MET exon 14 mutation

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.

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.

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).

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.

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

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.

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

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.

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.

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.

METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.

The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in patients with pulmonary sarcomatoid carcinoma in clinical practice, and some patients achieved long survival times after receiving targeted therapy. Further investigation is necessary to evaluate the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma.

TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. $$table_{7740CBC2-774F-48DA-932A-077113E7FED5}$$

TEs occurred later with EGFR and ALK , while earlier with ROS1 or KRAS with STK11, KEAP1 or SMARCA4 co-mutations compared to those with KRAS mutations alone. Cumulative incidence of venous and arterial TEs % 0 6 weeks 6 months 1 year 2 years 3 years Overall 2.8 6 11.7 15.8 21.5 26.2 ALK 5.3 10.7 12 14.8 14.8 17 BRAF 2.1 5.8 12.9 16.3 19.5 27.9 EGFR 2 5.8 10.2 14 17.9 23 HER2 0 3.5 7.2 9.2 19.5 23 KRAS 2.7 5.1 11.3 15.3 22.5 27.1 MET 14 6.8 11.3 21.2 21.2 23.9 27.7 RET 13.3 23.3 33.3 36.6 44.5 50.1 ROS1 12 20 34.2 34.2 45.1 53.3

Importantly, co-occurrence of rare fusions and EGFR classical activating mutations in patients pre-treated with anti-EGFR therapy suggests a potential resistance mechanism and consideration of upfront, dual mutation, targeted treatment to improve outcomes. Further clinical studies are needed to validate the best treatment options for these patients with rare fusions.

Conclusions : The integration of ODxTT alongside single gene tests provides significant additional information without compromising the performance of single gene tests. With ODxTT's high success rate, this integration expands the scope of comprehensive therapeutic strategies for advanced lung cancer.

However, NGS had a 12-day longer TAT compared to EGFR PCR. Gene fusion-panel PCR and NGS identified an additional 11.6% of patients harboring actionable alterations who may benefit from FDA-approved targeted therapies.

High ERBB3 expression was associated with better survival. These data support the role of HER3 as a viable therapeutic target across multiple molecular subsets.

This study represents one of the largest prospective cohorts of ctDNA assessment in patients with early stage resected NSCLC. Non-shedding patients were less likely to be male, current smokers, have PD-L1 high tumours, and were more likely to have an identifiable driver mutation. As data matures, we will be able to characterize non-shedding patients whom are at high risk of relapse and offer personalized approaches to escalation of treatment.

P1/2, N=111, Ongoing, Regeneron Pharmaceuticals, Inc.

Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status.

Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations.