MET amplification

This case underscores dynamic clonal evolution in advanced NSCLC: the initial L747S/L858R clone showed Osimertinib sensitivity, while subsequent resistance revealed a distinct profile (distinct TP53 mutation, MET amplification, high PD-L1/TMB) that explained the durable response to Pembrolizumab. These findings provide crucial evidence for sequential therapy strategies in compound EGFR mutations. Our findings also highlight the utility of Next Generation Sequencing (NGS) in identifying targetable resistance mechanisms, enabling prolonged survival in patients with compound EGFR mutations and offering valuable insights for clinical decision-making.

P2, N=66, Recruiting, SWOG Cancer Research Network | Trial completion date: May 2027 --> Jun 2028 | Trial primary completion date: May 2026 --> Jun 2027

Savolitinib monotherapy showed encouraging antitumor activities and a tolerable safety profile in heavily treated, later-line METamp G/GEJ cancers, supporting further investigation in randomized controlled trials. ClinicalTrials.gov identifier: NCT04923932 .

P3, N=216, Completed, Hutchison Medipharma Limited | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Aug 2025 | Trial primary completion date: Dec 2025 --> Aug 2025

Molecular docking simulations revealed that the evaluated compounds adopt a linear binding mode within the c-MET active site, in contrast to the U-shaped binding pattern characteristic of class Ib c-MET inhibitors. Overall, the newly developed isatin-1,2,4-triazine hybrids exhibited potent anticancer activity, highlighting their potential as promising lead structures for future anticancer drug development.

Prior anti-EGFR therapy and resistance alterations detected by baseline ctDNA profiling are associated with reduced efficacy of PER + TRA in HER2-amplified mCRC. Integrating treatment history with baseline ctDNA profiling might enable improved patient selection for dual HER2-targeted therapy.

Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS ≥ 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression.

MET alterations occur predominantly in the elderly, males, and smokers. MET-Ex14 shows driver-dependent characteristics with clear MET-TKI benefit. MET-Amp presents the most aggressive phenotype. MET IHC-Pos predominates (> 80%) with heterogeneity; the 2 + /3 + may benefit from MET-TKI. These findings inform subtype-based management of MET-altered NSCLC in southeastern China.

This study provides a comprehensive characterization of METΔex14 in NSCLC, revealing its dual role as a primary driver of oncogenesis and a potential resistance mechanism to EGFR/ALK inhibitors. The identification of concurrent genetic alterations and potential resistance mechanisms enhances our molecular understanding of treatment responses. These findings highlight the need for further investigation into targeted therapies that consider the genomic complexity of METΔex14 to improve treatment efficacy and patient outcomes.

The detection of uncommon EGFR mutations requires the expertise and advanced technological platforms available in specialized centers. Data evaluating the efficacy of the news therapies mainly bispecific anti-EGFR/MET in patients with lung cancer harboring uncommon EGFR alterations are needed, as well as the relationship between toxicity and efficacy.

Although clinical practice has attempted to combine targeted drugs for MET amplification, such as crizotinib, with first and second-generation ALK-TKIs and observed preliminary efficacy, there is no published research on the combination of third-generation ALK-TKI lorlatinib with new MET inhibitors such as vebreltinib. Our case report first successfully documented the use of third-generation ALK inhibitor (lorlatinib) in combination with novel MET inhibitor (vebreltinib) for the treatment of advanced NSCLC patients with ALK-TKI resistance due to MET amplification, enabling sustained clinical remission. This case highlights the importance of repeat biopsy to identify acquired resistance mechanisms arising from intratumoral heterogeneity in response to targeted therapy, which is critical for making clinical decisions and adjusting treatment plans for patients with NSCLC.

Different BRAF gene alterations affect the prognosis of GBM and are associated with molecular alterations in classical tumor signaling pathways, and BRAF AMP is often accompanied by amplification of MET, RHEB, and CUL1.