Disentangling <i>KEAP1</i> and <i>STK11</i> in <i>KRAS</i> -mutant ( <i>KRAS</i> m) non–small cell lung cancer (NSCLC) treated with immunotherapy.

e20583 Background: KEAP1 and STK11 are associated with poor response to immune checkpoint inhibitors (ICIs) in KRAS m NSCLC, but their distinct vs. combined effects are incompletely defined. Methods: We analyzed metastatic KRAS m NSCLC patients treated with ICIs at multiple centers, with external validation in the US-based deidentified Flatiron Health-Foundation Medicine NSCLC Clinico-Genomic Database. PFS/OS and real-world time-to-next-treatment (rwTTNT)/rwOS were the primary outcomes in the academic and Flatiron cohorts, respectively. Patients were stratified as KEAP1 m only (K), STK11 m only (S), co-mutant (KS), or wildtype (WT). To identify their predictive effects independent of other clinicogenomic variables, XGBoost models were trained to predict PFS &gt; 6 months from anti-PD-1 monotherapy (ICI-mono) or chemo-immunotherapy (ICI-chemo). SHAP identified feature importance. The academic cohort was split 80/20 into train/test and Flatiron served as external validation. CD8⁺ T-cell infiltration was assessed by immunofluorescence and validated using MCP-counter-inferred CD8⁺ T-cells from TCGA. Results: The academic and flatiron cohorts included 1019 and 2261 patients, respectively. As compared to WT tumors treated with ICI-mono (n=387), K tumors had no difference in PFS (n=58, HR 1.2, p=0.25), while S (n=56; HR 1.9, p&lt;0.001) and KS tumors (n=75; HR 2.2, p&lt;0.001) had progressively worse PFS. OS mirrored this: K tumors had no difference (HR 1.3, p=0.13); S (HR 1.6, p=0.0032) and KS tumors had progressively worse OS (HR 2.4, p&lt;0.001). As compared to WT tumors treated with ICI-chemo (n=219), K tumors trended toward worse PFS (n=35; HR 1.4, p=0.10), while S (n=60; HR 1.4, p=0.033) and KS tumors (n=89; HR 2.2, p&lt;0.001) had progressively worse PFS. OS was similar for S tumors (HR 1.2, p=0.38) but worse for K (HR 1.8, p&lt;0.001) and KS tumors (HR 1.9, p&lt;0.001). Flatiron validation confirmed these results. As compared to WT tumors (median PD-L1 30%), PD-L1 was lower in K (5%), and even lower in S (0%) and KS (0%) tumors. XGBoost models performed well for ICI-mono (test: AUC=0.70; Flatiron: rwTTNT HR 0.6, p&lt;0.001) and ICI-chemo (test: AUC=0.73; Flatiron: HR 0.6, p&lt;0.001). KS was the most predictive genomic feature in each model; K or S were not predictive. Compared with WT tumors, overall CD8 T-cell density was reduced in K and KS, but not S, tumors, a finding validated in TCGA. In contrast, CD8 T-cell density was reduced in the tumor-compartment in S and KS, but not K, tumors, suggesting that KEAP1 impairs global CD8 infiltration, whereas STK11 restricts intratumoral CD8 localization. Conclusions: In KRAS m NSCLC, KEAP1 and STK11 exhibit varying predictive and prognostic effects and immune-phenotypes depending on whether they occur alone or together. These findings have implications for risk stratification, treatment selection, and the development of therapeutics to overcome ICI resistance in these patients.