RESUMEN

Background: 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. Case summary: 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. Conclusion: 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.

RESUMEN

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. CASE REPORT: 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. CONCLUSION: 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.

Asunto(s)

RESUMEN

Background: 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). Case Description: 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. Conclusions: 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.

RESUMEN

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.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

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. CASE SUMMARY: 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. CONCLUSION: 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.

RESUMEN

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.

RESUMEN

Background: 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. Case Presentation: 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. Conclusion: 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.

RESUMEN

Objective To analyze therapeutic effect of savolitinib in patients with stage Ⅲ/Ⅳ non-small cell lung cancer (NSCLC). Methods A total of 95 patients with MET 14 exon (METex14) jumping mutation in stage Ⅲ/Ⅳ NSCLC were divided into a control group (47 cases) and an observation group (48 cases) through a random-number table method. The patients in the control group were treated with crizotinib, whereas those in the observation group were treated with savolitinib. The clinical efficacy and incidence of toxic side effects in both groups were evaluated through a chi-square test, and survival was evaluated through Kaplan-Meier survival analysis. Results Compared with control group (31.91% and 70.21%), the objective response rate and disease control rate of the observation group were 52.08% and 87.50%, respectively (P<0.05). According to Kaplan-Meier survival analysis, the overall survival and progression free survival rates in the observation group were higher than those in the control group (Log rank χ2=8.003, 4.528; P=0.005, 0.033). No statistically significant difference in the degree of toxic side effects was found between the groups (P>0.05). Conclusion Savolitinib can improve the efficacy of treatment for stage Ⅲ/Ⅳ METex14 skip mutation NSCLC patients, prolong survival, enhance the tolerance of patients to savolitinib, and facilitate the management of adverse reactions.

RESUMEN

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.

RESUMEN

Background: Cholangiocarcinoma (CCA) is an aggressive disease with limited treatment options. Despite substantial efforts to explore better regimens, gemcitabine-based chemotherapy has been the standard first-line treatment for decades. With the growing field of precision medicine, biomarker-guided treatments are gaining popularity. MET alteration is a frequent occurrence in various cancer types, making it a promising target. Case presentation: A 53-year-old man visited our hospital with a complaint of upper abdominal pain. Advanced CCA was diagnosed based on the biopsy of the metastatic lymph nodes and immunohistochemistry. Next-generation sequencing revealed MET amplification. As the patient was intolerant to traditional chemotherapy, savolitinib (a c-MET inhibitor) was administered. Partial response was achieved, and the treatment was well tolerated. After 1 year, the patient developed progressive disease, to which the emergence of epidermal growth factor receptor amplification may have contributed. Conclusion: Our study verified the therapeutic value of a c-MET inhibitor in advanced CCA-harboring MET amplification and provides an alternative strategy for patients who are intolerant to chemotherapy.

RESUMEN

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

RESUMEN

[This corrects the article DOI: 10.3389/fmed.2023.1130012.].

RESUMEN

Objective: Current treatment agents for HCC are mostly immune checkpoint inhibitors (ICIs) plus bevacizumab and multitarget tyrosine kinase inhibitors (TKIs); however, their limited overall response rate and shorter median progression-free survival (PFS) discourage their frequent use. The development of Mesenchymal Epithelial Transition Factor receptor (MET) Tyrosine Kinase Inhibitors (MET-TKI) has transformed the treatment pattern in MET-altered solid tumors and improved their prognosis. However, the benefits of MET-TKIs in MET-amplified hepatocellular carcinoma (HCC) remain unclear. Methods: Here, we present a case of advanced HCC amplified with MET treated with savolitinib, a MET-TKI, after progression from first-line treatment with bevacizumab plus sintilimab. Results: The patient achieved a partial response (PR) to savolitinib in the second line setting. The progression-free survival (PFS) of first-line of bevacizumab plus sintilimab and sequential second-line treatment with MET-TKI, savolitinib, are 3 and over 8 months, respectively. furthermore, the patient still had continuous PR status with manageable toxicities. Conclusions: The present case report provides first-hand evidence that savolitinib may be beneficial for patients with advanced MET-amplified HCC and offers a promising treatment option.

RESUMEN

MET gene is a proto-oncogene, which encodes MET protein with tyrosine kinase activity. After binding to its ligand, hepatocyte growth factor, MET protein can induce MET dimerization and activate downstream signaling pathways, which plays a crucial role in tumor formation and metastasis. Savolitinib, as a specific tyrosine kinase inhibitor (TKI) targeting MET, selectively inhibits the phosphorylation of MET kinase with a significant inhibitory effect on tumors with MET abnormalities. Based on its significant efficacy shown in the registration studies, savolitinib was approved for marketing in China on June 22, 2021 for the treatment of advanced non-small cell lung cancer with MET 14 exon skipping mutations. In addition, many studies have shown that MET TKIs are equally effective in patients with advanced solid tumors with MET gene amplification or MET protein overexpression, and relevant registration clinical studies are ongoing. The most common adverse reactions during treatment with savolitinib include nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. Based on two rounds of extensive nationwide investigations to guide clinicians, the consensus is compiled to use savolitinib rationally, prevent and treat various adverse reactions scientifically, and improve the clinical benefits and quality of life of patients. This consensus was prepared under the guidance of multidisciplinary experts, especially including the whole-process participation and valuable suggestions of experts in Traditional Chinese Medicine, thus reflecting the clinical treatment concept of integrated Chinese and western medicines.

Asunto(s)

RESUMEN

BACKGROUND: The c-MET protein, encoded by the mesenchymal-epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non-small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross-sectional comparisons between different agents are still not available. METHODS: Our study was a single-center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately. RESULTS: Patients with METex14 skipping (median PFS = 10.7 months) had a better clinical response to MET TKIs than MET amplification patients (median PFS = 4.1 months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS = 7.1 months) demonstrated a better progression-free survival benefit than crizotinib (median PFS = 1.4 months), p = 0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib. CONCLUSION: In METex14 skipping NSCLC patients, the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.

Asunto(s)

RESUMEN

Savolitinib, a small-molecule inhibitor of the receptor tyrosine kinase mesenchymal-epithelial transition (MET) factor, was approved for the treatment of non-small cell lung cancer (NSCLC) by the China National Medical Products Administration in June 2021. Its safety for NSCLC treatment has been confirmed in several prospective cohort studies. Herein, we report a rare case of shock, a serious adverse event, after treatment with savolitinib in an HIV-1-positive patient with advanced NSCLC. A 38-year-old man with an 8-year history of HIV-1 positivity was diagnosed with NSCLC 5 years ago; the lung cancer recurred after surgical resection. Despite chemotherapy, immunotherapy, and targeted therapy, tumor progression continued. He received savolitinib because of MET amplification. In the first 2 weeks of savolitinib use, he developed a mild rash on his trunk. In the following month, he was hospitalized for fever and circulatory shock thrice after taking savolitinib 400 mg. He had no urticaria or eosinophilia. During the three hospitalizations, he was negative for pathogens. His condition gradually improved after treatment with antibiotics, steroids, and vasopressors. Attention should be paid to the occurrence of septic shock-like presentations when using savolitinib in HIV-1 patients with NSCLC.

RESUMEN

Savolitinib is a highly selective MET tyrosine kinase inhibitor. MET is involved in numerous cellular processes such as proliferation, differentiation and the formation of distant metastases. MET amplification and MET overexpression are quite common in many cancers, but MET exon 14 skipping alteration is most common in non-small cell lung cancer (NSCLC). The role of MET signaling as a bypass pathway in the development of acquired resistance to tyrosine kinase inhibitor (TKI) epidermal growth factor receptor (EGFR) therapy in cancer patients with EGFR gene mutation was documented. Potential beneficiaries of savolitinib therapy are patients with NSCLC and initial diagnosis of MET ex 14 skipping mutation. Savolitinib therapy can be effective in NSCLC patients with EGFR-mutant MET with progression during first-line treatment with an EGFR-TKI. Antitumor activity of savolitinib in combination with osimertinib is very promising as first-line therapy of patients with advanced EGFR-mutated NSCLC, initially with MET expression. The safety profile of savolitinib as monotherapy and in combination with osimertinib or gefitinib is so favorable in all available studies that this drug has become a very promising therapeutic option and is being intensively investigated in ongoing clinical trials.

Asunto(s)

RESUMEN

Savolitinib is an oral MET (hepatocyte growth factor receptor) tyrosine kinase inhibitor, with demonstrated preliminary efficacy in several cancer types. Previous pharmacokinetics assessments showed that savolitinib is rapidly absorbed but there are limited data on the absolute bioavailability and absorption, distribution, metabolism, and excretion (ADME) of savolitinib. This open-label, two-part, phase 1 clinical study (NCT04675021) used a radiolabeled micro-tracer approach to evaluate absolute bioavailability and a traditional approach to determine the ADME of savolitinib in healthy male adult volunteers (N = 8). Pharmacokinetics, safety, and metabolic profiling and structural identification from plasma, urine, and fecal samples were also assessed. Volunteers received a single oral savolitinib 600 mg dose followed by intravenous 100 µg of [14 C]savolitinib in Part 1 and a single oral 300 mg [14 C]savolitinib dose (≤4.1 MBq [megabecquerel] [14 C]) in Part 2. Following Part 1, absolute oral bioavailability was 69%, the median time of maximum observed concentration was 3.5 hours, and the mean terminal half-life was 6.1 hours. Following Part 2, 94% of the radioactivity administered was recovered, with 56% and 38% in urine and feces, respectively. Exposure to savolitinib and metabolites M8, M44, M2, and M3 accounted for 22%, 36%, 13%, 7%, and 2%, respectively, of plasma total radioactivity. Approximately 3% of the dose was excreted as unchanged savolitinib in urine. Most savolitinib elimination occurred via metabolism by several different pathways. No new safety signals were observed. Our data show that the oral bioavailability of savolitinib is high and the majority of savolitinib elimination occurs via metabolism and is excreted in the urine.

Asunto(s)