occurred in January 2020. Despite maintaining a prolonged progression-free survival (PFS) with first-generation EGFR-TKI Afatinib, disease progression occurred in 2022 without detectable resistance mutations. Transition to second-generation TKI Furmonertinib resulted in poor control, with rapid progression including unusual bilateral breast metastases that exhibited inflammatory breast cancer-like peau d\'orange changes. Standard chemotherapy achieved only short-term stability. Upon detecting a MET amplification mutation, treatment with Savolitinib was initiated. Remarkably, this led to significant clinical and radiographic improvement, notably resolving the peau d\'orange appearance and reducing multiple lesions across the body.
UNASSIGNED: This case underscores the importance of continuous genetic profiling and tailored treatment approaches in managing advanced lung adenocarcinoma, particularly when presenting with rare metastatic sites and complex genetic landscapes. The successful application of Savolitinib following the identification of a MET amplification mutation highlights its potential in overcoming resistance mechanisms in NSCLC, providing a significant therapeutic option for similarly challenging cases.

BACKGROUND: Savolitinib, a small molecule inhibitor, has gained approval as the inaugural medication in China that specifically targets MET kinase. Patients with advanced non-small cell lung cancer (NSCLC) who show MET exon 14 skipping now have a new and innovative treatment option available.
METHODS: In this case report, we describe a patient who experienced drug-induced liver injury (DILI) due to the administration of savolitinib. After being prescribed with savolitinib (400 mg per day, oral), a 73-year-old male diagnosed with stage IV NSCLC with MET exon 14 skipping mutation experienced an increase in liver enzymes and bilirubin levels according to his laboratory tests conducted one month later. Following a 14-day course of hepatoprotective medication, the liver function reverted back to its normal state. After receiving savolitinib (200 mg per day, oral) for one week, the patient was once again diagnosed with severe liver impairment. Then savolitinib was discontinued and received treatment with hepatoprotective drugs for one week. Following the restoration of normal liver function, another attempt was made to administer a small amount of savolitinib (100 mg per day, oral). Thus far, the patient has been followed up and there has been no recurrence of liver damage. Additionally, the lung CT scan revealed ongoing tumor shrinkage with no apparent indications of spreading or metastasis. The Roussel Uclaf Causality Assessment Method (RUCAM) determined that savolitinib was \"highly probable\" cause of DILI. Moderate-severe was determined to be the extent of DILI severity.
CONCLUSIONS: To the best of our understanding, this is the initial instance of DILI resulting from the use of savolitinib as a standalone treatment in a real-world setting. During the administration of savolitinib, healthcare professionals should carefully consider the potential occurrence of DILI. Administering the patient with a small amount of savolitinib resulted in a remarkable response against the tumor, leading us to speculate that the effectiveness of savolitinib might be associated with its plasma concentration. Studying the pharmacokinetics and pharmacodynamics (PK/PD) of savolitinib is beneficial for tailoring and accurately prescribing the medication to each individual.

UNASSIGNED: Mesenchymal-epithelial transition (MET) represents a potential therapeutic target in various cancers, with amplification of the MET gene identified in a subset of patients with pulmonary adenocarcinomas. However, MET gene amplification is rarely observed in high-grade fetal adenocarcinoma (H-FLAC).
UNASSIGNED: Here we present a novel case of a patient diagnosed with stage IV H-FLAC harboring MET amplifications and treated with savolitinib. The 69-year-old male patient, who presented with a primary complaint of cough and white sputum, had a history of hypertension for over 10 years and a 45-year smoking history. The patient received savolitinib monotherapy treatment due to brain metastases. Despite the omission of radiotherapy for asymptomatic brain metastases, a notable response to savolitinib therapy was observed, with a partial response (PR) achieved after 4 weeks and a reduction in the brain tumor. At the time of the submission of this report, the patient received over 24 weeks of savolitinib treatment, and was maintained PR. The patient was still undergoing treatment. This highlights the potential clinical benefits of targeted therapy against MET amplification in H-FLAC.
UNASSIGNED: H-FLAC harboring MET amplification and brain metastasis is rare. Treatment with savolitinib monotherapy resulted in a PR, providing preliminary insights to the efficacy of savolitinib for H-FLAC with MET amplification.

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Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in achieving long survival of patients. MET fusion is a rare oncogenic factor, whose optimal detection and treatment are not well established. Here, we report on a 32-year-old female lung adenocarcinoma patient with positive PD-L1 and negative driver gene detected by DNA-based next-generation sequencing (NGS). A radical resection of the primary lesion after chemotherapy combined with PD-1 checkpoint inhibitor administration indicated primary immuno-resistance according to her pathological response and rapid relapse. A rare CD47-MET was detected by RNA-based NGS, which was confirmed by fluorescence in situ hybridization. Multiplex immunofluorescence revealed a PD-L1 related heterogeneous immunosuppressive microenvironment with little distribution of CD4+ T cells and CD8+ T cells. Savolitinib therapy resulted in a progression-free survival (PFS) of >12 months, until a new secondary resistance mutation in MET p.D1228H was detected by re-biopsy and joint DNA-RNA-based NGS after disease progression. In this case, CD47-MET fusion NSCLC was primarily resistant to immunotherapy, sensitive to savolitinib, and developed secondary MET p.D1228H mutation after targeted treatment. DNA-RNA-based NGS is useful in the detection of such molecular events and tracking of secondary mutations in drug resistance. To this end, DNA-RNA-based NGS may be of better value in guiding precise diagnosis and individualized treatment in this patient population.

BACKGROUND: Brain metastases (BM) are very rare in gastric adenocarcinoma (GaC), and patients with BMs have a higher mortality rate due to stronger tumor aggressiveness. However, its pathogenesis remains unclear. Genetic testing revealed cellular-mesenchymal epithelial transition factor receptor (MET) amplification. Therefore, treatment with savolitinib, a small molecule inhibitor of c-Met, was selected.
METHODS: A 66-year-old woman was diagnosed with advanced GaC 6 months prior to presentation due to back pain. Cerebellar and meningeal metastases were observed during candonilimab combined with oxaliplatin and capecitabine therapy. The patient experienced frequent generalized seizures and persistent drowsiness in the emergency department. Genetic testing of cerebrospinal fluid and peripheral blood revealed increased MET amplification. After discussing treatment options with the patient, savolitinib tablets were administered. After a month of treatment, the intracranial lesions shrank considerably.
CONCLUSIONS: BM is very rare in advanced GaC, especially in meningeal cancer, that is characterized by rapid disease deterioration. There are very few effective treatment options available; however, technological breakthroughs in genomics have provided a basis for personalized treatment. Furthermore, MET amplification may be a key driver of BM in gastric cancer; however, this conclusion requires further investigation.

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.

Lung cancer is the leading cause of cancer death, accounting for one-third of all cancer deaths worldwide. The MET (c-MET) gene, as one of the therapeutic target spots of NSCLC, has become increasingly more important. MET amplification/overexpression was divided into primary (intrinsic) and secondary (acquired). Studies indicated that the combination of Osimertinib and Savolitinib was safe and showed promising antitumor effect in NSCLC patients with secondary MET amplification after EGFR mutations. However, NSCLC patients with primary MET amplification/overexpression and EGFR mutations are rare in clinics, and the efficacy of dual-target therapy combined with EGFR-TKI and Savolitinib for them has not been studied yet. Here, we reported two NSCLC patients with primary MET amplification/overexpression and EGFR mutation, who benefited from T+S therapy (the dual-target therapy of EGFR-TKI plus Savolitinib) and achieved a progression-free survival (PFS) of approximately 5 months. The two cases indicated that T+S therapy has an acceptable safety profile and encouraging antitumor efficacy in NSCLC patients harboring concurrent primary MET amplification/overexpression and EGFR mutation. Meanwhile, the observation stresses the importance of genetic testing, and the MET gene needs to be detected at first diagnosis for the best choice of targeted therapies.

UNASSIGNED: Cellular-mesenchymal to epithelial transition factor (c-MET) alterations have significant therapeutic implications in non-small cell lung cancer (NSCLC). Although MET fusion is a rare genomic event, advances in detection technologies have enabled the identification of various MET fusion partner genes. However, standard therapeutic options for MET fusion in NSCLC cases remain undefined. This report presents a novel fusion variant, EML4-MET, encompassing exons 1 to 13 of EML4 and exons 15 to 21 of MET, including the entire MET kinase domain, and discusses the response of this case to savolitinib treatment.
UNASSIGNED: A 65-year-old woman was diagnosed with advanced poorly differentiated lung carcinoma. Molecular profiling of circulating tumor DNA (ctDNA), carried out by next-generation sequencing (NGS), identified a novel EML4-MET fusion. The patient was administered the MET receptor tyrosine kinase inhibitor savolitinib at 400 mg daily. One month later, computed tomography (CT) revealed some lesions with volume reduction. However, COVID-19 diminished the efficacy of savolitinib. Regrettably, the patient succumbed to respiratory and circulatory failure due to disease progression in March 2023.
UNASSIGNED: This case uncovers a new type of MET fusion and expands the range of potential MET fusion targets in NSCLC. The patient responded to savolitinib, suggesting a reference basis for the treatment of similar cases with EML4-MET fusion in the future. Additional research is warranted to assess the biological significance of the EML4-MET fusion in NSCLC.

Savolitinib is a highly selective mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor (TKI). Based on its significant efficacy shown in clinical studies, savolitinib was conditionally approved for marketing in China on 22 June 2021, for the treatment of advanced non-small cell lung cancer (NSCLC) with MET 14 exon skipping mutation. Additionally, many studies showed that MET TKIs were equally effective in patients with advanced solid tumors with MET gene amplification or MET protein overexpression. Several relevant registered clinical studies are in progress. The most common adverse reactions (ARs) due to savolitinib administration are nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. This consensus was developed through two rounds of extensive national surveys involving multidisciplinary experts in China, aiming to guide clinicians to prevent and treat various ARs scientifically, and improve the efficacy of the drug and the quality of life of patients.