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

Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non-small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy.

Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious mutation (del- ). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis.

Results: Our 3DMed cohort ( = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; = 1,499) uncovered marked correlation between mutation and better ICI outcomes in population, including objective response rate (2.20-fold, = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46-0.81; = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32-0.96; = 0.035). Del- exhibited better predictive function than non-deleterious mutation, potentially via greater transcription of genes related to DNA damage response 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- .

Conclusions: 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.