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Our 3DMed cohort (n=58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC [n=1499]) uncovered marked correlation between  mutation and better ICI outcomes in   population, including ORR (2.20-fold, P=0.001), PFS (HR=0.61, 95%CI 0.46-0.81, P=0.001) and OS (HR=0.56, 95%CI 0.32-0.96, P=0.035). Del-  exhibited better predictive function than non-deleterious  mutation (non-del- ), potentially via greater transcription of genes related to DDR and immune activation. Del-  was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic utility of del-  Conclusion: This work distinguishes del-  as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

Identification of Deleterious NOTCH Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC