MET exon 14 mutation

P=N/A, N=109, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Further large-scale studies are needed to establish links between these mutations and clinical features at baseline and following treatment. Furthermore, moving forward, the development of novel drugs will be essential to fulfill the clinical unmet needs.

Molecular targeted drugs (tepotinib) showed similar efficacy for IMA harboring MET exon 14 skipping mutation to their use for NSCLC. This case suggests the benefit of aggressive multiplex genetic testing in patients with IMA and subsequent treatment with molecular targeted drugs.

We generated a library of sixty PROTACs of which 37 used the MET inhibitor capmatinib as the protein of interest targeting ligand...Curve fitting live cell imaging data affords determination of time required to degrade 50% of the target protein (DT50), which was used in determining structure activity relationships. A promising candidate, 48-284, identified from the screen, exhibited classic PROTAC characteristics, was > 15-fold more potent than SJF8240, had fewer off targets compared to SJF8240, and degraded MET in multiple cell lines.

High c-MET expression and METex14s are common in apocrine carcinoma.

In a discovery application, the UIHC model assigned higher tumor proportion scores to MET amplification cases, but not MET exon 14 splicing or other non-small cell lung cancer cases. This UIHC model represents a novel role for DL that further advances quantitative analysis of IHC.

P2, N=124, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jan 2025 --> Dec 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

P2, N=4, Terminated, Novartis Pharmaceuticals | Completed --> Terminated; The study was terminated early due to recruitment challenges.

P1/2, N=450, Recruiting, DualityBio Inc. | N=280 --> 450 | Trial completion date: Apr 2025 --> Sep 2026 | Trial primary completion date: Apr 2025 --> Sep 2026

This study provides data on the molecular epidemiology of lung adenocarcinoma in Brazil, confirming high prevalence of EGFR mutations, ALK fusions, and MET exon 14 skipping alteration. Biomarker detection is largely affected by biospecimen collection and processing, with one third of the patients eligible for non-NGS testing only, which presents reduced coverage and sensitivity for actionable drivers.

Blood-based LB performed by NGS is a non-invasive viable alternative tool for molecular genotyping and identifiy tumor-derived somatic alterations to increase the number of pts elegible to target therapy and guide personalized medicine.

The study improved the understanding of AdCC providing the first documentation of tumor clinical behavior associated with MYB::MPDZ and FUS::MYB fusions and reporting potentially actionable SEC16A::NOTCH1 fusion and MET exon 14 skipping mutation. Further research is needed to explore the therapeutic utility of MET inhibition and the efficacy of γ-secretase inhibitors against rare NOTCH1 fusions in AdCC.

This report offers a thorough characterization of expected prevalence and expression levels for CSFs and NDFs with an NGS study of a broad scope. We describe ESR1 fusions in a cohort of thousands of breast tumors and show lower median expression levels relative to NDFs such as ALK, ROS1, and RET fusions. Our findings suggest that some CSFs, like ESR1 fusions in breast cancer, may be the result of tandem duplication with upstream partners, and may be subclonal and acquired later in cancer progression.

METex14 results by NGS and RNA STEP gene expression demonstrated strong correlation and were 100% concordant for 370 lung cases (25 positive) with a cut-off of ≥100 METex14 SRs for NGS and a METex14 log2 ratio cut-off of ≥4.0 for RNA STEP. Comparison of METex14 results with 2 assays, NGS and RNA STEP, provided practical insight into cutoffs for METex14 reporting with critical implications for clinical therapeutic decisions.

The OCAv3 assay on the GeneXus System provides a rapid and reliable method for CGP of solid tumors from FFPE samples, enabling the identification of clinically actionable mutations for personalized oncology. Whereas limitations exist in homopolymer regions and coverage variability through all targets, the assay's turnaround time, low input material requirement, and overall performance when using optimal cut-offs support its adoption in clinical practice.

Thus, for variants within the MET gene in patients with NSCLC, particular attention is required to assess for possible intronic variants that may lead to the METex14, especially if only sequencing DNA. The novelty of the intronic variant herein identified is heightened by being a net insertion rather than a deletion, as all reported intronic variants in the Catalogue of Somatic Mutations in Cancer (COSMIC) within this region are deletions. If sequencing DNA and RNA, both the intronic variant and RNA consequence should be used synergistically as evidence for the presence of METex14 skipping variant.

Our standard operating procedure (SOP) was updated to perform orthogonal confirmation testing for stand-alone equivocal NTRK1/2 and equivocal NTRK3 (5' failure), but to ignore equivocal NTRK3 (5' intact) and report as NTRK2/3 indeterminate. Re-verification showed no change to ALK, ROS1, RET, MET ex14, and NTRK1 results. Sensitivity of NTRK2 detection was significantly increased (80% after orthogonal testing).

These data support further clinical testing using the best performing model and development of ASPYRE-Lung blood for liquid biopsy samples.

Emerging structural variants (eSVs) were found to have a combined prevalence to be 0.7%, with only 47.5% of eSVs detected by DNA-NGS. In this cohort study, the detection of structural variants via concurrent RNA-NGS and DNA-NGS was higher across multiple NCCN-guideline recommended biomarkers compared with DNA-NGS alone, suggesting that RNA-NGS should be routinely implemented in the care of patients with advanced NSCLC.

P1, N=250, Recruiting, Mythic Therapeutics | N=150 --> 250

P2, N=88, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

P2, N=90, Recruiting, Lantern Pharma Inc. | Trial completion date: May 2025 --> Jun 2026 | Trial primary completion date: Nov 2024 --> Dec 2025

P2, N=106, Terminated, Gilead Sciences | Active, not recruiting --> Terminated; Sponsor decision to terminate study

P2, N=47, Active, not recruiting, AstraZeneca | Suspended --> Active, not recruiting | Trial completion date: Dec 2024 --> Aug 2025 | Trial primary completion date: Oct 2024 --> Aug 2025

The technology is simple and fast, requiring only four reagent transfer steps using standard laboratory equipment (PCR and qPCR instruments) with analysis via a cloud-based algorithm. The ASPYRE-Lung assay has the potential to be transformative in facilitating access to rapid, actionable molecular profiling of tissue for patients with non-small cell carcinoma.

Current sub-studies: S1900E (KRAS) activated on April 2, 2021 and is studying sotorasib (AMG 510) in non-squamous NSCLC...S1900G (EGFR and MET) activated on April 3, 2023 and is studying capmatinib and osimertinib with or without ramucirumab in NSCLC. S1900K (MET exon 14 skipping) activated on December 18, 2023 and is studying tepotinib with or without ramucirumab in NSCLC. S1900J (MET amplification) is opening fall 2024 and is studying amivantamab in NSCLC...One hundred seventy-four (5%) were submitted with the classification of "Other". The most common reasons included: no sub-studies available, patient chose hospice, and patient transferred to different hospital.

P1, N=56, Completed, Haihe Biopharma Co., Ltd. | Unknown status --> Completed | N=113 --> 56

These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC.

P2, N=56, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

After initial treatment with savolitinib was discontinued due to grade 4 transaminitis, the patient was switched to tepotinib, resulting in significant tumor regression. Postoperative tepotinib continued, with no relapse at 6-month follow-up. This case highlights the potential of tepotinib as neoadjuvant therapy for resectable METex14 skipping-mutated NSCLC, warranting further clinical trials.

P1/2, N=231, Active, not recruiting, Regeneron Pharmaceuticals | N=82 --> 231 | Trial completion date: Oct 2024 --> Jan 2032 | Trial primary completion date: Oct 2024 --> Jan 2032

P2, N=106, Active, not recruiting, Gilead Sciences | Trial completion date: Mar 2025 --> Oct 2024

Co-fusions involved EML4-ALK (1.9%), STRN-ALK (1.2%), and CCDC6-RET (0.7%). Conclusions Comprehensive ctDNA NGS can identify METa and associated co-alterations that may inform therapeutic decisions for patients with AC in AME.

Conclusions Our analysis revealed that this CGP assay can detect actionable and rare alterations with expected frequency with a median TAT of 13 days. Biomarker detection was feasible even when TC<20%.

Known under low incidence – mutations require research for 0.4% to 1.1 in pulmonary adenocarcinomas, IDH1/2 inhibitors prescription due to high prevalence of lung carcinoma worldwide. Mutations in IDH1/2 gene may be branching drivers leading to lower subclonality evolution with predictable benefit of IDH1/2 inhibitors.The accumulation of more known cases with IDH1/2 mutations is necessary to elucidate clinicopathological characteristics/clinical evolution after target therapy, in order to reforce the new interpretation of malignant tumours postponed survival through conversion of cell cycle.

KRAS is an attractive therapeutic strategy due to its high prevalence and its role in initiating and sustaining tumour growth. Approval of KRAS G12C inhibitors in locally advanced or metastatic NSCLC has brought hope to many patients. Studies show that non G12C KRAS mutation are found in 53% of adenocarcinomas.

Oncogenic activation of genes-drivers are responsible for resistance mechanisms either understood has resistance to METtargeted therapies and as primary resistance. Recently it has been reported that PI3K pathway alteration is common in concomitancy with METex14 and believed that confers primary resistance to MET TKI. Early identification of alterations in MET kinase domain at diagnosis, is crucial for understanding progression and resistance mechanism, to develop novel therapies or to design treatment strategies in order to improve patient outcomes.

Our study showed the heterogeneity in PD-L1 expression with respect to major oncogenic drivers in Turkey. KRAS, BRAF, MET mutations and ALK and ROS1 rearrangements were more frequent, while EGFR and HER2 mutations were less frequent compared with the overall PD-L1 expression levels. Molecular testing of non-small cell lung carcinomas (NSCLC) for oncogenic driver mutations has become standard in pathology practice.

Savolitinib showed manageable toxicity and promising efficacy in treatment-naive patients with advanced or metastatic METex14-mutated NSCLC.

No abstract available

These findings also reveal the low uptake of approved targeted therapies when self-funding is required for access. Inclusion of NGS-based genomic profiling and targeted therapies as part of standard of care within the public healthcare system supports appropriate clinical management to optimize patient outcome among those with actionable oncogenic fusions.