MET amplification

Finally, we highlight unresolved challenges including the lack of standardized biomarker thresholds, optimal timing of MET inhibition, and rational sequencing of available agents. As the therapeutic landscape continues to evolve, improved biomarker precision and optimization of treatment strategies will be essential to maximize the benefit of MET-targeted therapies in EGFRm NSCLC.

Inhibition of downstream signaling and cell proliferation by vabametkib plus lazertinib were evaluated in osimertinib-resistance NSCLC cell lines (HCC827-AR) and patient-derived organoid (YUO-010) by western blot and Cell Titer-Glo assay. Consistent with the in vitro findings, treatment with vabametkib plus lazertinib produced pronounced suppression of tumor growth in both models through a synergistic mechanism. These findings establish vabametkib plus lazertinib as a promising strategy for MET-amplified NSCLC, currently under evaluation in an ongoing phase II clinical trial (NCT05541822).

Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 7 of 9 TR.1 tumors and both deepened and prolonged the duration of response in TR.2 tumors. The findings provide new insight into mechanisms of acquired resistance through bypass signaling and highlight the therapeutic benefit of simultaneous upfront blockade of driver oncogenes and dominant resistance mechanisms in LUAD.

Temab-A monotherapy demonstrated antitumor activity and a manageable safety profile in patients with advanced GEA. The findings support further clinical development of Temab-A, particularly in combination with other agents to improve outcomes for patients with 2L+ GEA.

Pralsetinib was added to osimertinib, resulting in a response lasting 4 months...After one month with alectinib only, osimertinib was added due to the progression, resulting in another response of more than two months. Upon progression with quadruple alterations (EGFR 19del, EGFR C797S, MET amplification, and RET fusions), cabozantinib-gefitinib combination was initiated, leading to rapid deterioration...At the same time, comprehensive genomic testing remains essential for therapeutic decision-making, with ctDNA analysis complementing tissue-based approaches. Notably, the FGFR3-TACC3 fusion may represent a novel resistance mechanism contributing to the limited efficacy of EGFR-TKI.

This is the largest NSCLC dataset analyzed for biomarker distribution across histologies, age, sex and genetic ancestry. This dataset confirms sufficient enough biomarker prevalence across many histological subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.

P1, N=40, Active, not recruiting, Avistone Biotechnology Co., Ltd. | Recruiting --> Active, not recruiting | N=264 --> 40

He received afatinib as frontline treatment and showed a partial response; however, the right lung lesion progressed after 14 months of treatment...Because EGFR testing using resected tissue showed only the original mutation, we switched his regimen to pemetrexed and carboplatin...Although an association between MET amplification and rapidly progressive lung cancer has been predicted previously, to the best of our knowledge, this is the first report on the potential contribution of other mutations, such as those in RNA-binding motif 10, during MET-driven rapid progression. Our report highlights the importance of more active utilization of molecular profiling for the emergence of resistance during tyrosine kinase inhibitor use and the early identification of MET amplification and timely initiation of MET-targeted therapy, such as MET inhibitors in combination with EGFR-TKIs, to potentially mitigate rapid disease progression and clinical deterioration.

A focused translational approach that combines structural insights with innovative therapeutic strategies is urgently needed to achieve lasting clinical benefits in EGFR-driven cancers.

P2, N=44, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2026 --> Dec 2026

The SACHI trial demonstrated that savolitinib plus osimertinib nearly doubled progression-free survival (PFS) compared with chemotherapy (9.8 vs. 5.4 months; hazard ratio 0.34) in patients with EGFR-mutated, MET-amplified non-small-cell lung cancer (NSCLC) after EGFR tyrosine kinase inhibitor (TKI) failure-the first phase 3 evidence for dual EGFR/MET inhibition in this setting.1.

This study underscores the presence of sex-specific therapeutic vulnerabilities in GCTs, which warrant further exploration in larger cohorts.