Abstract 6776: Spatial transcriptomics of response to tepotinib treatment in a patient with NSCLC

Background: While cancer therapies are becoming increasingly more targeted, our understanding of the genomic changes occurring during these treatments is lacking. Moreover, the tumoral heterogeneity and its spatial distribution remain important obstacles in predicting tumor evolution and treatment responses. In recent years, genomic spatial profiling techniques have shed light on this complexity by detecting gene expression changes in heterogenous tumor regions and their microenvironment over the course of treatment. Methods: Tepotinib is a highly selective and potent MET class Ib inhibitor, approved for the treatment of patients with NSCLC with MET exon 14 skipping alterations. To detect genomic changes during neoadjuvant treatment with tepotinib, a GeoMx® digital spatial profiler (DSP; Nanostring Technologies) analysis was conducted in paired baseline and on-treatment patient samples. GeoMx® DSP was performed by selecting regions of interest with nuclear, TTF-1, CD3 and CD33 morphology markers followed by next-generation sequencing (NGS) using the Cancer Transcriptome Atlas RNA panel (>1,800 cancer-related genes). Results: Following a poor response to chemotherapy, neoadjuvant tepotinib treatment was initiated in a 54-year-old female, never-smoker with NSCLC harboring a MET exon 14 alteration. Owing to a good response to tepotinib, surgical resection of the tumor was decided by the tumor board given the downgrading (from IIIB to IA1) and resulting in a major pathological response. This resection allowed spatial transcriptomics to be compared to a baseline biopsy from the same patient. MET signaling inhibition by tepotinib treatment increased immune cell infiltration in the tumor microenvironment compared to the baseline sample. This enhanced tumoral immune cell density was shown by the fluorescent morphology markers and confirmed through spatial deconvolution of the NGS results. It was further characterized by the significantly altered gene expression levels between the two samples. Gene ontology (GO) assessment of the differentially expressed genes revealed GO terms associated with tumorigenesis in the basal sample, such as cell mobility and motility, vascular epithelial growth factor production and cell communication. In turn, the tepotinib-treated tissue mainly exhibited tumor-clearing characteristics, including antigen processing and presentation through major histocompatibility complex classes I & II, T cell-mediated toxicity, and granulocyte and le