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Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2–8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3–19 months.

Background/Objectives: Mesenchymal–epithelial transition (MET) gene amplification is a critical biomarker in non-small cell lung cancer (NSCLC), significantly influencing treatment decisions and prognostic evaluations. However, current detection methods such as fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) have limitations in speed, cost, and specificity, particularly when distinguishing between focal MET amplification and MET polysomy. Methods: This study introduces a novel digital PCR (dPCR) assay designed not only to detect MET amplification but also to differentiate between its focal and non-focal subtypes. The assay was evaluated against established FISH and targeted NGS panels using 55 NSCLC samples with known MET amplification statuses (26 positive and 29 negative) confirmed by FISH and NGS. Results The dPCR assay demonstrated high sensitivity (96.0%) and specificity (96.7%), achieving 100% concordance with FISH in differentiating focal MET amplification from MET polysomy. Additionally, the assay exhibited excellent precision, accuracy, and linearity (R2 = 1.00) in MET copy number quantification, surpassing NGS in diagnostic performance. Offering a robust, cost-effective, and efficient alternative to FISH, the dPCR assay significantly reduces the turnaround time (3 h versus 2 days) and provides a quantitative and objective method for MET amplification detection and subtype differentiation. This makes it suitable for clinical laboratories with limited molecular expertise. Conclusions: This study highlights the potential of the dPCR assay to complement existing molecular diagnostic techniques, delivering reliable and actionable results for MET-targeted therapy selection in NSCLC patients and thereby advancing precision oncology.

Background: Prediction of resistance mechanisms for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) remains challenging. Thus, we investigated whether resistant cancer cells that expand shortly after EGFR-TKI treatment would eventually cause the resistant phenotype. Methods: We generated two EGFR-mutant lung cancer cell lines resistant to gefitinib (PC9GR and HCC827GR). The parent cell lines were exposed to short-term treatment with gefitinib or paclitaxel and then were assessed for EGFR T790M mutation and C-MET expression. These experiments were repeated in vivo and in clinically relevant patient-derived cell (PDC) models. For validation in clinical cases, we measured these gene alterations in plasma circulating tumor DNA (ctDNA) before and 8 weeks after starting EGFR-TKIs in four patients with EGFR-mutant lung cancer. Results: T790M mutation was only detected in the PC9GR cells, whereas C-MET amplification was detected in the HCC827GR cells. The T790M mutation level significantly increased in PC9 cells after short-term treatment with gefitinib but not in the paclitaxel. C-MET mRNA expression was only significantly increased in gefitinib-treated HCC827 cells. We confirmed that the C-MET copy number in HCC827 cells that survived after short-term gefitinib treatment was significantly higher than that in dead HCC827 cells. These findings were reproduced in the in vivo and PDC models. An early on-treatment increase in the plasma ctDNA level of these gene alterations was correlated with the corresponding resistance mechanism to EGFR-TKIs, a finding that was confirmed in post-treatment tumor tissues. Conclusions: Early on-treatment kinetics in resistance-related gene alterations may predict the final mechanism of EGFR-TKI resistance.

Background Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (EBV‐posDLBCL) is an aggressive B‐cell lymphoma that often presents similar morphological and immune phenotype features to that of EBV‐negative DLBCL (EBV‐negDLBCL). Aims and Methods To better understand their difference in genomic landscape, we performed whole‐exome sequencing (WES) of EBV‐posDLBCL and EBV‐negDLBCL. Results This analysis revealed a new mutational signature 17 (unknown) and signature 29 (smoking) in EBV‐posDLBCL as well as a specific mutational signature 24 (associated with aflatoxin) in EBV‐negDLBCL. Compared with EBV‐negDLBCL, more somatic copy number alterations (CNAs) and deletions were detected in EBV‐posDLBCL (p = 0.01). The most frequent CNAs specifically detected in EBV‐posDLBCL were gains at 9p24.1 (PDL1 and JAK2), 8q22.2‐q24.23 (DEPTOR and MYC), and 7q31.31‐q32.2 (MET), which were validated in additional EBV‐posDLBCL cases. Overall, 53.7% (22/41) and 62.9% (22/35) of the cases expressed PD‐L1 and c‐MET, respectively, in neoplastic cells, whereas only 15.4% (4/26) expressed c‐MYC. Neoplastic c‐MET expression was positively correlated with PD‐L1 (p < 0.001) and MYC expression (p = 0.016). However, EBV‐posDLBCL cases did not show any differences in overall survival between PD‐L1‐, c‐MET‐, or c‐MYC‐positive and ‐negative cases or between age‐related groups. Analysis of the association between somatic mutation load and EBV status showed no difference in the distribution of tumor mutant burden between the two lymphomas (p = 0.41). Recurrent mutations in EBV‐posDLBCL implicated several genes, including DCAF8L1, KLF2, and NOL9, while in EBV‐negDLBCL, ANK2, BPTF, and CNIH3 were more frequently mutated. Additionally, PIM1 is the most altered gene in all the WES‐detected cases. Conclusions Our results confirm that genomic alteration differs significantly between EBV‐posDLBCL and EBV‐negDLBCL, and reveal new genetic alterations in EBV‐posDLBCL. The positive correlation of c‐MET and PD‐L1/c‐Myc expression may be involved in the pathogenesis of EBV‐posDLBCL, which is should be explored prospectively in trials involving MET‐directed therapies. Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (EBV‐posDLBCL) is an aggressive B‐cell lymphoma that often presents similar morphological and immune phenotype features to that of EBV‐negative DLBCL (EBV‐negDLBCL). To better understand the difference in genomic landscape, we performed whole‐exome sequencing (WES) of EBV‐posDLBCL and EBV‐negDLBCL. Thr results confirm that genomic alteration differs significantly between EBV‐posDLBCL and EBV‐negDLBCL and reveal new genetic alterations in EBV‐posDLBCL. The positive correlation of c‐MET and PDL1/c‐Myc expression may be involved in the pathogenesis of EBV‐posDLBC, which is should be explored prospectively in trials involving MET‐directed therapies.

Carcinomas of unknown primary (CUPs) have poor prognosis due to the paucity of data on their clinical characteristics and laboratory features, and empirical chemotherapy still remains the critical management for this kind of disease. This study aimed to present the knowledge of treating an elderly man with metastatic adenocarcinoma of unknown primary and also with a history of long-term hypertension and renal cysts. He was identified to harbor mesenchymal-epithelial transition factor (MET) gene amplification and neurotrophic tyrosine receptor kinase 1 (NTRK1) gene co-occurring mutation by targeted next-generation sequencing analysis upon the progression of empirical chemotherapy. He was then treated with a standard dose of crizotinib (250 mg, twice daily), which exhibited a satisfactory complete response (CR) of the targeted lesions after 1 month of treatment. When the number of renal cysts increased and renal inadequacy occurred after treatment for 2 months, crizotinib was reduced to half-dose (250 mg, once daily), and still conferred maintenance of CR for another 6.5 months and good quality life of the patient. These results suggested that treatments based on driver genes rather than primary tumor types could be a promising manipulation for achieving better treatment outcome, and a half-dose of crizotinib might be both effective and tolerable for MET-overexpressed CUPs with underlying renal diseases.

Capmatinib is an oral, ATP‐competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose‐escalation results for capmatinib in advanced MET‐positive solid tumor patients and dose expansion in advanced non‐lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose‐limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c‐MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose‐expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near‐complete immunohistochemically determined phospho‐MET inhibition (H‐score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high‐level MET GCN (GCN ≥6) and MET‐overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479). MET dysregulation is an important newly established molecular driver of tumorigenesis in various cancers and is recognized as a negative prognostic factor. The findings of this study provide the recommended phase 2 dose (RP2D) of capmatinib and also safety and efficacy data in selected expansion cohorts treated at the RP2D.

Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the ‘druggable’ molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.

The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification.

Abstract Background Biliary tract cancer (BTC), as a relatively rare tumor, carries a poor prognosis. While immunotherapy combined with chemotherapy can extend survival, response rates remain low. Targeted therapies tailored to specific genetic mutations may improve outcomes when paired with immune checkpoint inhibitors. This report examines 2 cases of advanced BTC with distinct genetic alterations, treated with targeted therapy and immune checkpoint inhibitors, to assess efficacy and feasibility. Case Presentation A 45-year-old patient with a BRAF V600E-mutated intrahepatic cholangiocarcinoma received dabrafenib, trametinib, and durvalumab. This led to significant tumor reduction, enabling complete surgical resection with clear margins. Postoperative analysis showed a major pathological response. A 39-year-old patient with MET-amplified gallbladder cancer was treated with tepotinib, durvalumab, and chemotherapy, resulting in metastases regression and successful tumor downstaging. Surgery achieved no evidence of disease. Conclusions Combining targeted therapies with immune checkpoint inhibitors showed promising results in 2 patients with advanced BTC driven by specific genetic mutations. Significant tumor reduction and successful surgeries suggest this approach may improve resectability and outcomes. These cases highlight the potential of personalized treatment guided by genetic profiling. Further research is needed to confirm these findings and explore broader applications for this strategy.

Seung Hyeun Lee, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University College of Medicine, Kyungheedae-ro 23, Dongdaemun-gu, Seoul, 02447, South Korea, Tel +82 2 958 8511, Fax +82 2 968 1848, Email v3mann@naver.comAbstract: Although mesenchymal–epithelial transition proto-oncogene (MET) amplification is a common resistance mechanism in targeted therapy for lung cancer, rapid disease progression associated with this resistance mechanism in patients with epidermal growth factor receptor (EGFR) mutation has scarcely been reported. Herein, we report a fatal case of lung adenocarcinoma that rapidly progressed after failure of EGFR-tyrosine kinase inhibitor treatment following the emergence of MET amplification. A 62-year-old man was diagnosed with metastatic lung adenocarcinoma containing mutations in EGFR exon L858R and RNA-binding motif 10. He received afatinib as frontline treatment and showed a partial response; however, the right lung lesion progressed after 14 months of treatment. Although the drug was maintained after salvage segmentectomy of the lesion, lung nodules and pleural effusion developed shortly thereafter. Because EGFR testing using resected tissue showed only the original mutation, we switched his regimen to pemetrexed and carboplatin. However, the disease rapidly progressed with a very large mass in the right lung and massive pleural effusion, which led to death within 7 weeks of treatment. Next-generation sequencing was performed at the time of first progression and second progression revealed acquired MET amplification (copy number gain 15.5 and 9.1, respectively) in addition to baseline mutations. Although an association between MET amplification and rapidly progressive lung cancer has been predicted previously, to the best of our knowledge, this is the first report on the potential contribution of other mutations, such as those in RNA-binding motif 10, during MET-driven rapid progression. Our report highlights the importance of more active utilization of molecular profiling for the emergence of resistance during tyrosine kinase inhibitor use and the early identification of MET amplification and timely initiation of MET-targeted therapy, such as MET inhibitors in combination with EGFR-TKIs, to potentially mitigate rapid disease progression and clinical deterioration.