MET amplification

We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

P2, N=109, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Sep 2024

NSCLC patients with MET alterations can benefit from immunotherapy, especially the patients treated by combined ICI therapy. However, special attention should be paid to the occurrence of grade 3/4 adverse reactions while using the combined ICI therapy.

P2, N=9, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | N=70 --> 9 | Trial completion date: Oct 2027 --> Mar 2026 | Trial primary completion date: Oct 2026 --> Mar 2025

Real-world datasets from clinical panel testing revealed the genomic landscape in gastric cancer by subgroup. These findings provide insights for the current therapeutic strategies and future development of treatments in gastric cancer.

P2, N=88, Not yet recruiting, SWOG Cancer Research Network | Initiation date: Feb 2024 --> May 2024

There are three currently active sub-studies and one soon to be activated sub-study studying amivantamab-vmjw in MET amplification positive NSCLC (S1900J). 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...One hundred seventy (7%) 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=751, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Jun 2025

Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6 weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13 weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.

EGFR p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. MET amplification and TP53 mutations were associated with poorer overall survival.

P4, N=200, Recruiting, AstraZeneca | Trial completion date: Mar 2024 --> Jun 2024

TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism.

In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.

At the 24 h time point, clearance from secondary and nontarget tissues was also observed. Altogether, our data suggest that 1E7-Fc represents a platform technology that can be employed to potentially both image and treat MET-altered NSCLC.

This study revealed a heterogeneous landscape of resistance mechanisms to EGFR/MET DTT, with a similar prevalence of on- and off-target mechanisms. Targeted therapy or CT, as compared to BSC, exhibited the potential to improve survival outcomes for patients with advanced NSCLC following resistance to DTT.

cMET and TROP2 were frequently expressed in RET+ aNSCLC, EGFR and HER3 were present in a lower proportion, HER2 was rarely found. These markers were not associated with a prognostic or predictive impact on RETi outcomes. The activity of novel therapeutic agents should be evaluated in this setting.

In LUAD, metastatic specimens exhibit increased chromosomal instability in relation to their matched primaries. This translates into unique copy number alterations detected only in the metastasis. By contrast, driver mutations - which account for most of the clinically targetable alterations with currently approved FDA drugs - are more often shared between paired samples from the same patient.

In addition, the fold changes in ctDNA dynamics during treatment significantly correlated with changes in tumor size and CEA levels, as well as with droplet digital PCR copy number fold changes. In a patient with MET amplification, ctDNA NGS identified MET Y1230H as a potential acquired resistance mutation after crizotinib treatment, which responded to cabozantinib but not to capmatinib.Conclusions Initial tumor profiling using ctDNA NGS yielded outcomes comparable to those of tumor tissue NGS in guiding treatment for patients with newly diagnosed mCRC, thereby suggesting its utility as an initial profiling method in mCRC.

P2, N=60, Suspended, AstraZeneca | Recruiting --> Suspended

EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.

These findings suggest that the therapeutic efficacy of chemotherapy approximates to that of personalized therapy, which signifies that chemotherapy is still a reliable choice for patients who develop resistance to EGFR-TKIs and that further research is awaited to explore the benefit of personalized treatment.

Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET).

This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

P1, N=78, Recruiting, Abion Inc | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.

Notably, a strong correlation was observed between focal amplification and PD-L1 expression, indicating potential therapeutic implications with combined MET inhibitor and immunotherapy for patients with both alterations. Our findings provide insights into the molecular complexity and clinical relevance of METamp in lung cancer, highlighting the role of MET focal amplification as an oncogenic driver and its feasibility as a primary biomarker to further investigate the clinical activity of MET inhibitors in future studies.

One patient received Capmatinib and one patient Pembrolizumab. This study showed that NSCLC with METex14 are poorly differenciated tumors with necrotic background,multinucleation,atypical mitoses,and pleomorphic/sarcomatoid features. Larger studies are needed to confirm our preliminary findings. Routine NGS testing on cytological specimens is feasible and essential for METex14 testing and select patients with advanced lung NSCLC for targeted therapies.

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.

These in vitro findings suggest that compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibits the growth of c-MET-positive GC cells, cells lacking MET amplification but containing phosphorylated MET, and cells containing MET mutations. Clinical studies are required to confirm the therapeutic effects of these regimens.

The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

Actionable alterations were identified in 53.4% of the patients, and KRAS was the most common oncogenic driver alteration. Our study revealed a lower prevalence of patients whose tumor harbors ALK, ROS1, and RET fusions, compared with similar data sets.

Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection.

P2, N=44, Active, not recruiting, Guangdong Association of Clinical Trials | Recruiting --> Active, not recruiting

This tumor thus warrants careful consideration. Accurate diagnosis can greatly improve early diagnosis and treatment of these tumors.

P2, N=219, Active, not recruiting, University of Campania "Luigi Vanvitelli" | Recruiting --> Active, not recruiting

Our results suggest osimertinib and savolitinib combination is most effective for osimertinib resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal MET amplification may be evident in MET polysomy tumor progression, MET polysomy warrants close clinical follow up with phospho-MET IHC in parallel with FISH diagnostic.

Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines...Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

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.

SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy.

The low sensitivity for HER2 amplification may be confounded by the small sample size and disproportionate number of cases with low level amplification. In summary, the NGS assay has good concordance with conventional testing methods but may be less sensitive in detecting low level gene amplification.