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 > 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<0.001) and KS tumors (n=75; HR 2.2, p<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<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<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<0.001) and KS tumors (HR 1.9, p<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<0.001) and ICI-chemo (test: AUC=0.73; Flatiron: HR 0.6, p<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.
Boiarsky et al. (Thu,) studied this question.