Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of <i>KRAS</i>-Mutated Non-Small-Cell Lung Cancer.

Abstract

<i>KRAS</i>-mutated (<i>KRAS</i>^MUT) non-small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among <i>KRAS</i>^MUT NSCLC molecular subgroups. In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with <i>KRAS</i>^MUT NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers). Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: <i>KRAS</i>^<i>MUT</i>/<i>TP53</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>CDKN2A</i>/<i>B</i>/<i>C</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>STK11</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>KEAP1</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>STK11</i>^<i>MUT</i>/<i>KEAP1</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>PIK3CA</i>^<i>MUT</i>, <i>KRAS</i> ^<i>MUT</i>/<i>ATM</i>^<i>MUT</i>, and <i>KRAS</i>^<i>MUT</i> without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the <i>KRAS</i>^<i>MUT</i>/<i>TP53</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>PIK3CA</i>^<i>MUT</i>, and <i>KRAS</i>^<i>MUT</i> alone subgroups and resistance in the <i>KEAP1</i>^<i>MUT</i> containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the <i>KRAS</i>^<i>MUT</i>/<i>CDKN2A</i>/<i>B</i>/<i>C</i>^<i>MUT</i>, <i>KRAS</i>^<i>MUT</i>/<i>STK11</i>^<i>MUT</i>, and <i>KRAS</i>^<i>MUT</i>/<i>ATM</i>^<i>MUT</i> subgroups. In an exploratory clinical cohort of 34 patients with advanced <i>KRAS</i>^MUT NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival (<i>r</i> = 0.80, <i>P</i> < .001). CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of <i>KRAS</i>^MUT NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.