55P Impact of KRAS/TP53 and KEAP1/STK11 co-mutations on immune checkpoint inhibitor outcomes for metastatic NSCLC patients: Insights from real-world data

Background: Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy (ICI+CTx), are standard first-line treatments for metastatic non-small cell lung cancer (mNSCLC).While PD-L1 expression is currently the only biomarker used to guide the therapy choice, its predictive power is limited, and clinical outcome remains heterogeneous.We evaluated the impact of KRAS/TP53 and KEAP1/STK11 alterations on the clinical benefit of ICI/ICI+CTx therapy using data from the Baden-Wuerttemberg Cancer Registry (BWCR), Germany.Methods: A total of 905 mNSCLC wild type patients with no targetable genetic alterations, but known KEAP1/STK11 status, were treated with first-line ICI/ICI-CTx.Median overall survival (mOS) was assessed using Kaplan-Meier statistics.Multivariate Cox proportional hazards models adjusted for KRAS (G12C vs other mutations[mut]), TP53, and PD-L1 status, metastatic stage, and sex, were used to evaluate the impact of KEAP1/STK11 status on OS.Results: KEAP1-mut and KEAP1/STK11 co-mutation were associated with poorer outcomes in multivariate analysis, together with stage and negative PD-L1 status (HR =1.26/1.79,95% CI: 0.97-1.63/1.39-2.32,p=0.084/0.001for mut/wt and mut/mut KEAP1/STK11 status, respectively).In the KEAP/STK11 wt/wt group, the longest mOS was observed in patients with KRAS/TP53 mut/mut and G12C/wt status (21.9 and 20.9 months, respectively), compared with 14.5 month for the wt/wt subgroup.In contrast, among patients with KEAP and/or STK11 mutations, mOS was comparable at approximately 15 months only in KRAS/TP53 wt/wt subgroup, whereas it was shortened to 10 months across all other subgroups.The most pronounced loss of ICI/ICI-CTx therapy benefit (reduction of 10 months) was observed in the KRAS/ TP53 mut/mut and G12C/wt subgroups (HR =1.8/2.6,95% CI: 1.1-3.2/1.4-4.8,p=0.018/0.002,respectively). Conclusions:Our findings confirmed that ICI/ICI-CTx therapy benefit is strongly influenced by the combined KEAP1/STK11 and KRAS/TP53 mutational status, highlighting the potential for improved therapeutic stratification of mNSCLC patients based on these biomarkers.