MET Pathway Inhibition Increases Chemo-Immunotherapy Efficacy in Small Cell Lung Cancer

Chemotherapy in combination with immunotherapy offers limited benefit in advanced Small Cell Lung Cancer (SCLC). This study explores the potential of combining MET pathway inhibition with chemo-immunotherapy for treating advanced SCLC. MET pathway activation triggers epithelial-mesenchymal transition, fostering chemoresistance and potentially undermining the efficacy of immunotherapy. In a SCLC mouse model, MET inhibition added to chemo-immunotherapy (anti-PD-L1) reduced tumor growth and extended survival by reshaping the tumor microenvironment, decreasing suppressive myeloid cells, and promoting an effective immune response. Analysis of patient samples revealed that myeloid-enriched immune infiltrates during chemo-immunotherapy might contribute to treatment resistance. Notably, elevated serum hepatocyte growth factor (HGF) levels were associated with a mesenchymal and inflamed phenotype, indicating that this subgroup of patients could potentially benefit from MET inhibitor (METi)-based therapeutic strategies. B6129SF1/J mice bearing subcutaneous SCLC tumours (KP1 or 5B) were randomly assigned to receive a) Cisplatin; b) Cisplatin + anti-PD-L1; c) Cisplatin + anti-PD-L1 + savolitinib. Animals were sacrificed at day 19 (KP1) or day 22 (5B) and tumours were extracted and processed for the transcriptomic assessment through RNAseq.