MET amplification

P1, N=41, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2028 --> Apr 2026 | Trial primary completion date: Jun 2026 --> Apr 2025

The cellular inhibitory effects of single and co-treatment of CB538 with EGFR-TKIs were evaluated in the established EGFR-TKI-resistant cells [PC9/ER (erlotinib resistance), HCC827/OR (osimertinib resistance)]. Additional treatment with CB538 enhanced sensitivity to EGFR-TKIs in two EGFR-TKI-resistant NSCLC cells by inhibiting EGFR/MET/Axl pathway axis. Overall, the treatment effects of CB538 were confirmed to relieve EGFR-TKI-driven resistance in EGFR-mutant NSCLC cells.

Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014-000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

This consensus addresses key areas, such as optimal testing timing, testing methods, testing strategies, quality control measures, and treatment approaches. By offering standardized recommendations, this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.

The tumor immune microenvironment (TIME) of EGFR-mutated LUSC showed a downregulation of CD4 (p = 0.047) and CD8 (p = 0.14), and an upregulation of PD-L1 (p = 0.0021) after EGFR-TKI treatment failure. EGFR-mutated LUSC patients receiving EGFR-TKIs treatment had higher ORR and longer PFS than EGFR wild-type LUSC patients.

Key PT signals included protein deficiency, scrotal edema, and chylothorax for capmatinib; edema and decreased blood albumin for tepotinib; and abnormal hepatic function for savolitinib. The study highlights differences in the safety profiles of Type Ib MET TKIs, underscoring the need for further regulatory review and possible updates to product labels to better inform clinicians and patients.

P2, N=43, Completed, Shandong First Medical University and Shandong Academy of Medical Sciences (Shandong Cancer Hospital Institute); Shandong First Medical University an

This review explores the history and pathophysiology of the MET pathway by focusing on METex14 skipping, and highlights insights gained since its discovery. Both unsuccessful and successful treatments that have emerged alongside the evolution of next-generation sequencing are examined, as well as current approved therapies and future options that target potential resistance mechanisms.

P1, N=50, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | Trial completion date: Jun 2028 --> Jun 2026

Our single-center experience demonstrates that advances in the field of targeted NSCLC therapy are quickly incorporated into clinical routine in Germany. Noteworthy, no new safety information was found.

Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized a panel of experts to provide professional recommendations on current clinical issues in the diagnosis and treatment of MET-aberrant NSCLC, combining clinical practice experiences and evidence-based medical evidences. The "Expert Consensus on Diagnosis and Treatment of NSCLC with MET Abnormalities (2025 Version)" has been formulated to provide standardized guidances for clinical practice in China, with the aim of optimizing the treatment outcomes..

P1, N=111, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2025 --> Dec 2027 | Trial primary completion date: Sep 2025 --> Dec 2027

Recent trials support the predictive value of ctDNA-defined negative hyperselection, revealing superior outcomes for patients stratified through liquid biopsy. This narrative review explores the evolving role of molecular hyperselection in first-line anti-EGFR therapy, emphasizing the integration of ctDNA to refine patient selection, enhance therapeutic efficacy, and pave the way for personalized treatment strategies in metastatic CRC.

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.

Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.

Liquid biopsy is a transformative tool in NSCLC management, offering a minimally invasive approach for mutation detection, disease monitoring, and treatment guidance. Future research should focus on multicenter trials and emerging technologies to enhance clinical integration and broaden applicability across different cancer types.

We propose that patients with EGFR Ex19del mutation and MET de novo amplification may benefit more from dual-targeted therapy than pemetrexed and carboplatin chemotherapy along with bevacizumab. Timely intervention is needed to avoid greater harm when ILD occurs and, when ILD is effectively controlled, seize the opportunity to rechallenge the dual-targeted therapy may contribute to a better prognosis. In addition, the patients with targeted-induced ILD in the past need more rigorous monitoring and follow-up in the process of rechallenging the targeted drug therapy.

This case underscores the importance of re-challenge using third-generation EGFR-TKI with novel MET-TKI after the failure of second-generation EGFR-TKI plus crizotinib in EGFR-TKI resistant NSCLC patients with MET amplification, especially in patients with brain metastases. The successful application of aumolertinib plus gumarontinib highlights its potential in overcoming MET amplification-induced EGFR-TKI resistance, which warrants further investigation in future large-scale clinical trials.

Patients with METex14 skipping and/or METamp NSCLC require targeted and personalized treatment approaches to optimize treatment effect and have an unmet medical need. With targeted therapies recently available and others under exploration, treatment outcomes could significantly improve for patients with NSCLC harboring these rare drivers.

Screening for METamp detection followed by stratification based on METamp levels may be considered in all NSCLC patients at diagnosis. This approach could potentially enhance treatment management effectiveness by facilitating inclusion in clinical trials.

P1, N=520, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting

The patient developed resistance to Lorlatinib treatment accompanied by mesenchymal-epithelial transition factor (MET) amplification. Effective tumor control was achieved with the combined use of Crizotinib and Lorlatinib, providing a valuable reference for further exploration of treatment strategies following resistance to ALK-TKIs in clinical practice..

Initial treatment with savolitinib resulted in a sustained partial response lasting more than sixteen months. Our results suggest that savolitinib is effective and safe for the treatment of elderly patients with de novo amplified MET metastatic NSCLC and may therefore be considered a potential treatment option worthy of prospective study confirmation.

Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC.

Small molecule highly selective MET inhibitors such as carmatinib, tepotinib, and cervotinib have shown promising efficacy and safety in clinical trials...In this review, we summarize the current application and research of MET inhibitors and immune checkpoint inhibitors in NSCLC with METΔ14ex and provide recommendations for precise treatment of NSCLC patients with MET gene changes mutations. It also provides new ideas for solving the problems of synergistic effect and drug resistance in targeted therapy and immunotherapy.

P2, N=770, Recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences | Not yet recruiting --> Recruiting | Trial completion date: Jul 2023 --> Jul 2028 | Trial primary completion date: Jul 2022 --> Jul 2026

Nonetheless, other oncogenic alterations are associated with an immunosuppressive TME, low TMB counts, and downregulation of targetable immune checkpoints, in which novel therapeutic approaches are currently being tested to overcome their intrinsic resistance. In this context, this review discusses the fundamental mechanisms by which frequent driver alterations affect ICIs efficacy in patients with NSCLC, and outlines their prognostic relevance in the era of immunotherapy.

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2028

P2, N=30, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2024 --> Mar 2025

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2025 --> Jun 2026 | Trial primary completion date: Jan 2025 --> Jun 2026

In addition, bozitinib efficiently inhibits c-Met resistance-conferring mutations G1163R and Y1230H, although its potency is significantly decreased against the D1228N and Y1230C mutations. Overall, our study reveals the molecular mechanism of bozitinib against c-Met, highlights its ability to overcome acquired resistance mutations, and provides valuable insights into further design and improvement of selective c-Met inhibitors.

The final analysis showed that trametinib exhibited a strong inhibition of tumor cell growth in this sample. Until now. The patient got a good quality of life for three years, which is relatively rare among the reported cases.

NSCLC patients with METex14 skipping mutations benefit more from targeted therapies, especially those with splice donor mutations. MET amplification patients benefit universally from targeted therapies; primary MET amplifications show higher benefits with increased copy numbers. For secondary MET amplifications post-EGFR-TKI resistance, dual-target therapy surpasses Crizotinib monotherapy, independent of MET copy number.

In patients with KRAS G12C-mutated non-Sq NSCLC, sotorasib plus carboplatin/pemetrexed demonstrated favorable efficacy especially in PD-L1 <1%, with manageable toxicity.

P4, N=20, Beijing Hospital; Beijing Hospital

P4, N=40, Jiangsu Cancer Hospital; Jiangsu Cancer Hospital

P2, N=88, Recruiting, SWOG Cancer Research Network | Trial completion date: May 2029 --> May 2028

This report describes a case of a locally advanced NSCLC patient with dual driver gene mutations (EGFR L858R combined with primary METamp), the tumor did not shrink after 1 month of Gefitinib monotherapy, but significantly subsided after 4 months of Savolitinib monotherapy. After radical surgery, the pathological results proved pathological complete response (pCR) of the tumor, and the patient had a good response to postoperative continual Savolitinib treatment, with no recurrence nor metastasis observed to date. This case reports the feasibility and effectiveness of neoadjuvant targeted therapy for locally advanced NSCLC with primary METamp, aiming to provide effective reference for perioperative treatment of locally advanced NSCLC with primary METamp..

At present, some selective tyrosine kinase inhibitors (TKIs) of MET has been approved for non-small cell lung cancer with MET gene 14 exon skipping mutation, such as Glumetinib, Savolitinib, Tepotinib, Capmatinib, etc. Drugs that target secondary MET amplification are still in clinical trials. This paper retrospectively analyzed the clinical data of a female patient with EGFR-TKIs resistant secondary MET amplified squamous cell lung cancer, and reviewed relevant literature to explore how to optimize the treatment of lung squamous cell carcinoma patients with EGFR mutation, so as to provide clinical reference for the diagnosis and treatment of such patients..

MET AmpRatio positively correlated with focal amplification and absence of co-drivers and trended with increased benefit from MET inhibitors. Further studies evaluatingcombinatorial data including MET AmpRatio, amplicon size and presence of other potential drivers, as predictive biomarkers for therapies targeting MET amplification in NSCLC are warranted.

Patients with EGFR-positive NSCLC in stage IVB exhibited significantly shorter PFS and OS than those in earlier stages when treated with first-line osimertinib. The prevalence of baseline TP53 mutations, EGFR amplification, and MET amplification in plasma were significantly higher in stage IVB cases, implicating them in the worse outcomes of this group.

P1, N=24, Completed, Abion Inc | Recruiting --> Completed | N=78 --> 24