MET-TKIs selectively inhibit growth of hepatobiliary carcinoma harboring high copy number MET amplification: 2 cases and literature review

MET-TKIs selectively inhibit growth of hepatobiliary carcinoma harboring high copy number MET amplification: 2 cases and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article MET-TKIs selectively inhibit growth of hepatobiliary carcinoma harboring high copy number MET amplification: 2 cases and literature review Jingshu Wang, Xinxin He, Wei Chen, Junyu Zhu, Jianwei Liao, Yuanyuan Yin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8898860/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 7 You are reading this latest preprint version Abstract Objective To investigate the efficacy of highly selective MET-TKIs, targeting met exon14 skipping muation, in patients with hepatobiliary carcinoma harboring MET amplification. Methods Clinical data from two patients with advanced metastatic hepatobiliary carcinoma and MET gene amplification were collected. Literature review was conducted to analyze the clinical characteristics of the patients, the efficacy and safety of MET inhibitor targeted therapy. Results Two middle-aged male patients with metastatic hepatobiliary carcinoma, who had poor response to multiple lines of targeted therapy, chemotherapy, and immunotherapy, achieved partial response lasting more than 5 months by treating with single-agent MET-TKI with or without combination of chemotherapy/immunotherapy. During the treatment, both patients had good safety profiles. Grade 2 anemia and Grade 1 thrombocytopenia occurred during MET-TKI therapy, but both resolved after symptomatic treatment. No decrease in white blood cells or neutrophils was observed, and no abnormalities in ALT, AST, total bilirubin, or creatinine related to targeted therapy were noted. Conclusion For patients with advanced metastatic liver cancer and MET amplification, MET-TKI targeted therapy can significantly control disease progression and has a good safety profile, which deserved further study. Liver cancer MET amplification Targeted therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Worldwide, primary liver cancer represents a malignancy with significant epidemiological burden, characterized by elevated incidence and mortality rates[ 1 ]. Hepatocellular carcinoma (HCC) constitutes 85%–90% of cases, while intrahepatic cholangiocarcinoma (iCCA) ranks among the most prevalent primary hepatic malignancies. According to GLOBOCAN 2020 estimates, approximately 906,000 new cases and 830,000 deaths occur annually, with projections indicating a 55% increase by 2040, underscoring substantial challenges in disease management and prevention[ 2 ].For patients with unresectable advanced-stage disease, first-line standard therapy for HCC relies on multikinase inhibitors (e.g., sorafenib, lenvatinib), which demonstrate constrained objective response rates and are frequently associated with acquired resistance[ 3 , 4 ]. Similarly, first-line chemotherapeutic regimens for iCCA (e.g., gemcitabine plus cisplatin) exhibit limited efficacy, necessitating urgent therapeutic advancements to improve survival outcomes[ 5 ]. Although combination immunotherapy and targeted therapy have provided clinical benefit for select patients, overall response rates and durability remain suboptimal, compounded by the absence of validated predictive biomarkers to guide precision stratification[ 6 – 9 ]. In this clinical context, molecular profiling of tumors and investigation into mechanisms of targeted therapy resistance have emerged as pivotal strategies to address therapeutic limitations. Comprehensive genomic analysis via large-panel next-generation sequencing in advanced cohorts has revealed that aberrant MET activation—through gene amplification, mutations, or exon 14 skipping—represents a potential resistance mechanism to existing targeted therapies in both HCC and iCCA, independent of established drivers such as FGFR2 fusions or IDH1 mutations in iCCA[ 10 – 14 ]. Such alterations lead to constitutive activation of the c-MET receptor tyrosine kinase, promoting oncogenic signaling cascades that drive tumor proliferation, invasion, and therapeutic evasion[ 15 – 18 ]. MET gene amplification is observed in approximately 1%–5% of HCC and 3%–5% of iCCA cases, with high-level amplification (gene copy number ≥ 6) accounting for 1%–2%[ 19 – 22 ]. This genetic alteration, mediated through chromosomal polysomy or focal amplification, results in c-MET protein overexpression and correlates with aggressive tumor behavior, including poorer prognosis and resistance to multiple therapeutic modalities, including targeted and immune-based regimens[ 23 , 24 ]. In contrast to non-small cell lung cancer (NSCLC), where MET tyrosine kinase inhibitors (TKIs) are approved for MET exon 14 skipping mutations and selected cases of MET-amplified, EGFR-TKI-resistant disease, no targeted therapies are currently endorsed in clinical guidelines for MET-amplified hepatobiliary malignancies[ 25 , 26 ]. The heterogeneity in defining MET amplification across tumor types further complicates therapeutic translation. In iCCA, high-level amplification is variably defined as gene copy number ≥ 6 or MET/CEP7 ratio ≥ 2.0, while some studies utilize a threshold of > 5 copies[ 23 , 27 ]. Although preliminary clinical evidence suggests potential efficacy of selective MET-TKIs (e.g., tepotinib, capmatinib) in subset analyses, these findings are derived from limited trials or anecdotal reports and lack robust validation[ 28 , 29 ]. Consequently, the real-world clinical utility, safety profile, and survival impact of MET-directed therapy in Chinese patients with MET-amplified hepatobiliary tumors remain to be systematically evaluated.This article reports on two patients with advanced liver cancer harboring MET gene amplification who had previously received systemic therapies such as immunotherapy, targeted therapy, and chemotherapy, as well as interventional local treatments, but experienced poor efficacy and rapid progression. They subsequently received monotherapy with MET-TKI or combination therapy with chemotherapy and immunotherapy, achieving radiological responses with partial remission lasting more than 5 months. These cases provide important reference for further exploring the optimal treatment strategy for liver cancer with MET amplification and for the targeted therapy of advanced liver cancer. Methods We retrospectively reviewed 24 patients with hepatocellular carcinoma or cholangiocarcinoma who underwent NGS testing treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between July 2020 and December 2025. Tumor tissues underwent high-throughput NGS analysis, which identified MET amplification in two cases. One patient was diagnosed with hepatocellular carcinoma, and another patient was diagnosed with combined hepatocellular-cholangiocarcinoma and received MET TKI therapy. The anti-tumor treatments and therapeutic outcomes of each line of treatment were analyzed. Tumor staging was assessed using thoracoabdominal CT or MRI. Histopathological and Immunohistochemical Evaluation All tumor specimens were fixed in formalin and embedded in paraffin according to standard protocols. Serial tissue sections with a thickness of approximately 5 µm were prepared and stained with hematoxylin and eosin (H&E) for routine histopathological evaluation. Morphological assessment focused on tumor cellularity, architectural patterns (including pseudorosette-like structures), presence of microvascular proliferation, necrotic areas, and mitotic figures. Immunohistochemical (IHC) staining was performed on representative FFPE sections using validated protocols. Primary antibodies included c-MET, and appropriate positive and negative controls were applied in each staining run. Immunoreactivity was independently evaluated by experienced pathologists. Molecular Genetic Analysis All cases underwent targeted next-generation sequencing (NGS) using a cancer-associated gene panel, which has been analytically validated by the Department of Molecular Pathology, Sun Yat-sen University. Genomic DNA was extracted from FFPE sections using the QIAamp DNA FFPE Tissue Kit (Qiagen). Libraries were prepared with the KAPA Hyper Prep Kit (KAPA Biosystems) and enriched using custom xGen lockdown probes (IDT) targeting cancer-related genes. Sequencing was performed on the Illumina Novaseq6000 platform, achieving an average depth of 1000× for FFPE samples. Blood-derived white blood cells served as germline controls. Follow-up and Evaluation: Follow-up was conducted through outpatient visits and telephone calls. Follow-up evaluations included blood tests (e.g., complete blood count, liver and kidney function tests) and imaging assessments (CT or MRI) to evaluate tumor status. The frequency and timing of imaging and blood tests were determined based on the individual patient's condition. Progression-free survival (PFS) was defined as the time from the start of treatment to tumor progression or death (measured in months). Overall survival (OS) was defined as the time from the start of treatment to death (measured in months). Literature Review A comprehensive literature review was conducted using the PubMed database to identify previously published cases related to liver malignancies. Searches were performed using combinations of the following keywords in the title and abstract fields: “hepatocellular carcinoma,” “cholangiocarcinoma,” “c-met”and “MET.” Relevant articles were screened and reviewed to contextualize the present findings. Result We performed a retrospective analysis of the genetic testing results for primary liver malignancies at our institution. From From July 3, 2020 to September 26, 2025, 24 patients with primary liver tumors underwent large‑panel NGS; three patients received two separate tests, for a total of 27 sequencing assays. The histologic subtypes included 17 males and 7 females. Among them, 10 patients were diagnosed with hepatocellular carcinoma and 6 with intrahepatic cholangiocarcinoma, while 4 patients had mixed hepatocellular–cholangiocarcinoma, and one case of primary hepatic sarcoma. We identified TP53 was the most frequently altered gene across the cohort, mutations in KRAS and PIK3CA were present in a subset of cases, one patient was MSI‑H, and two patients harbored MET amplification. Notably, MET gene amplification was identified in two patients (8.3%), including one patient with hepatocellular carcinoma and one with mixed liver cancer. Most tumors were microsatellite stable, with only one case exhibiting MSI-high status (Fig. 1 ). Clinical Case Summaries Case 1 General Information Patient 1, a 48-year-old male, presented with dull pain in the right upper abdomen in May 2024. He had a 4-year history of hepatitis B, for which he had taken oral antiviral therapy for several months before discontinuing. He had a 20-year history of smoking (20 cigarettes per day) and a 20-year history of alcohol consumption (approximately 300 g of white liquor per week). Thoracoabdominal CT revealed multiple hepatic lesions suggestive of hepatocellular carcinoma (HCC) with intrahepatic metastasis (the largest lesion in liver segment 4 measured approximately 96 × 94 mm), with metastatic lesions or satellite nodules in liver segments 6 and 7. The middle hepatic vein was invaded, and there was extensive tumor thrombus formation in the right branch of the portal vein. The right diaphragmatic crus was indistinct and slightly thickened, raising suspicion of tumor involvement. Multiple enlarged lymph nodes were observed in the right cardiophrenic angle, hepatic hilum, and retroperitoneum, suggestive of lymph node metastasis. Multiple small lymph nodes were also seen in the mediastinum and right pulmonary hilum. Multiple solid pulmonary nodules were considered metastatic. Liver biopsy pathology showed poorly differentiated carcinoma (Fig. 2 A-C). Immunohistochemistry results were as follows: CK(+), GPC3(+), CK19(+), AFP(+), Ki67 approximately 90%(+), P53(+, mutated type), CK7(−), CK20(−), Muc-1(−), Muc-2(−), TTF-1(−), PSA(−), Syn(−), CgA(−), Hep(−), Arginase-1(−)(Fig. 3 A-H). In situ hybridization results showed EBER(−). The diagnosis favored poorly differentiated hepatocellular carcinoma,. Laboratory tests on May 24, 2024, showed AFP 30,378 ng/ml, ALT 65 U/L, AST 94 U/L, TBIL 16.6 µmol/L, PT 11.6 s, PTA 94%, ALB 42.4 g/L, creatinine 65 µmol/L, creatinine clearance 108.6 ml/min, and blood ammonia 79.1 µmol/L. There was no ascites or hepatic encephalopathy. On July 15, 2024, genetic testing revealed a potentially clinically significant somatic variant: focal copy number amplification of the MET gene (GCN 19.97)(Fig. 2 D).TP53 gene (p.R337L). The tumor was microsatellite stable (MSS) with a tumor mutation burden of 3.17 mutations/Mb. The initial diagnosis was primary massive hepatocellular carcinoma (poorly differentiated cancer), BCLC C, CNLC IIIb, and Child-Pugh A (5), MET gene: focal copy number amplification. From May 31 to July 12, 2024, the patient received first-line treatment with lenvatinib 8 mg orally once daily and camrelizumab 200 mg intravenously every 3 weeks for two cycles. Thoracoabdominal CT showed disease progression (PD) with an increase in the size and number of hepatic and pulmonary tumors and multiple lymph nodes. On July 13, 2024, second-line treatment was initiated with atezolizumab plus bevacizumab for three cycles. Concurrently, the patient underwent two cycles of hepatic arterial angiography with catheter arterial infusion chemotherapy (oxaliplatin 125 mg + 5-FU 0.6 g, 2 g for 23 h) and one cycle of transarterial embolization (TAE) with lipiodol 15 ml + oxaliplatin 140 mg + 5-FU (0.68 g, 2 g). However, the disease progressed (PD) with an increase in pulmonary metastases, massive ascites, hepatic encephalopathy, and altered mental status. The ECOG performance status was 4. From July to October 2024, the patient experienced grade 1 anemia, grade 1 thrombocytopenia, normal white blood cell count, normal neutrophil count, normal renal function, and grade 1 elevation in liver enzymes (ALT, AST, total bilirubin, rGGT). On July 18, 2024, AFP was 43,319 ng/ml (normal range: 0.00–25.00), CEA was 15.10 ng/ml (normal range: 0.00–5.00 ng/ml), CA19-9 was 128 U/ml (normal range: 0.00–35.00). On July 18, 2024, renal function was normal with creatinine. Liver function tests showed grade 1 elevation in ALT, AST, GGT, and LDH. On August 26, 2024, AFP was 41,307 ng/ml (normal range: 0.00–25.00), CEA was 11.00 ng/ml (normal range: 0.00–5.00), CA19-9 was 112 U/ml (normal range: 0.00–35.00), and PIVKA-II was 48.20 ng/ml (normal range: 0–21.29). On October 18, 2024, alanine aminotransferase was 28 U/L (normal range: 10–60 U/L), aspartate aminotransferase was 89 U/L (normal range: ≤50), total bilirubin was 29 µmol/L, direct bilirubin was 10.82 µmol/L, indirect bilirubin was 18.18 µmol/L, rGGT was 220 U/L, urea was 4.6 mmol/L, and creatinine was 55 µmol/L. On September 19, 2024, AFP was 45,401 ng/ml (normal range: 0.00–25.00), CEA was 22.90 ng/ml (normal range: 0.00–5.00), and CA19-9 was 44.9 U/ml (normal range: 0.00–35.00). Due to the unavailability of cabozantinib, third-line treatment with the highly selective MET-TKI glumetinib was initiated. Starting from October 19, 2024, the patient regularly took the oral targeted drug glumetinib (250 mg, once daily) without interruption. Follow-up CT scans at approximately 4 months showed that multiple pulmonary and mediastinal metastases had decreased in size. The hepatic lesions after interventional therapy and the hilar metastatic lesions were similar to the previous findings(Fig. 4 A-D). The therapeutic response was partial remission (PR). The patient's symptoms of abdominal pain, bloating, and fatigue significantly improved, and the ECOG performance status was 1. On November 19, 2024, AFP was 10,188.50 ng/ml (normal range: <9 ng/ml). On January 17, 2025, AFP was 3000.00 ng/ml, CEA was 6.67 ng/mL, CA-125 was 108.1 U/ml (≤ 24), CA19-9 was 18.9 U/mL (≤ 25), AFP was 4876.40 ng/ml (< 9 ng/ml), and CA19-9 was 23.2 U/mL (≤ 25). On February 18, 2025, AFP was 121,901.00 ng/ml. More than 5 months after starting glumetinib, a CT scan on March 28, 2025, showed an increase in the size of the pulmonary and mediastinal lesions compared with the previous scan, as well as an increase in the size of the hepatic lesions and the hilar mass, and an increase in the portal vein tumor thrombus. The disease had progressed (PD). The changes in tumor markers during treatment are shown in Fig. 2 E. On April 5, 2025, the patient experienced a rupture and bleeding of the liver cancer and received best supportive care. The patient died on May 1, 2025, due to tumor progression and multiple organ failure. The progression-free survival (PFS) for third-line glumetinib monotherapy was 5.4 months, Duration of response(DOR) was 4 months and the overall survival (OS) was 6.5 months. The main adverse reactions during targeted MET-TKI therapy were grade 2 anemia and grade 2 thrombocytopenia,no abnormalities in ALT, AST, bilirubin, creatinine,or urea were observed. Summary: This case involved a middle-aged male patient with advanced metastatic massive hepatocellular carcinoma (HCC), BCLC C, CNLC IIIb, and Child-Pugh A. Next-generation sequencing (NGS) revealed focal copy number amplification of the MET gene. First-line treatment with PD-1 inhibitor plus lenvatinib was initiated on May 31, 2024. After two cycles, enhanced CT showed an increase in the number and size of hepatic and pulmonary lesions, indicating disease progression. The PFS for first-line treatment was 1.4 months. Second-line treatment with three cycles of atezolizumab plus bevacizumab was started on July 13, 2024, along with interventional therapy for hepatic metastases, including three sessions of hepatic arterial infusion chemotherapy with the FOLFOX regimen and one session of lipiodol embolization. Enhanced CT on October 18, 2024, showed an increase in the number and size of pulmonary metastases, indicating disease progression. The PFS for second-line treatment was 3.3 months. Given the detection of MET amplification, glumetinib (250 mg, once daily) was initiated on October 19, 2024. After treatment, the patient's symptoms of fatigue, ascites, hepatic encephalopathy, and cancer pain significantly improved. Follow-up enhanced CT scans of the chest and abdomen at 1 and 3 months showed a significant reduction in the size and number of pulmonary metastases, as well as a decrease and disappearance of ascites. The therapeutic response was partial remission (PR). On March 28, 2025, follow-up scans indicated disease progression. The PFS for third-line glumetinib monotherapy was 5 months(Fig. 2 F). The safety profile during treatment was good, with grade 2 anemia and grade 2 thrombocytopenia occurring during targeted therapy. These resolved after symptomatic treatment. There were no decreases in white blood cells or neutrophils, and no abnormalities related to targeted therapy were observed in ALT, AST, total bilirubin, or creatinine. The patient died on May 1, 2025, due to tumor progression, liver cancer rupture and bleeding, and multiple organ failure. Case 2 General Information Patient 2, a 52-year-old male, presented with persistent colicky pain in the epigastric and subxiphoid region on February 20, 2024, without fever, jaundice, nausea, or vomiting. MRI suggested a nodule in the lower segment of the right posterior lobe of the liver, with a high suspicion of hepatocellular carcinoma (HCC). On March 11, 2023, the patient underwent laparoscopic partial hepatectomy (S6 segment liver cancer resection + S4/8 segment liver mass resection + S4 segment hepatic hemangioma resection) and laparoscopic cholecystectomy under general anesthesia. Pathological biopsy on March 18, 2024, c, with necrosis and individual vascular tumor thrombi, but without capsular invasion, immunohistochemistry revealed high c-MET protein expression(Fig. 5 A-D). Past medical history: unremarkable. Personal history: never smoked; occasional alcohol consumption. Initial Diagnosis:Liver cancer (mixed moderately differentiated hepatocellular carcinoma and poorly differentiated cholangiocarcinoma, T1bN0M0 Ib, CNLC Ia, BCLC A), Hepatitis B virus carrier. From April 11 to May 25, 2024, the patient received two cycles of hepatic arterial infusion chemotherapy (HAIC) combined with transarterial embolization (TAE) and PD-1 inhibitor. The HAIC regimen was FOLFOX (oxaliplatin 150 mg + leucovorin 360 mg + fluorouracil 0.7 g + 4.25 g arterial pump infusion). On August 24, 2024, follow-up CT revealed tumor recurrence and metastasis: new enlarged abdominal lymph nodes, consistent with disease relapse and peritoneal metastasis . First-line systemic therapy was initiated on 28 August 2024 and comprised pembrolizumab 200 mg, lenvatinib 8 mg once daily, oxaliplatin 150 mg, and gemcitabine 1,800 mg every 3 weeks. After two cycles, CT demonstrated new pulmonary metastases and progressive intra-abdominal disease; progression-free survival (PFS) was 1.5 months. Second-line treatment, started on 15 October 2024, consisted of pembrolizumab 200 mg, lenvatinib 8 mg once daily, and modified FOLFOX (oxaliplatin 146 mg, levofolinate 343 mg, bolus 5-fluorouracil 680 mg followed by 4.12 g continuous infusion over 46 h). Two cycles later, imaging showed new hepatic, pulmonary, and peritoneal lesions; tumor-related abdominal pain, distension, lower-limb oedema, and fatigue worsened. PFS remained 1.5 months. Third-line therapy commenced on 29 November 2024 with pembrolizumab 200 mg, FOLFOX (oxaliplatin 150 mg, levofolinate 343 mg, 5-fluorouracil 680 mg bolus plus 4.12 g infusion), and regorafenib 80 mg once daily. On 5 December, 2024, NGS disclosed MET amplification (gene copy number 13.58), together with pathogenic variants in TP53, AMER1, TERT, and AXIN1; microsatellite-stable status and low tumor mutational burden (3.33 Mut/Mb). Consequently, on 27 December 2024, the regimen was intensified to include gemcitabine 1,000 mg, oxaliplatin 100 mg, irinotecan 180 mg, tislelizumab 200 mg, and MET tyrosine-kinase inhibitor savolitinib 300 mg once daily for four cycles. Re-evaluation 2.5 months later demonstrated a partial response (PR) (Fig. 6 A–D). Concurrently, serum α-fetoprotein and carcinoembryonic antigen declined substantially (Fig. 6 E). PFS exceeded 5 months. Throughout chemotherapy, immunotherapy, and MET-TKI treatment, the only significant adverse event was grade 1 anaemia, which resolved promptly with supportive care, no drug-related elevations in alanine aminotransferase, aspartate aminotransferase, total bilirubin, or creatinine were observed. In summary, this middle-aged male with resected mixed HCC–intrahepatic cholangiocarcinoma relapsed 5 months after surgery. Conventional regimens incorporating PD-1 blockade, anti-angiogenic agents, and cytotoxics produced rapid progression (PFS 1.5 months for both first- and second-line). Identification of MET amplification prompted the addition of savolitinib to chemotherapy and immunotherapy, resulting in objective tumour regression (PR), symptomatic improvement, and durable disease control (PFS > 5 months) (Fig. 6 E). Prior immunotherapies, locoregional interventions and cytotoxic regimens failed to achieve disease control. The introduction of the highly selective MET tyrosine-kinase inhibitor savolitinib in combination with immunochemotherapy resulted in durable tumour regression and symptomatic relief, underscoring the antitumour efficacy of MET inhibition in MET-amplified metastatic liver cancer(Fig. 7 ). These findings indicate the clinical value of using high selective MET TKI in MET-amplified metastatic liver cancer refractory to standard systemic therapies. Throughout combination treatment, the only adverse event was grade 1 anaemia, which resolved with conservative management; no drug-related elevations in ALT, AST, total bilirubin or creatinine were observed. Literature Review and Survival Analysis Our case series adds to the limited but growing body of evidence on the clinical activity of selective MET tyrosine kinase inhibitors (MET TKIs) in patients with advanced hepatobiliary cancers harboring MET alterations. Six cases have been reported in the literature, derived from five individual case reports. These include:4 cases of advanced hepatocellular carcinoma (HCC) ; 2 cases of intrahepatic cholangiocarcinoma (iCCA); 1 case of metastatic gallbladder carcinoma[ 22 , 30 – 33 ]. Notably, one patient with iCCA was included in the report by Wu JH et al. (2024), bringing the total number of unique patients to six, as all other reports describe single individuals. Clinical follow-up data were available for all 6 patients. The affected population primarily consisted of middle-aged adults, with ages ranging from 48 to 67 years; the median age at initiation of MET TKI therapy was 59 years. There was a marked male predominance: 5 out of 6 patients (83%) were male, consistent with the known epidemiological bias in hepatobiliary malignancies.All 6 patients presented with advanced or recurrent disease, either at diagnosis or following prior curative-intent treatment. Upon initiation of MET TKI therapy (crizotinib, savolitinib, or capmatinib), the median progression-free survival (PFS) was 11.0 months (range: 3–34 + months), substantially exceeding historical PFS expectations for standard second-line therapies in these cancers.At the time of last follow-up, 3 out of 6 patients (50%) remained alive, including two individuals who achieved exceptionally durable responses — one iCCA patient with ZKSCAN1–MET fusion treated with crizotinib maintained response for over 34 months [Wu JH et al., 2024], and another with MET amplification showed sustained control beyond 16 months(Tabe 1). The median overall survival (OS) after initiation of MET TKI therapy across these 6 patients was 11.8 months (Kaplan-Meier estimate). The survival curve suggesting that a molecularly defined subset may derive long-term benefit from MET inhibition. Efficacy and Safety from Prospective Clinical Trials To contextualize our findings, we reviewed key prospective clinical trials evaluating MET-targeted therapies in advanced hepatocellular carcinoma (HCC). Four major studies have assessed the role of MET inhibition in this setting: the phase III METIV-HCC trial of tivantinib, the phase 1b/2 study of tepotinib, the phase II capmatinib monotherapy trial, and the phase III CELESTIAL trial of cabozantinib—a multikinase inhibitor with potent anti-MET activity. The METIV-HCC trial (NCT01755767), a randomized, double-blind, placebo-controlled phase III study, evaluated tivantinib versus placebo as second-line therapy in 571 patients with MET-high advanced HCC defined by immunohistochemistry (IHC 2+/3+) after sorafenib failure. Contrary to expectations, tivantinib did not improve overall survival (OS): median OS was 8.4 months in the tivantinib arm vs 9.1 months in the placebo group (HR 1.04; 95% CI: 0.85–1.28; p = 0.70). Progression-free survival (PFS) was modestly improved (2.8 vs 2.3 months; HR 0.71; p < 0.001). Objective response rate (ORR) was low at 6%, and disease control rate (DCR) was 62%. Notably, patients receiving tivantinib experienced higher rates of neutropenia, anemia, fatigue, and gastrointestinal symptoms. Subsequent analyses revealed that tivantinib has weak MET-inhibitory activity and may function more as a microtubule disruptor than a true MET TKI, which likely contributed to its lack of efficacy [ 2 ]. A randomized phase 1b/2 trial (NCT01988493) evaluated tepotinib versus sorafenib as first-line therapy in 90 Asian patients with advanced hepatocellular carcinoma and MET overexpression (IHC 2+/3+). The combination significantly improved median PFS (2.8 vs 1.4 months; HR 0.52; p = 0.006), but did not translate into a significant overall survival benefit (9.3 vs 8.6 months; HR 0.71; p = 0.17). Objective response rate was 10.5%, with a disease control rate of 50%. Notably, the combination had a more favorable safety profile, with lower rates of grade ≥ 3 adverse events (28.9% vs 45.5%) and fewer dose reductions compared to sorafenib monotherapy. These results suggest that adding tepotinib delays progression but does not substantially improve long-term outcomes in IHC-selected patients, highlighting the limitations of immunohistochemistry as a sole biomarker for patient selection. The most encouraging results come from a phase II, single-arm trial of capmatinib, a highly selective MET inhibitor, in patients with MET-dysregulated advanced HCC (defined by NGS, FISH, or IHC) regardless of prior therapy (NCT01737827). Among 38 evaluable patients, capmatinib achieved an objective response rate (ORR) of 30% and a disease control rate (DCR) of 64%. Median PFS was 5.2 months (vs 1.9 months in historical controls), and median OS was 10.2 months — among the highest reported for any targeted agent in biomarker-selected HCC. Safety was manageable: the most common treatment-related AEs were nausea, vomiting, diarrhea, and transient liver enzyme elevations. Only 16% experienced grade ≥ 3 AEs, and no treatment-related deaths were reported. This trial provides that selective MET inhibition can induce meaningful tumor regression in molecularly defined subsets, particularly those with high-level amplification or functional fusions. Although not a dedicated MET-targeted trial, the phase III CELESTIAL study (NCT01908426) of cabozantinib in previously treated advanced HCC demonstrated a median OS of 11.3 months vs 7.2 months with placebo (HR 0.76; p < 0.001), with corresponding improvements in PFS (5.2 vs 1.9 months) and ORR (4%) [ 5 ]. Cabozantinib is a multi-target TKI inhibiting VEGFR2, MET, and AXL — all implicated in HCC pathogenesis. While the trial did not select patients based on MET status, exploratory analyses suggested enhanced benefit in subgroups with elevated phospho-MET or HGF levels. Common AEs included hypertension, fatigue, diarrhea, hand-foot skin reaction (HFSR), and hepatic enzyme elevation — consistent with its broad target profile. Approximately 60% required dose reductions due to toxicity. In patients with genuine functional MET alterations—such as high-level gene amplification or oncogenic fusions—and when treated with highly selective MET inhibitors, can significant clinical responses be observed. Our case series further validates this paradigm, demonstrating that high selective MET tyrosine kinase inhibitors (such as glutimatinib and savolitinib) can achieve durable responses in real-world patients even after multiple lines of prior therapy. Discussion As an oncogene, MET mutations are generally associated with poor prognosis in lung adenocarcinoma, pulmonary sarcomatoid carcinoma, and cancers of unknown primary (CUPs) [ 34 ]. The incidence of MET genomic alterations across various tumor types—including renal cancer, hepatobiliary cancers, colorectal cancer, ovarian cancer, breast cancer, and prostate cancer—is approximately 5%, encompassing point mutations, gene amplifications, and exon 14-skipping mutations.[ 35 ]. Notably, the frequency of MET alterations in cancers of unknown primary (CUPs) reaches up to 30%, whereas it is only around 4% in early-stage metastatic cancers[ 36 ]. Patients harboring MET exon 14-skipping mutations have demonstrated favorable antitumor activity and acceptable safety profiles in response to MET inhibitors, such as capmatinib, tepotinib, and savolitinib[ 37 – 43 ]. This study presents two cases of metastatic hepatocellular carcinoma (HCC) patients with MET gene amplification (GCN > 10). Previous standard treatments, including immunotherapy, anti-angiogenic therapy, and chemotherapy, showed limited efficacy. Subsequent treatment with highly selective MET tyrosine kinase inhibitors (TKIs), either as monotherapy or in combination with chemotherapy, resulted in significant clinical benefits, achieving partial responses (PRs) in both patients. The durations of response (DOR) were ≥ 4 months, respectively. Major adverse events included grade 2 hematologic toxicities such as anemia and thrombocytopenia, which were generally manageable. Similar results have been reported in case studies. A 35-year-old male patient with HCC treated with savolitinib as first-line therapy experienced a significant reduction in tumor marker levels and achieved PR within two months. This patient maintained PR status for nearly one year[ 32 ]. For multi-targeted agent cabozantinib, it also demonstrates certain efficacy in the second-line treatment of hepatocellular carcinoma. The CELESTIAL phase III trial demonstrated that among previously sorafenib-treated advanced HCC patients (n = 707), median progression-free survival (PFS) and overall survival (OS) were 5.2 months and 10.2 months in the cabozantinib group, compared to 1.9 months and 8.0 months in the placebo group, respectively. Disease control rate (DCR) and objective response rate (ORR) were 64% and 4%, respectively, in the cabozantinib group, versus 33% and < 1% in the placebo group [ 44 ]. In the COSMIC-312 study, untreated HCC patients receiving single-agent cabozantinib had a median PFS of 5.8 months[ 45 ]. In the CheckMate 040 phase I/II trial, the median duration of response for nivolumab plus ipilimumab was 7.1 months (95% CI: 3.9–13.6 months), and for nivolumab, cabozantinib, plus ipilimumab, it was 7.8 months (95% CI: 3.3–11.5 months) [ 46 ]. Furthermore, MET gene amplification occurs in approximately 10% of gastric cancers. Savolitinib monotherapy in MET-amplified gastric and gastroesophageal junction adenocarcinoma (GC/GEJ) patients achieved an ORR of 45%, with a 50% response rate in those with high MET copy numbers[ 47 ] [ 46 – 50 ]. These data suggest that MET TKIs can effectively control MET-amplified solid tumors. However, whether MET gene amplification benefits from MET-TKI treatment remains controversial. One reason is that MET amplification includes whole chromosome duplication (aneuploidy) and focal gene region duplication (focal amplification). Focal amplification is typically considered a driver of cancer, while the oncogenicity of aneuploidy is debatable, showing poor response to MET inhibitors alone. Therefore, distinguishing between polyploidy and focal amplification may be crucial for ensuring the efficacy of MET inhibitors [ 34 , 36 ]. Polyploidy involves an increase in the copy number of genes on chromosome 7, often accompanied by co-amplification of neighboring genes such as EGFR, CDK6, and BRAF. Therefore, a study proposed using next-generation sequencing (NGS) to simultaneously examine the amplification of genes on chromosome 7 (such as BRAF and CDK6) to distinguish polyploidy from focal MET amplification. If there is no co-amplification of neighboring genes (such as CDK6 or BRAF), the MET gene is classified as focal amplification. Conversely, non-focal MET amplification is defined as MET copy number increases associated with polyploidy, where MET copy numbers increase along with CDK6 and/or BRAF[ 34 , 36 ]Another reason why not all patients with focal amplification may benefit from MET-TKI treatment could depend on the threshold set for amplification[ 55 ]. The PROFILE 1001 study indicated that MET-amplified NSCLC patients treated with crizotinib had limited efficacy when MET/CEP ≥ 2.0, but the efficacy of MET-TKIs increased with higher levels of MET amplification. Specifically, crizotinib treatment in MET-amplified (MET/CEP7 ≥ 5) patients achieved an objective response rate (ORR) of 40%, with higher amplification levels leading to more significant efficacy[ 56 ].A MET gene copy number (GCN) ≥ 10 is considered a critical threshold for effective MET-TKI treatment. When GCN ≥ 10, MET protein expression significantly increases, enhancing tumor cell dependency on the MET signaling pathway ("oncogene addiction"), thereby making MET inhibition more effective in blocking tumor growth[ 51 , 52 ]. At GCN ≥ 10, MET amplification becomes a primary driver, with tumor survival highly dependent on MET signaling [ 53 ]. Single-agent TKI can significantly inhibit proliferation. GCN ≥ 10 leads to sustained MET phosphorylation, activating the ERBB3/PI3K pathway and bypassing EGFR inhibition (especially in EGFR-mutant resistant patients)[ 54 ]. MET-TKIs can block ERBB3 phosphorylation, restoring drug sensitivity. In cases of low GCN (< 10), MET may only be co-amplified or coexist with other driver genes (such as EGFR), requiring combination targeted therapy (e.g., EGFR-TKI + MET-TKI) to overcome resistancel[ 55 ].Focal MET amplification at GCN ≥ 10 suggests that MET is an independent driver gene, making it sensitive to single-agent TKI. Polyploidy is more common when GCN < 10, where MET is not a primary driver, limiting the efficacy of TKIs[ 56 ].[ 57 ]. The GEOMETRY mono-1 study showed that capmatinib treatment in MET-amplified NSCLC had an ORR of 40% (95% CI: 16–68%) in treatment-naive patients and 29% (19–41%) in previously treated patients, establishing GCN ≥ 10 as a core criterion for selecting patients likely to benefit from MET-TKI[ 37 ]. Tepotinib treatment in NSCLC patients with GCN ≥ 10 had an ORR of 40–60%, whereas the ORR was only 7–12% in the GCN 5 responded better to MET-TKIs, but the response rate (60%) and median PFS (7.3 months) were further enhanced in the GCN ≥ 10 group. In this study, two patients with metastatic hepatocellular carcinoma (HCC) exhibiting MET amplification or focal amplification (GCN > 10) were analyzed. One patient, from whom tissue samples were obtainable, exhibited no response to combined immunotherapy and chemotherapy. Subsequent addition of the MET TKI savolitinib resulted in a significant therapeutic effect, achieving a partial response (PR). The patient was then maintained on savolitinib monotherapy for two months, with the PR confirmed. Further MET immunohistochemistry (IHC) analysis revealed strongly positive MET expression in tumor tissues. Significant tumor regression was observed following treatment with MET TKI monotherapy or combination chemotherapy. During tumor progression, a re-biopsy performed on a patient failed to detect MET amplification via NGS, indicating that the loss of this driver gene alteration or clonal selection could be a potential mechanism of resistance to MET-TKIs. Regarding adverse events, both patients experienced hematologic toxicities including anemia and thrombocytopenia. The treatments were well-tolerated overall, with all adverse events being manageable. These findings suggest that MET-TKIs administered at standard therapeutic doses exhibit an acceptable safety profile in metastatic liver cancer. In conclusion, our findings indicate that patients with focal MET amplification in advanced HCC may benefit from MET-TKI targeted therapy with manageable safety profiles. Due to the small sample size, larger prospective studies are needed to confirm the role of MET-TKIs in HCC and to establish criteria for selecting patients who will benefit from these therapies. Additionally, further research is required to explore the predictive value of immunohistochemistry for MET amplification and therapeutic response. Declarations Ethics approval and consent to participate : Ethical approval were approved by Medical Ethics Committee, Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSU) (No.SYSKY-2023-622-01). All procedures complied with the Declaration of Helsinki. Consent for publication: Written informed consent was obtained from each patient or their legal guardians. Availability of data and materials: All data generated or analysed during this study are included in this published article. Conflict of interest : The authors have no relevant financial or non-financial interests to disclose. Funding: National Natural Science Foundation of China (Grant No. 81702762); Science and Technology Projects in Guangzhou (Project No. 2023A04J2105) Author Contributions: Jingshu Wang: Conceptualization, methodology, investigation, writing, funding acquisition, original draft preparation. Xinxin He: Conceptualization, investigation, writing, original draft preparation. Wei Chen: Methodology, investigation, writing, funding acquisition- original draft preparation. Junyu Zhu: Formal analysis, visualization. Jianwei Liao: Investigation, resources, writing - review & editing. Yuanyuan Yin: Investigation, resources, writing - review & editing. Qiong Yang: Supervision, funding acquisition, writing - review & editing. All authors have read and agreed to the published version of the manuscript. Acknowledgements: Not applicable. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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Supplementary Files Tables.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 10 May, 2026 Reviews received at journal 30 Apr, 2026 Reviewers agreed at journal 12 Apr, 2026 Reviewers invited by journal 09 Apr, 2026 Editor assigned by journal 18 Feb, 2026 Submission checks completed at journal 18 Feb, 2026 First submitted to journal 17 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8898860","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":621631365,"identity":"fba2528f-925f-44c4-ae38-f4f42c44ade3","order_by":0,"name":"Jingshu Wang","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Jingshu","middleName":"","lastName":"Wang","suffix":""},{"id":621631376,"identity":"cd1692d4-7a90-46a4-b37d-ffe4c6a39c3f","order_by":1,"name":"Xinxin He","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Xinxin","middleName":"","lastName":"He","suffix":""},{"id":621631378,"identity":"3ab644c4-1841-4e89-9d83-48cf3457059a","order_by":2,"name":"Wei Chen","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Chen","suffix":""},{"id":621631385,"identity":"de49cacc-6666-4d30-ad49-51cfa8e8920b","order_by":3,"name":"Junyu Zhu","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Junyu","middleName":"","lastName":"Zhu","suffix":""},{"id":621631389,"identity":"26e2ab14-6c44-4689-baba-efd8e3ecee25","order_by":4,"name":"Jianwei Liao","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Jianwei","middleName":"","lastName":"Liao","suffix":""},{"id":621631390,"identity":"098a0edb-1e02-45d4-9eb1-09f5ce6c4545","order_by":5,"name":"Yuanyuan Yin","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yuanyuan","middleName":"","lastName":"Yin","suffix":""},{"id":621631391,"identity":"963ad905-5fd1-44b0-a20b-3acf698d5cd1","order_by":6,"name":"Qiong Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIiWNgGAWjYNCCiv9yDAyMjQdgfAnCWs4wGwO1NJCghbGFObEBSBOnxeD42cMv3jawpa9tPwy05c9he4MDzAdv8zDY5eHUciYvzXLuDp7cbWcSGw4wth1O3HCALdmahyG5GKeWAzlmxrxnJHK3HQBpaTicYHCAx0yah+EA2KlYtZx/A9TSZpBudv4hzGH83/BruZFj/Ji3LSHB7AbQFga2w4wbDvCw4dUieeONGeOcMwcMt90A2pLYlp448zCbseUcg2ScWvjO5xh/eFNxQN7sfPrDBx/+WNvzHW9+eONNhR1OLQpAx0jwwHgJDM0MDMxgB+NQDwTyDQzMH3gQ/DrcSkfBKBgFo2DEAgAMr2R+4dtDjwAAAABJRU5ErkJggg==","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Qiong","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2026-02-17 08:09:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8898860/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8898860/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107484631,"identity":"6eaa988c-0efe-4cd2-94f8-ee25cc94c751","added_by":"auto","created_at":"2026-04-22 02:32:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95115,"visible":true,"origin":"","legend":"\u003cp\u003e24 patients with primary liver tumors underwent large‑panel NGS; three patients received two separate tests, for a total of 27 sequencing assays. TP53 was the most frequently altered gene across the cohort, mutations in KRAS and PIK3CA were present in a subset of cases, MET gene amplification was identified in two patients (8.3%).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/e54abbffd973f201374dc094.png"},{"id":107257549,"identity":"3fc7bf2e-b791-47f3-9048-9e3a6df8a508","added_by":"auto","created_at":"2026-04-19 12:31:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":310581,"visible":true,"origin":"","legend":"\u003cp\u003e(A-C) Pathological and molecular features of Patient 1. H\u0026amp;E-stained liver biopsy sections demonstrating poorly differentiated hepatocellular carcinoma. (D) Focal MET gene amplification identified by next-generation sequencing in tumor tissue of Patient 1.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/e568e802aa8c0f7a477b6c7f.png"},{"id":107483083,"identity":"10281bea-1bb2-4122-a2a5-8f9566d0413a","added_by":"auto","created_at":"2026-04-22 02:26:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":544555,"visible":true,"origin":"","legend":"\u003cp\u003e(A-H)Characteristic immunohistochemistry for Patient 2.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/abb5e40939f77e75fdec5568.png"},{"id":107257553,"identity":"5b1f8fde-7ec6-4299-a3ad-4214e6754fb1","added_by":"auto","created_at":"2026-04-19 12:31:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":194679,"visible":true,"origin":"","legend":"\u003cp\u003e(A, B) Post-treatment contrast-enhanced CT demonstrates a slight decrease in hepatic metastatic burden following glumetinib in Patient 1. (C, D) Chest CT reveals substantial regression and decreased number of pulmonary metastases. (E) Serial serum tumor-marker measurements reveal pronounced declines in AFP and CA19-9 following glumetinib therapy. (F) Swimmer plot depicting progression-free survival (PFS) across first-, second-, and third-line treatments; glumetinib was administered as third-line therapy.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/c295c09152e09826aeeb1a0f.png"},{"id":107257556,"identity":"e5f7c5e0-fa62-46bd-8f7c-3f1741dbddec","added_by":"auto","created_at":"2026-04-19 12:31:39","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":371834,"visible":true,"origin":"","legend":"\u003cp\u003e(A, B) Histopathological features of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) in Patient 2. Representative H\u0026amp;E-stained sections (20× magnification) demonstrating characteristic cHCC-CCA morphology. (C, D) Immunohistochemistry reveals positive c-MET immunoreactivity in tumor cells. (E) MET gene amplification detected by next-generation sequencing in tumor tissue of Patient 2.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/59a16a3421f341afaa15c52d.png"},{"id":107484940,"identity":"c806c2eb-2674-4a37-b81d-854128fee2c1","added_by":"auto","created_at":"2026-04-22 02:33:20","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":201393,"visible":true,"origin":"","legend":"\u003cp\u003e(A, B) Post-treatment contrast-enhanced CT demonstrates regression in spleen metastatic burden following savolitinib, chemotherapy and immunotherapy in Patient 2. (C, D) Chest CT reveals substantial regression and decreased number of pulmonary metastases. (E) Serial serum measurements show marked declines in AFP and CEA levels after savolitinib teatment. (F) Swimmer plot summarizing progression-free survival (PFS) durations achieved during first-, second-, and third-line therapies; savolitinib was employed as the third-line regimen.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/30afa6c7b16abc4f9ce30a86.png"},{"id":107257555,"identity":"d624ad49-070e-4d84-bae2-db81d3710d2c","added_by":"auto","created_at":"2026-04-19 12:31:39","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":124731,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of diagnosis and treatment process of patient1(A) and patient2 (B).\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/ea188ae14e08fbf5707a87fb.png"},{"id":107487350,"identity":"24d10fb6-cd6a-43b9-9932-b5bc623eded3","added_by":"auto","created_at":"2026-04-22 02:41:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2113115,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/fb9d3dbf-10bb-4339-8c5b-379be87e5fb3.pdf"},{"id":107483610,"identity":"45432160-35a7-4347-8942-10943ab1864c","added_by":"auto","created_at":"2026-04-22 02:28:24","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":332716,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8898860/v1/877e2f622d1d49729ca7a5f3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eMET-TKIs selectively inhibit growth of hepatobiliary carcinoma harboring high copy number MET amplification: 2 cases and literature review\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWorldwide, primary liver cancer represents a malignancy with significant epidemiological burden, characterized by elevated incidence and mortality rates[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hepatocellular carcinoma (HCC) constitutes 85%\u0026ndash;90% of cases, while intrahepatic cholangiocarcinoma (iCCA) ranks among the most prevalent primary hepatic malignancies. According to GLOBOCAN 2020 estimates, approximately 906,000 new cases and 830,000 deaths occur annually, with projections indicating a 55% increase by 2040, underscoring substantial challenges in disease management and prevention[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].For patients with unresectable advanced-stage disease, first-line standard therapy for HCC relies on multikinase inhibitors (e.g., sorafenib, lenvatinib), which demonstrate constrained objective response rates and are frequently associated with acquired resistance[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Similarly, first-line chemotherapeutic regimens for iCCA (e.g., gemcitabine plus cisplatin) exhibit limited efficacy, necessitating urgent therapeutic advancements to improve survival outcomes[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although combination immunotherapy and targeted therapy have provided clinical benefit for select patients, overall response rates and durability remain suboptimal, compounded by the absence of validated predictive biomarkers to guide precision stratification[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this clinical context, molecular profiling of tumors and investigation into mechanisms of targeted therapy resistance have emerged as pivotal strategies to address therapeutic limitations. Comprehensive genomic analysis via large-panel next-generation sequencing in advanced cohorts has revealed that aberrant MET activation\u0026mdash;through gene amplification, mutations, or exon 14 skipping\u0026mdash;represents a potential resistance mechanism to existing targeted therapies in both HCC and iCCA, independent of established drivers such as FGFR2 fusions or IDH1 mutations in iCCA[\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Such alterations lead to constitutive activation of the c-MET receptor tyrosine kinase, promoting oncogenic signaling cascades that drive tumor proliferation, invasion, and therapeutic evasion[\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. MET gene amplification is observed in approximately 1%\u0026ndash;5% of HCC and 3%\u0026ndash;5% of iCCA cases, with high-level amplification (gene copy number\u0026thinsp;\u0026ge;\u0026thinsp;6) accounting for 1%\u0026ndash;2%[\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This genetic alteration, mediated through chromosomal polysomy or focal amplification, results in c-MET protein overexpression and correlates with aggressive tumor behavior, including poorer prognosis and resistance to multiple therapeutic modalities, including targeted and immune-based regimens[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In contrast to non-small cell lung cancer (NSCLC), where MET tyrosine kinase inhibitors (TKIs) are approved for MET exon 14 skipping mutations and selected cases of MET-amplified, EGFR-TKI-resistant disease, no targeted therapies are currently endorsed in clinical guidelines for MET-amplified hepatobiliary malignancies[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe heterogeneity in defining MET amplification across tumor types further complicates therapeutic translation. In iCCA, high-level amplification is variably defined as gene copy number\u0026thinsp;\u0026ge;\u0026thinsp;6 or MET/CEP7 ratio\u0026thinsp;\u0026ge;\u0026thinsp;2.0, while some studies utilize a threshold of \u0026gt;\u0026thinsp;5 copies[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Although preliminary clinical evidence suggests potential efficacy of selective MET-TKIs (e.g., tepotinib, capmatinib) in subset analyses, these findings are derived from limited trials or anecdotal reports and lack robust validation[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Consequently, the real-world clinical utility, safety profile, and survival impact of MET-directed therapy in Chinese patients with MET-amplified hepatobiliary tumors remain to be systematically evaluated.This article reports on two patients with advanced liver cancer harboring MET gene amplification who had previously received systemic therapies such as immunotherapy, targeted therapy, and chemotherapy, as well as interventional local treatments, but experienced poor efficacy and rapid progression. They subsequently received monotherapy with MET-TKI or combination therapy with chemotherapy and immunotherapy, achieving radiological responses with partial remission lasting more than 5 months. These cases provide important reference for further exploring the optimal treatment strategy for liver cancer with MET amplification and for the targeted therapy of advanced liver cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe retrospectively reviewed 24 patients with hepatocellular carcinoma or cholangiocarcinoma who underwent NGS testing treated at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between July 2020 and December 2025. Tumor tissues underwent high-throughput NGS analysis, which identified MET amplification in two cases. One patient was diagnosed with hepatocellular carcinoma, and another patient was diagnosed with combined hepatocellular-cholangiocarcinoma and received MET TKI therapy. The anti-tumor treatments and therapeutic outcomes of each line of treatment were analyzed. Tumor staging was assessed using thoracoabdominal CT or MRI.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eHistopathological and Immunohistochemical Evaluation\u003c/h2\u003e \u003cp\u003eAll tumor specimens were fixed in formalin and embedded in paraffin according to standard protocols. Serial tissue sections with a thickness of approximately 5 \u0026micro;m were prepared and stained with hematoxylin and eosin (H\u0026amp;E) for routine histopathological evaluation. Morphological assessment focused on tumor cellularity, architectural patterns (including pseudorosette-like structures), presence of microvascular proliferation, necrotic areas, and mitotic figures.\u003c/p\u003e \u003cp\u003eImmunohistochemical (IHC) staining was performed on representative FFPE sections using validated protocols. Primary antibodies included c-MET, and appropriate positive and negative controls were applied in each staining run. Immunoreactivity was independently evaluated by experienced pathologists.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMolecular Genetic Analysis\u003c/h3\u003e\n\u003cp\u003eAll cases underwent targeted next-generation sequencing (NGS) using a cancer-associated gene panel, which has been analytically validated by the Department of Molecular Pathology, Sun Yat-sen University.\u003c/p\u003e \u003cp\u003eGenomic DNA was extracted from FFPE sections using the QIAamp DNA FFPE Tissue Kit (Qiagen). Libraries were prepared with the KAPA Hyper Prep Kit (KAPA Biosystems) and enriched using custom xGen lockdown probes (IDT) targeting cancer-related genes. Sequencing was performed on the Illumina Novaseq6000 platform, achieving an average depth of 1000\u0026times; for FFPE samples. Blood-derived white blood cells served as germline controls.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Evaluation:\u003c/h3\u003e\n\u003cp\u003eFollow-up was conducted through outpatient visits and telephone calls. Follow-up evaluations included blood tests (e.g., complete blood count, liver and kidney function tests) and imaging assessments (CT or MRI) to evaluate tumor status. The frequency and timing of imaging and blood tests were determined based on the individual patient's condition. Progression-free survival (PFS) was defined as the time from the start of treatment to tumor progression or death (measured in months). Overall survival (OS) was defined as the time from the start of treatment to death (measured in months).\u003c/p\u003e\n\u003ch3\u003eLiterature Review\u003c/h3\u003e\n\u003cp\u003eA comprehensive literature review was conducted using the PubMed database to identify previously published cases related to liver malignancies. Searches were performed using combinations of the following keywords in the title and abstract fields: \u0026ldquo;hepatocellular carcinoma,\u0026rdquo; \u0026ldquo;cholangiocarcinoma,\u0026rdquo; \u0026ldquo;c-met\u0026rdquo;and \u0026ldquo;MET.\u0026rdquo; Relevant articles were screened and reviewed to contextualize the present findings.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eWe performed a retrospective analysis of the genetic testing results for primary liver malignancies at our institution. From From July 3, 2020 to September 26, 2025, 24 patients with primary liver tumors underwent large‑panel NGS; three patients received two separate tests, for a total of 27 sequencing assays. The histologic subtypes included 17 males and 7 females. Among them, 10 patients were diagnosed with hepatocellular carcinoma and 6 with intrahepatic cholangiocarcinoma, while 4 patients had mixed hepatocellular\u0026ndash;cholangiocarcinoma, and one case of primary hepatic sarcoma. We identified TP53 was the most frequently altered gene across the cohort, mutations in KRAS and PIK3CA were present in a subset of cases, one patient was MSI‑H, and two patients harbored MET amplification. Notably, MET gene amplification was identified in two patients (8.3%), including one patient with hepatocellular carcinoma and one with mixed liver cancer. Most tumors were microsatellite stable, with only one case exhibiting MSI-high status (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eClinical Case Summaries\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003eGeneral Information\u003c/p\u003e \u003c/p\u003e \u003cp\u003ePatient 1, a 48-year-old male, presented with dull pain in the right upper abdomen in May 2024. He had a 4-year history of hepatitis B, for which he had taken oral antiviral therapy for several months before discontinuing. He had a 20-year history of smoking (20 cigarettes per day) and a 20-year history of alcohol consumption (approximately 300 g of white liquor per week). Thoracoabdominal CT revealed multiple hepatic lesions suggestive of hepatocellular carcinoma (HCC) with intrahepatic metastasis (the largest lesion in liver segment 4 measured approximately 96 \u0026times; 94 mm), with metastatic lesions or satellite nodules in liver segments 6 and 7. The middle hepatic vein was invaded, and there was extensive tumor thrombus formation in the right branch of the portal vein. The right diaphragmatic crus was indistinct and slightly thickened, raising suspicion of tumor involvement. Multiple enlarged lymph nodes were observed in the right cardiophrenic angle, hepatic hilum, and retroperitoneum, suggestive of lymph node metastasis. Multiple small lymph nodes were also seen in the mediastinum and right pulmonary hilum. Multiple solid pulmonary nodules were considered metastatic. Liver biopsy pathology showed poorly differentiated carcinoma (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-C). Immunohistochemistry results were as follows: CK(+), GPC3(+), CK19(+), AFP(+), Ki67 approximately 90%(+), P53(+, mutated type), CK7(\u0026minus;), CK20(\u0026minus;), Muc-1(\u0026minus;), Muc-2(\u0026minus;), TTF-1(\u0026minus;), PSA(\u0026minus;), Syn(\u0026minus;), CgA(\u0026minus;), Hep(\u0026minus;), Arginase-1(\u0026minus;)(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-H). In situ hybridization results showed EBER(\u0026minus;). The diagnosis favored poorly differentiated hepatocellular carcinoma,. Laboratory tests on May 24, 2024, showed AFP 30,378 ng/ml, ALT 65 U/L, AST 94 U/L, TBIL 16.6 \u0026micro;mol/L, PT 11.6 s, PTA 94%, ALB 42.4 g/L, creatinine 65 \u0026micro;mol/L, creatinine clearance 108.6 ml/min, and blood ammonia 79.1 \u0026micro;mol/L. There was no ascites or hepatic encephalopathy.\u003c/p\u003e \u003cp\u003eOn July 15, 2024, genetic testing revealed a potentially clinically significant somatic variant: focal copy number amplification of the MET gene (GCN 19.97)(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).TP53 gene (p.R337L). The tumor was microsatellite stable (MSS) with a tumor mutation burden of 3.17 mutations/Mb. The initial diagnosis was primary massive hepatocellular carcinoma (poorly differentiated cancer), BCLC C, CNLC IIIb, and Child-Pugh A (5), MET gene: focal copy number amplification.\u003c/p\u003e \u003cp\u003eFrom May 31 to July 12, 2024, the patient received first-line treatment with lenvatinib 8 mg orally once daily and camrelizumab 200 mg intravenously every 3 weeks for two cycles. Thoracoabdominal CT showed disease progression (PD) with an increase in the size and number of hepatic and pulmonary tumors and multiple lymph nodes.\u003c/p\u003e \u003cp\u003eOn July 13, 2024, second-line treatment was initiated with atezolizumab plus bevacizumab for three cycles. Concurrently, the patient underwent two cycles of hepatic arterial angiography with catheter arterial infusion chemotherapy (oxaliplatin 125 mg\u0026thinsp;+\u0026thinsp;5-FU 0.6 g, 2 g for 23 h) and one cycle of transarterial embolization (TAE) with lipiodol 15 ml\u0026thinsp;+\u0026thinsp;oxaliplatin 140 mg\u0026thinsp;+\u0026thinsp;5-FU (0.68 g, 2 g). However, the disease progressed (PD) with an increase in pulmonary metastases, massive ascites, hepatic encephalopathy, and altered mental status. The ECOG performance status was 4. From July to October 2024, the patient experienced grade 1 anemia, grade 1 thrombocytopenia, normal white blood cell count, normal neutrophil count, normal renal function, and grade 1 elevation in liver enzymes (ALT, AST, total bilirubin, rGGT). On July 18, 2024, AFP was 43,319 ng/ml (normal range: 0.00\u0026ndash;25.00), CEA was 15.10 ng/ml (normal range: 0.00\u0026ndash;5.00 ng/ml), CA19-9 was 128 U/ml (normal range: 0.00\u0026ndash;35.00).\u003c/p\u003e \u003cp\u003eOn July 18, 2024, renal function was normal with creatinine. Liver function tests showed grade 1 elevation in ALT, AST, GGT, and LDH. On August 26, 2024, AFP was 41,307 ng/ml (normal range: 0.00\u0026ndash;25.00), CEA was 11.00 ng/ml (normal range: 0.00\u0026ndash;5.00), CA19-9 was 112 U/ml (normal range: 0.00\u0026ndash;35.00), and PIVKA-II was 48.20 ng/ml (normal range: 0\u0026ndash;21.29). On October 18, 2024, alanine aminotransferase was 28 U/L (normal range: 10\u0026ndash;60 U/L), aspartate aminotransferase was 89 U/L (normal range: \u0026le;50), total bilirubin was 29 \u0026micro;mol/L, direct bilirubin was 10.82 \u0026micro;mol/L, indirect bilirubin was 18.18 \u0026micro;mol/L, rGGT was 220 U/L, urea was 4.6 mmol/L, and creatinine was 55 \u0026micro;mol/L. On September 19, 2024, AFP was 45,401 ng/ml (normal range: 0.00\u0026ndash;25.00), CEA was 22.90 ng/ml (normal range: 0.00\u0026ndash;5.00), and CA19-9 was 44.9 U/ml (normal range: 0.00\u0026ndash;35.00).\u003c/p\u003e \u003cp\u003eDue to the unavailability of cabozantinib, third-line treatment with the highly selective MET-TKI glumetinib was initiated. Starting from October 19, 2024, the patient regularly took the oral targeted drug glumetinib (250 mg, once daily) without interruption. Follow-up CT scans at approximately 4 months showed that multiple pulmonary and mediastinal metastases had decreased in size. The hepatic lesions after interventional therapy and the hilar metastatic lesions were similar to the previous findings(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-D). The therapeutic response was partial remission (PR). The patient's symptoms of abdominal pain, bloating, and fatigue significantly improved, and the ECOG performance status was 1. On November 19, 2024, AFP was 10,188.50 ng/ml (normal range: \u0026lt;9 ng/ml).\u003c/p\u003e \u003cp\u003eOn January 17, 2025, AFP was 3000.00 ng/ml, CEA was 6.67 ng/mL, CA-125 was 108.1 U/ml (\u0026le;\u0026thinsp;24), CA19-9 was 18.9 U/mL (\u0026le;\u0026thinsp;25), AFP was 4876.40 ng/ml (\u0026lt;\u0026thinsp;9 ng/ml), and CA19-9 was 23.2 U/mL (\u0026le;\u0026thinsp;25). On February 18, 2025, AFP was 121,901.00 ng/ml.\u003c/p\u003e \u003cp\u003eMore than 5 months after starting glumetinib, a CT scan on March 28, 2025, showed an increase in the size of the pulmonary and mediastinal lesions compared with the previous scan, as well as an increase in the size of the hepatic lesions and the hilar mass, and an increase in the portal vein tumor thrombus. The disease had progressed (PD). The changes in tumor markers during treatment are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE. On April 5, 2025, the patient experienced a rupture and bleeding of the liver cancer and received best supportive care. The patient died on May 1, 2025, due to tumor progression and multiple organ failure. The progression-free survival (PFS) for third-line glumetinib monotherapy was 5.4 months, Duration of response(DOR) was 4 months and the overall survival (OS) was 6.5 months. The main adverse reactions during targeted MET-TKI therapy were grade 2 anemia and grade 2 thrombocytopenia,no abnormalities in ALT, AST, bilirubin, creatinine,or urea were observed.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSummary:\u003c/h3\u003e\n\u003cp\u003eThis case involved a middle-aged male patient with advanced metastatic massive hepatocellular carcinoma (HCC), BCLC C, CNLC IIIb, and Child-Pugh A. Next-generation sequencing (NGS) revealed focal copy number amplification of the MET gene. First-line treatment with PD-1 inhibitor plus lenvatinib was initiated on May 31, 2024. After two cycles, enhanced CT showed an increase in the number and size of hepatic and pulmonary lesions, indicating disease progression. The PFS for first-line treatment was 1.4 months. Second-line treatment with three cycles of atezolizumab plus bevacizumab was started on July 13, 2024, along with interventional therapy for hepatic metastases, including three sessions of hepatic arterial infusion chemotherapy with the FOLFOX regimen and one session of lipiodol embolization. Enhanced CT on October 18, 2024, showed an increase in the number and size of pulmonary metastases, indicating disease progression. The PFS for second-line treatment was 3.3 months. Given the detection of MET amplification, glumetinib (250 mg, once daily) was initiated on October 19, 2024. After treatment, the patient's symptoms of fatigue, ascites, hepatic encephalopathy, and cancer pain significantly improved. Follow-up enhanced CT scans of the chest and abdomen at 1 and 3 months showed a significant reduction in the size and number of pulmonary metastases, as well as a decrease and disappearance of ascites. The therapeutic response was partial remission (PR). On March 28, 2025, follow-up scans indicated disease progression. The PFS for third-line glumetinib monotherapy was 5 months(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). The safety profile during treatment was good, with grade 2 anemia and grade 2 thrombocytopenia occurring during targeted therapy. These resolved after symptomatic treatment. There were no decreases in white blood cells or neutrophils, and no abnormalities related to targeted therapy were observed in ALT, AST, total bilirubin, or creatinine. The patient died on May 1, 2025, due to tumor progression, liver cancer rupture and bleeding, and multiple organ failure.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e \u003cp\u003eGeneral Information\u003c/p\u003e \u003c/p\u003e \u003cp\u003ePatient 2, a 52-year-old male, presented with persistent colicky pain in the epigastric and subxiphoid region on February 20, 2024, without fever, jaundice, nausea, or vomiting. MRI suggested a nodule in the lower segment of the right posterior lobe of the liver, with a high suspicion of hepatocellular carcinoma (HCC). On March 11, 2023, the patient underwent laparoscopic partial hepatectomy (S6 segment liver cancer resection\u0026thinsp;+\u0026thinsp;S4/8 segment liver mass resection\u0026thinsp;+\u0026thinsp;S4 segment hepatic hemangioma resection) and laparoscopic cholecystectomy under general anesthesia. Pathological biopsy on March 18, 2024, c, with necrosis and individual vascular tumor thrombi, but without capsular invasion, immunohistochemistry revealed high c-MET protein expression(Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA-D). Past medical history: unremarkable. Personal history: never smoked; occasional alcohol consumption.\u003c/p\u003e \u003cp\u003eInitial Diagnosis:Liver cancer (mixed moderately differentiated hepatocellular carcinoma and poorly differentiated cholangiocarcinoma, T1bN0M0 Ib, CNLC Ia, BCLC A), Hepatitis B virus carrier.\u003c/p\u003e \u003cp\u003eFrom April 11 to May 25, 2024, the patient received two cycles of hepatic arterial infusion chemotherapy (HAIC) combined with transarterial embolization (TAE) and PD-1 inhibitor. The HAIC regimen was FOLFOX (oxaliplatin 150 mg\u0026thinsp;+\u0026thinsp;leucovorin 360 mg\u0026thinsp;+\u0026thinsp;fluorouracil 0.7 g\u0026thinsp;+\u0026thinsp;4.25 g arterial pump infusion).\u003c/p\u003e \u003cp\u003eOn August 24, 2024, follow-up CT revealed tumor recurrence and metastasis: new enlarged abdominal lymph nodes, consistent with disease relapse and peritoneal metastasis .\u003c/p\u003e \u003cp\u003eFirst-line systemic therapy was initiated on 28 August 2024 and comprised pembrolizumab 200 mg, lenvatinib 8 mg once daily, oxaliplatin 150 mg, and gemcitabine 1,800 mg every 3 weeks. After two cycles, CT demonstrated new pulmonary metastases and progressive intra-abdominal disease; progression-free survival (PFS) was 1.5 months.\u003c/p\u003e \u003cp\u003eSecond-line treatment, started on 15 October 2024, consisted of pembrolizumab 200 mg, lenvatinib 8 mg once daily, and modified FOLFOX (oxaliplatin 146 mg, levofolinate 343 mg, bolus 5-fluorouracil 680 mg followed by 4.12 g continuous infusion over 46 h). Two cycles later, imaging showed new hepatic, pulmonary, and peritoneal lesions; tumor-related abdominal pain, distension, lower-limb oedema, and fatigue worsened. PFS remained 1.5 months.\u003c/p\u003e \u003cp\u003eThird-line therapy commenced on 29 November 2024 with pembrolizumab 200 mg, FOLFOX (oxaliplatin 150 mg, levofolinate 343 mg, 5-fluorouracil 680 mg bolus plus 4.12 g infusion), and regorafenib 80 mg once daily. On 5 December, 2024, NGS disclosed MET amplification (gene copy number 13.58), together with pathogenic variants in TP53, AMER1, TERT, and AXIN1; microsatellite-stable status and low tumor mutational burden (3.33 Mut/Mb). Consequently, on 27 December 2024, the regimen was intensified to include gemcitabine 1,000 mg, oxaliplatin 100 mg, irinotecan 180 mg, tislelizumab 200 mg, and MET tyrosine-kinase inhibitor savolitinib 300 mg once daily for four cycles. Re-evaluation 2.5 months later demonstrated a partial response (PR) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA\u0026ndash;D). Concurrently, serum α-fetoprotein and carcinoembryonic antigen declined substantially (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eE). PFS exceeded 5 months. Throughout chemotherapy, immunotherapy, and MET-TKI treatment, the only significant adverse event was grade 1 anaemia, which resolved promptly with supportive care, no drug-related elevations in alanine aminotransferase, aspartate aminotransferase, total bilirubin, or creatinine were observed.\u003c/p\u003e \u003cp\u003eIn summary, this middle-aged male with resected mixed HCC\u0026ndash;intrahepatic cholangiocarcinoma relapsed 5 months after surgery. Conventional regimens incorporating PD-1 blockade, anti-angiogenic agents, and cytotoxics produced rapid progression (PFS 1.5 months for both first- and second-line). Identification of MET amplification prompted the addition of savolitinib to chemotherapy and immunotherapy, resulting in objective tumour regression (PR), symptomatic improvement, and durable disease control (PFS\u0026thinsp;\u0026gt;\u0026thinsp;5 months) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eE). Prior immunotherapies, locoregional interventions and cytotoxic regimens failed to achieve disease control. The introduction of the highly selective MET tyrosine-kinase inhibitor savolitinib in combination with immunochemotherapy resulted in durable tumour regression and symptomatic relief, underscoring the antitumour efficacy of MET inhibition in MET-amplified metastatic liver cancer(Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). These findings indicate the clinical value of using high selective MET TKI in MET-amplified metastatic liver cancer refractory to standard systemic therapies. Throughout combination treatment, the only adverse event was grade 1 anaemia, which resolved with conservative management; no drug-related elevations in ALT, AST, total bilirubin or creatinine were observed.\u003c/p\u003e\n\u003ch3\u003eLiterature Review and Survival Analysis\u003c/h3\u003e\n\u003cp\u003eOur case series adds to the limited but growing body of evidence on the clinical activity of selective MET tyrosine kinase inhibitors (MET TKIs) in patients with advanced hepatobiliary cancers harboring MET alterations. Six cases have been reported in the literature, derived from five individual case reports. These include:4 cases of advanced hepatocellular carcinoma (HCC) ; 2 cases of intrahepatic cholangiocarcinoma (iCCA); 1 case of metastatic gallbladder carcinoma[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, one patient with iCCA was included in the report by Wu JH et al. (2024), bringing the total number of unique patients to six, as all other reports describe single individuals. Clinical follow-up data were available for all 6 patients. The affected population primarily consisted of middle-aged adults, with ages ranging from 48 to 67 years; the median age at initiation of MET TKI therapy was 59 years. There was a marked male predominance: 5 out of 6 patients (83%) were male, consistent with the known epidemiological bias in hepatobiliary malignancies.All 6 patients presented with advanced or recurrent disease, either at diagnosis or following prior curative-intent treatment. Upon initiation of MET TKI therapy (crizotinib, savolitinib, or capmatinib), the median progression-free survival (PFS) was 11.0 months (range: 3\u0026ndash;34\u0026thinsp;+\u0026thinsp;months), substantially exceeding historical PFS expectations for standard second-line therapies in these cancers.At the time of last follow-up, 3 out of 6 patients (50%) remained alive, including two individuals who achieved exceptionally durable responses \u0026mdash; one iCCA patient with ZKSCAN1\u0026ndash;MET fusion treated with crizotinib maintained response for over 34 months [Wu JH et al., 2024], and another with MET amplification showed sustained control beyond 16 months(Tabe 1). The median overall survival (OS) after initiation of MET TKI therapy across these 6 patients was 11.8 months (Kaplan-Meier estimate). The survival curve suggesting that a molecularly defined subset may derive long-term benefit from MET inhibition.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy and Safety from Prospective Clinical Trials\u003c/h2\u003e \u003cp\u003eTo contextualize our findings, we reviewed key prospective clinical trials evaluating MET-targeted therapies in advanced hepatocellular carcinoma (HCC). Four major studies have assessed the role of MET inhibition in this setting: the phase III METIV-HCC trial of tivantinib, the phase 1b/2 study of tepotinib, the phase II capmatinib monotherapy trial, and the phase III CELESTIAL trial of cabozantinib\u0026mdash;a multikinase inhibitor with potent anti-MET activity.\u003c/p\u003e \u003cp\u003eThe METIV-HCC trial (NCT01755767), a randomized, double-blind, placebo-controlled phase III study, evaluated tivantinib versus placebo as second-line therapy in 571 patients with MET-high advanced HCC defined by immunohistochemistry (IHC 2+/3+) after sorafenib failure. Contrary to expectations, tivantinib did not improve overall survival (OS): median OS was 8.4 months in the tivantinib arm vs 9.1 months in the placebo group (HR 1.04; 95% CI: 0.85\u0026ndash;1.28; p\u0026thinsp;=\u0026thinsp;0.70). Progression-free survival (PFS) was modestly improved (2.8 vs 2.3 months; HR 0.71; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Objective response rate (ORR) was low at 6%, and disease control rate (DCR) was 62%. Notably, patients receiving tivantinib experienced higher rates of neutropenia, anemia, fatigue, and gastrointestinal symptoms. Subsequent analyses revealed that tivantinib has weak MET-inhibitory activity and may function more as a microtubule disruptor than a true MET TKI, which likely contributed to its lack of efficacy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA randomized phase 1b/2 trial (NCT01988493) evaluated tepotinib versus sorafenib as first-line therapy in 90 Asian patients with advanced hepatocellular carcinoma and MET overexpression (IHC 2+/3+). The combination significantly improved median PFS (2.8 vs 1.4 months; HR 0.52; p\u0026thinsp;=\u0026thinsp;0.006), but did not translate into a significant overall survival benefit (9.3 vs 8.6 months; HR 0.71; p\u0026thinsp;=\u0026thinsp;0.17). Objective response rate was 10.5%, with a disease control rate of 50%. Notably, the combination had a more favorable safety profile, with lower rates of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events (28.9% vs 45.5%) and fewer dose reductions compared to sorafenib monotherapy. These results suggest that adding tepotinib delays progression but does not substantially improve long-term outcomes in IHC-selected patients, highlighting the limitations of immunohistochemistry as a sole biomarker for patient selection.\u003c/p\u003e \u003cp\u003eThe most encouraging results come from a phase II, single-arm trial of capmatinib, a highly selective MET inhibitor, in patients with MET-dysregulated advanced HCC (defined by NGS, FISH, or IHC) regardless of prior therapy (NCT01737827). Among 38 evaluable patients, capmatinib achieved an objective response rate (ORR) of 30% and a disease control rate (DCR) of 64%. Median PFS was 5.2 months (vs 1.9 months in historical controls), and median OS was 10.2 months \u0026mdash; among the highest reported for any targeted agent in biomarker-selected HCC. Safety was manageable: the most common treatment-related AEs were nausea, vomiting, diarrhea, and transient liver enzyme elevations. Only 16% experienced grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, and no treatment-related deaths were reported. This trial provides that selective MET inhibition can induce meaningful tumor regression in molecularly defined subsets, particularly those with high-level amplification or functional fusions.\u003c/p\u003e \u003cp\u003eAlthough not a dedicated MET-targeted trial, the phase III CELESTIAL study (NCT01908426) of cabozantinib in previously treated advanced HCC demonstrated a median OS of 11.3 months vs 7.2 months with placebo (HR 0.76; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with corresponding improvements in PFS (5.2 vs 1.9 months) and ORR (4%) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Cabozantinib is a multi-target TKI inhibiting VEGFR2, MET, and AXL \u0026mdash; all implicated in HCC pathogenesis. While the trial did not select patients based on MET status, exploratory analyses suggested enhanced benefit in subgroups with elevated phospho-MET or HGF levels. Common AEs included hypertension, fatigue, diarrhea, hand-foot skin reaction (HFSR), and hepatic enzyme elevation \u0026mdash; consistent with its broad target profile. Approximately 60% required dose reductions due to toxicity.\u003c/p\u003e \u003cp\u003eIn patients with genuine functional MET alterations\u0026mdash;such as high-level gene amplification or oncogenic fusions\u0026mdash;and when treated with highly selective MET inhibitors, can significant clinical responses be observed. Our case series further validates this paradigm, demonstrating that high selective MET tyrosine kinase inhibitors (such as glutimatinib and savolitinib) can achieve durable responses in real-world patients even after multiple lines of prior therapy.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs an oncogene, MET mutations are generally associated with poor prognosis in lung adenocarcinoma, pulmonary sarcomatoid carcinoma, and cancers of unknown primary (CUPs) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The incidence of MET genomic alterations across various tumor types\u0026mdash;including renal cancer, hepatobiliary cancers, colorectal cancer, ovarian cancer, breast cancer, and prostate cancer\u0026mdash;is approximately 5%, encompassing point mutations, gene amplifications, and exon 14-skipping mutations.[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Notably, the frequency of MET alterations in cancers of unknown primary (CUPs) reaches up to 30%, whereas it is only around 4% in early-stage metastatic cancers[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Patients harboring MET exon 14-skipping mutations have demonstrated favorable antitumor activity and acceptable safety profiles in response to MET inhibitors, such as capmatinib, tepotinib, and savolitinib[\u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study presents two cases of metastatic hepatocellular carcinoma (HCC) patients with MET gene amplification (GCN\u0026thinsp;\u0026gt;\u0026thinsp;10). Previous standard treatments, including immunotherapy, anti-angiogenic therapy, and chemotherapy, showed limited efficacy. Subsequent treatment with highly selective MET tyrosine kinase inhibitors (TKIs), either as monotherapy or in combination with chemotherapy, resulted in significant clinical benefits, achieving partial responses (PRs) in both patients. The durations of response (DOR) were \u0026ge;\u0026thinsp;4 months, respectively. Major adverse events included grade 2 hematologic toxicities such as anemia and thrombocytopenia, which were generally manageable. Similar results have been reported in case studies. A 35-year-old male patient with HCC treated with savolitinib as first-line therapy experienced a significant reduction in tumor marker levels and achieved PR within two months. This patient maintained PR status for nearly one year[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. For multi-targeted agent cabozantinib, it also demonstrates certain efficacy in the second-line treatment of hepatocellular carcinoma.\u003c/p\u003e \u003cp\u003eThe CELESTIAL phase III trial demonstrated that among previously sorafenib-treated advanced HCC patients (n\u0026thinsp;=\u0026thinsp;707), median progression-free survival (PFS) and overall survival (OS) were 5.2 months and 10.2 months in the cabozantinib group, compared to 1.9 months and 8.0 months in the placebo group, respectively. Disease control rate (DCR) and objective response rate (ORR) were 64% and 4%, respectively, in the cabozantinib group, versus 33% and \u0026lt;\u0026thinsp;1% in the placebo group [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In the COSMIC-312 study, untreated HCC patients receiving single-agent cabozantinib had a median PFS of 5.8 months[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. In the CheckMate 040 phase I/II trial, the median duration of response for nivolumab plus ipilimumab was 7.1 months (95% CI: 3.9\u0026ndash;13.6 months), and for nivolumab, cabozantinib, plus ipilimumab, it was 7.8 months (95% CI: 3.3\u0026ndash;11.5 months) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Furthermore, MET gene amplification occurs in approximately 10% of gastric cancers. Savolitinib monotherapy in MET-amplified gastric and gastroesophageal junction adenocarcinoma (GC/GEJ) patients achieved an ORR of 45%, with a 50% response rate in those with high MET copy numbers[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] [\u003cspan additionalcitationids=\"CR47 CR48 CR49\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. These data suggest that MET TKIs can effectively control MET-amplified solid tumors.\u003c/p\u003e \u003cp\u003eHowever, whether MET gene amplification benefits from MET-TKI treatment remains controversial. One reason is that MET amplification includes whole chromosome duplication (aneuploidy) and focal gene region duplication (focal amplification). Focal amplification is typically considered a driver of cancer, while the oncogenicity of aneuploidy is debatable, showing poor response to MET inhibitors alone. Therefore, distinguishing between polyploidy and focal amplification may be crucial for ensuring the efficacy of MET inhibitors [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Polyploidy involves an increase in the copy number of genes on chromosome 7, often accompanied by co-amplification of neighboring genes such as EGFR, CDK6, and BRAF. Therefore, a study proposed using next-generation sequencing (NGS) to simultaneously examine the amplification of genes on chromosome 7 (such as BRAF and CDK6) to distinguish polyploidy from focal MET amplification. If there is no co-amplification of neighboring genes (such as CDK6 or BRAF), the MET gene is classified as focal amplification. Conversely, non-focal MET amplification is defined as MET copy number increases associated with polyploidy, where MET copy numbers increase along with CDK6 and/or BRAF[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]Another reason why not all patients with focal amplification may benefit from MET-TKI treatment could depend on the threshold set for amplification[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. The PROFILE 1001 study indicated that MET-amplified NSCLC patients treated with crizotinib had limited efficacy when MET/CEP\u0026thinsp;\u0026ge;\u0026thinsp;2.0, but the efficacy of MET-TKIs increased with higher levels of MET amplification. Specifically, crizotinib treatment in MET-amplified (MET/CEP7\u0026thinsp;\u0026ge;\u0026thinsp;5) patients achieved an objective response rate (ORR) of 40%, with higher amplification levels leading to more significant efficacy[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].A MET gene copy number (GCN)\u0026thinsp;\u0026ge;\u0026thinsp;10 is considered a critical threshold for effective MET-TKI treatment. When GCN\u0026thinsp;\u0026ge;\u0026thinsp;10, MET protein expression significantly increases, enhancing tumor cell dependency on the MET signaling pathway (\"oncogene addiction\"), thereby making MET inhibition more effective in blocking tumor growth[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. At GCN\u0026thinsp;\u0026ge;\u0026thinsp;10, MET amplification becomes a primary driver, with tumor survival highly dependent on MET signaling [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Single-agent TKI can significantly inhibit proliferation. GCN\u0026thinsp;\u0026ge;\u0026thinsp;10 leads to sustained MET phosphorylation, activating the ERBB3/PI3K pathway and bypassing EGFR inhibition (especially in EGFR-mutant resistant patients)[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. MET-TKIs can block ERBB3 phosphorylation, restoring drug sensitivity. In cases of low GCN (\u0026lt;\u0026thinsp;10), MET may only be co-amplified or coexist with other driver genes (such as EGFR), requiring combination targeted therapy (e.g., EGFR-TKI\u0026thinsp;+\u0026thinsp;MET-TKI) to overcome resistancel[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e].Focal MET amplification at GCN\u0026thinsp;\u0026ge;\u0026thinsp;10 suggests that MET is an independent driver gene, making it sensitive to single-agent TKI. Polyploidy is more common when GCN\u0026thinsp;\u0026lt;\u0026thinsp;10, where MET is not a primary driver, limiting the efficacy of TKIs[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. The GEOMETRY mono-1 study showed that capmatinib treatment in MET-amplified NSCLC had an ORR of 40% (95% CI: 16\u0026ndash;68%) in treatment-naive patients and 29% (19\u0026ndash;41%) in previously treated patients, establishing GCN\u0026thinsp;\u0026ge;\u0026thinsp;10 as a core criterion for selecting patients likely to benefit from MET-TKI[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Tepotinib treatment in NSCLC patients with GCN\u0026thinsp;\u0026ge;\u0026thinsp;10 had an ORR of 40\u0026ndash;60%, whereas the ORR was only 7\u0026ndash;12% in the GCN\u0026thinsp;\u0026lt;\u0026thinsp;10 group, indicating significantly reduced efficacy. The TATTON study suggested that in NSCLC, patients with GCN\u0026thinsp;\u0026gt;\u0026thinsp;5 responded better to MET-TKIs, but the response rate (60%) and median PFS (7.3 months) were further enhanced in the GCN\u0026thinsp;\u0026ge;\u0026thinsp;10 group.\u003c/p\u003e \u003cp\u003eIn this study, two patients with metastatic hepatocellular carcinoma (HCC) exhibiting MET amplification or focal amplification (GCN\u0026thinsp;\u0026gt;\u0026thinsp;10) were analyzed. One patient, from whom tissue samples were obtainable, exhibited no response to combined immunotherapy and chemotherapy. Subsequent addition of the MET TKI savolitinib resulted in a significant therapeutic effect, achieving a partial response (PR). The patient was then maintained on savolitinib monotherapy for two months, with the PR confirmed. Further MET immunohistochemistry (IHC) analysis revealed strongly positive MET expression in tumor tissues. Significant tumor regression was observed following treatment with MET TKI monotherapy or combination chemotherapy. During tumor progression, a re-biopsy performed on a patient failed to detect MET amplification via NGS, indicating that the loss of this driver gene alteration or clonal selection could be a potential mechanism of resistance to MET-TKIs. Regarding adverse events, both patients experienced hematologic toxicities including anemia and thrombocytopenia. The treatments were well-tolerated overall, with all adverse events being manageable. These findings suggest that MET-TKIs administered at standard therapeutic doses exhibit an acceptable safety profile in metastatic liver cancer.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings indicate that patients with focal MET amplification in advanced HCC may benefit from MET-TKI targeted therapy with manageable safety profiles. Due to the small sample size, larger prospective studies are needed to confirm the role of MET-TKIs in HCC and to establish criteria for selecting patients who will benefit from these therapies. Additionally, further research is required to explore the predictive value of immunohistochemistry for MET amplification and therapeutic response.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical approval were approved by Medical Ethics Committee, Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSU) (No.SYSKY-2023-622-01). All procedures complied with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from each patient or their legal guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e: The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Natural Science Foundation of China (Grant No. 81702762); Science and Technology Projects in Guangzhou (Project No. 2023A04J2105)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJingshu Wang: Conceptualization, methodology, investigation, writing, funding acquisition, original draft preparation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eXinxin He: Conceptualization, investigation, writing, original draft preparation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWei Chen: Methodology, investigation, writing, funding acquisition- original draft preparation.\u003c/p\u003e\n\u003cp\u003eJunyu Zhu: Formal analysis, visualization.\u003c/p\u003e\n\u003cp\u003eJianwei Liao: Investigation, resources, writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eYuanyuan Yin: Investigation, resources, writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eQiong Yang: Supervision, funding acquisition, writing - review \u0026amp; editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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Proc Natl Acad Sci U S A. 2007;104(52):20932\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeldt SL, Bestvina CM. The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications. Cancers (Basel) 2023, 15(11).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReita D, Pabst L, Pencreach E, Guerin E, Dano L, Rimelen V, Voegeli AC, Vallat L, Mascaux C, Beau-Faller M. Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring. \u003cem\u003eCancers (Basel)\u003c/em\u003e 2021, 13(19).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumaki Y, Oda G, Ikeda S. Targeting MET Amplification: Opportunities and Obstacles in Therapeutic Approaches. Cancers (Basel) 2023, 15(18).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Liver cancer, MET amplification, Targeted therapy","lastPublishedDoi":"10.21203/rs.3.rs-8898860/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8898860/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo investigate the efficacy of highly selective MET-TKIs, targeting met exon14 skipping muation, in patients with hepatobiliary carcinoma harboring MET amplification.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eClinical data from two patients with advanced metastatic hepatobiliary carcinoma and MET gene amplification were collected. Literature review was conducted to analyze the clinical characteristics of the patients, the efficacy and safety of MET inhibitor targeted therapy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwo middle-aged male patients with metastatic hepatobiliary carcinoma, who had poor response to multiple lines of targeted therapy, chemotherapy, and immunotherapy, achieved partial response lasting more than 5 months by treating with single-agent MET-TKI with or without combination of chemotherapy/immunotherapy. During the treatment, both patients had good safety profiles. Grade 2 anemia and Grade 1 thrombocytopenia occurred during MET-TKI therapy, but both resolved after symptomatic treatment. No decrease in white blood cells or neutrophils was observed, and no abnormalities in ALT, AST, total bilirubin, or creatinine related to targeted therapy were noted.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFor patients with advanced metastatic liver cancer and MET amplification, MET-TKI targeted therapy can significantly control disease progression and has a good safety profile, which deserved further study.\u003c/p\u003e","manuscriptTitle":"MET-TKIs selectively inhibit growth of hepatobiliary carcinoma harboring high copy number MET amplification: 2 cases and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:31:34","doi":"10.21203/rs.3.rs-8898860/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-10T06:47:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T04:53:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294581198303989196048013476808070500903","date":"2026-04-12T08:37:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-10T03:05:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-19T04:37:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-18T06:09:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Surgical Oncology","date":"2026-02-17T07:59:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1d0516c9-c20a-4c04-9c67-91956dd40fc6","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-10T06:47:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T04:53:58+00:00","index":17,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-10T06:55:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:31:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8898860","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8898860","identity":"rs-8898860","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}