Data from Identification of Deleterious <i>NOTCH</i> Mutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

Abstract

<div>AbstractPurpose:<p>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 <i>NOTCH</i> mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy.</p>Experimental Design:<p>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 <i>NOTCH</i> mutation (del-<i>NOTCH</i><sup>mut</sup>). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis.</p>Results:<p>Our 3DMed cohort (<i>n</i> = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; <i>n</i> = 1,499) uncovered marked correlation between <i>NOTCH1/2/3</i> mutation and better ICI outcomes in <i>EGFR/ALK</i><sup>WT</sup> population, including objective response rate (2.20-fold, <i>P</i> = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; <i>P</i> = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; <i>P</i> = 0.035). Del-<i>NOTCH</i><sup>mut</sup> exhibited better predictive function than non-deleterious <i>NOTCH</i> mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-<i>NOTCH</i><sup>mut</sup> 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-<i>NOTCH</i><sup>mut</sup>.</p>Conclusions:<p>This work distinguishes del-<i>NOTCH</i><sup>mut</sup> 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.</p></div>