Protein expression from paired biopsies from a patient with METex14 skiping non-small cell lung cancer before and after treatment with neoadjuvant tepotinib (42 days)

Background: MET inhibitors have demonstrated efficacy in treating patients with non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Advancements in spatial profiling technologies have unveiled the complex dynamics of the tumor microenvironment, a crucial factor in cancer progression and therapeutic response. Using spatial profiling, this study investigates the effects of the MET inhibitor tepotinib on the TME in a case of locally advanced NSCLC with a METex14 skipping alteration. Methods: A patient with resectable stage IIIB NSCLC, unresponsive to neoadjuvant platinum-based doublet chemotherapy, received tepotinib following detection of a METex14 skipping alteration. Paired pre- and post-treatment biopsies were subjected to GeoMx Digital Spatial Profiling using the Cancer Transcriptome Atlas and immune-related protein panels to evaluate shifts in the tumor immune microenvironment (TIME). Results: Tepotinib administration resulted in pathological downstaging to stage IA1, which allowed for a successful lobectomy and evidenced a significant pathological response. The TIME was transformed from an immunosuppressive to a more permissive state, with upregulation of antigen-presenting and pro-inflammatory immune cells. Moreover, a marked decrease in immune checkpoint molecules, including PD-L1, was noted. Spatial profiling identified discrete immune-enriched clusters, indicating the role of tepotinib in modulating immune cell trafficking and function. Conclusions: Tepotinib appears to remodel the TIME in a patient with METex14 skipping NSCLC, possibly increasing responsiveness to immunotherapy. This case supports the integration of genetic profiling into the management of early and locally advanced NSCLC to guide personalized, targeted interventions. These findings highlight the need to further evaluate combinations of MET inhibitors and immunotherapies. On the GeoMx Digital Spatial Profiler, regions of interest of 250 micrometers in diameter were selected in the pre-treatment biopsy (15) and tepotinib-treated surgical resection (79) from the same patient, following barcoded antibody incubation (Immune Cell Profiling, Immune Cell Typing, Immune Activation Status, IO Drug Target & PI3K/AKT Signaling panels) and morphology marker staining using SYTO13, TTF1, CD3 and CD33.