MET fusion

Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added...The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Moreover, our review provides an overview of and recommendations on the selection of various cross-platform technologies for the detection of MET exon 14 skipping variants, MET amplification, MET overexpression, and MET fusion. Furthermore, challenges and hurdles underlying these common detection platforms are discussed.

Since there are many types of MET alterations and related testing methods, as well as many problems and challenges during clinical testing, further sorting and standardization are required. Combined with clinical practice experience, literature review, and expert discussion, the writing group developed this consensus on the three main types of MET alterations (METex14 skipping, MET gene amplification, and MET protein overexpression) in order to guide the practical applications of clinical MET testing.

P1/2, N=180, Active, not recruiting, Turning Point Therapeutics, Inc. | Trial completion date: Nov 2023 --> Mar 2025 | Trial primary completion date: Nov 2023 --> Mar 2025

In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

TOP RNA panel detects more fusions than DNA panel and is utilized not only for the detection of molecular targets but also for the molecular classification of glioma, providing treatments optimized for the individual patients.

P2/3, N=84, Active, not recruiting, Beijing Pearl Biotechnology Limited Liability Company

P2, N=497, Recruiting, Apollomics Inc. | Phase classification: P1/2 --> P2 | N=344 --> 497

P1/2, N=2, Terminated, Criterium, Inc. | N=65 --> 2 | Trial completion date: Jul 2027 --> Jun 2023 | Recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Jun 2023; Study was terminated due to lack of lack of enrollment and difficult patient population.

The cohort’s clinical characteristics contrasted ROS1 -fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

describe the adverse prognostic role of MET fusions and splicing variants in astrocytoma, isocitrate dehydrogenase mutant. On this basis, MET fusions and splicing variants was suggested to be a biomarker for the diagnosis of high-grade astrocytoma, isocitrate dehydrogenase mutant.

Treatment with type 2 (cabozantinib) or type 1 (crizotinib, capmatinib, savolitinib) MET TKIs blocked growth of SJ-GBM2 cells with IC50 values of 0.3, 0.2, 0.1 and 0.04 μM, respectively, reflecting the sensitivity observed in H1993 and EBC1...Conclusions Our findings indicate MET fusions are widely distributed among tumor types and are sensitive to type 1 and type 2 MET TKIs. Clinical trials evaluating MET inhibitors for patients whose cancers are driven by MET fusions are ongoing.

Most pts (84%, 20/24) received a prior MET TKI (crizotinib, n=15; capmatinib, n=4; tepotinib, n=1); 16 pts (67%) and 13 pts (54%) received one or more prior lines of chemotherapy and immunotherapy, respectively...Due to its alternative type II binding mode, cabozantinib can be useful in the treatment of type I TKI resistance. As proof of concept, 3 of 4 responses were observed in patients with type I MET TKI progression.

Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

Conclusions The combination of RNA- and DNA-based NGS provides information about molecular alterations for the management of patients with CNS tumors. Those with actionable gene fusions or other alterations may benefit from target therapy, especially in the setting of limited choice of treatments.

All pts received radiotherapy and temozolomide as first-line...TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), vebreltinib (2 pts), capmatinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts)...We had a dramatic response to a MET inhibitor. Deeper explorations are needed in targeting FGFR e ROS1.

MET fusions are a rare, but potentially actionable, genomic alteration. Our study provides a comprehensive characterization of MET fusions in NSCLC, revealing their diverse fusion partners and co-occurring genomic alterations. Further research is warranted to elucidate the clinical implications of MET fusions in the treatment of various types of cancer, including lung cancer.

To our knowledge, this is currently the largest study in characterizing MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.

If proven effective, this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors.

MET fusions are very rare oncogenic driver events in NSCLC and predominantly appear in adenocarcinomas. They are heterogeneous in terms of fusion partners and breakpoints. Patients with MET fusion can benefit from MET TKI therapy.

P1/2, N=180, Active, not recruiting, Turning Point Therapeutics, Inc. | Recruiting --> Active, not recruiting

The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLE and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.

In this review, current molecular technologies for the detection of the different MET aberrations are highlighted, including the benefits and drawbacks. In the future, another focus will be on the standardization of detection technologies for the delivery of reliable, quick, and affordable tests in clinical molecular diagnostics.

TOP RNA panel is utilized not only for the detection of molecular targets but also for the molecular classification of glioma, both of which is essential for providing treatments optimized for the individual patients.

MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.

MET fusions are rare, and half of the fusion types were intragenic fusions. Lung cancer patients harboring primary or acquired MET fusions could benefit from crizotinib. In addition, EML4-MET was first reported in this study as a novel MET fusion type.

Taken together, our work provided a comprehensive analysis of driver and targetable alterations in SBA, which can facilitate the practice of precision oncology in this challenging disease.

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Jan 2025 | Trial primary completion date: Dec 2023 --> Jan 2025

P1/2, N=180, Recruiting, Turning Point Therapeutics, Inc. | N=330 --> 180 | Trial primary completion date: Nov 2022 --> Nov 2023

Resistance to MET inhibition is heterogeneous with on- and off-target mechanisms occurring regardless of the initial MET aberration. Switching therapy between different types of kinase inhibitors can lead to repeated responses in cases with second-site mutations. Controlled clinical trials in this setting with larger patient numbers are needed, as evidence to date is limited to preclinical data and case series.

Thus, MET aberration was determined to be a factor of response to chemotherapy. Approximately 2.1% and 0.4% of patients with advanced solid tumors demonstrated MET gene amplification and fusion, respectively, and displayed a worse response to chemotherapy and significantly shorter OS and PFS than those without MET gene amplification or fusion.

It seems some of these low-grade cases may transform into a high-grade variant with IFS/MPNST-like morphology as has been observed in other tumors with kinase gene fusions. While most cases seem to follow an indolent clinical course, the recognition of these tumors is clinically relevant as MET tyrosine kinase inhibitors might represent an effective treatment option for clinically aggressive or unresectable cases.

Our findings confirm that SCN-NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.

In addition, we revealed that DNA-based NGS might serve as the clinical test for common MET fusions; however, rare MET fusions must be validated by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the treatment efficacy of MET inhibitors.

We provided a comprehensive genomic landscape of MET rearrangement and updated MET fusions database for clinical test. In addition, we revealed that DNA-based NGS might meet the clinical test for MET common fusions, whereas it was necessary to validate MET rare fusions by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the efficacy of MET inhibitors treatment.

MET amplification and fusion alterations were observed in both low and high grade gliomas, suggesting that they may be involved in early tumorigenesis. Survival outcomes were poor compared with historical data, with no differences observed between treatment groups, suggesting that current therapeutic modalities may be inadequate. This study indicates that MET may be an appropriate therapeutic target, laying the groundwork for clinical trials investigating MET-targeted agents.

P1/2, N=65, Recruiting, Criterium, Inc. | Not yet recruiting --> Recruiting

NOTCH1 and TP53 mutations may be associated with the progression of MSFT. Some patients have FGFR1 gene fusion and MET gene fusion, which may be potential therapeutic targets.