8641 Background: Recent research suggests that loss of heterozygosity (LOH) in KEAP1/STK11 mutated lung adenocarcinoma (LUAD) may present a new immunological and biological aggressive subtype unresponsive to current standard of care treatment options. Currently, there is limited data on the clinical impact of LOH in KEAP1/STK11 co-alterations in real-world settings. Methods: From November 1st, 2021, to October 1st, 2023, patients with LUAD and mutations detected by FoundationOne CDx in any of the genes KEAP1, STK11, KRAS were enrolled in the study. Clinical data, including overall survival (OS), duration of response to different treatment lines (DOR), and real-world progression-free survival (rwPFS) according to the treatment lines, were retrospectively assessed in patients who had given informed general consent. Multivariate Cox regression models included patient characteristics, selected two-way interactions, OS, LOH, PD-L1 status and rwPFS for patients with STK11, KEAP1, KRAS mutations. Results: A total of 104 patients were included, 63 (60.6%) males with a median age of 64.4 years; [range: 38-90]). 23 (22.1%) patients with STK11/KEAP1/KRASmutations, 15 (14.4%) patients with KEAP1/LOH mutations, 10 (10.4%) patients with STK11/KRAS mutations and six (5.8%) patients with STK11/KEAP1. In the KEAP1/LOH mutated subgroup, median OS (mOS) was 14 months (ms), whereas in the subgroup with KEAP1/KRASmutations mOS was 13 ms. Across all groups mOS was 14 ms. Compared to Keynote 189 with a PFS of 8.8 ms, rwPFS for the first treatment line (rwPFS1) was shorter in patients with KEAP1/LOH status and KRAS/STK11 mutations at 3.5 ms and 3 ms respectively. Additionally, DOR and rwPFS for further treatment lines were analyzed according to PD-L1 and TMB status, as well as the treatment lines patients received. Conclusions: Patients with mutations on STK11/KEAP1/KRAS or with LOH presented an mOS inferior to what is currently expected from historic data for metastatic LUAD, with a worse prognosis and shorter rwPFS1 for the subgroup of K EAP1/LOH, KEAP1/KRAS and KRAS/STK11. Surprisingly, the percentage of patients carrying concurrent mutations of interest was much higher in the analyzed population than previously described, emphasizing the importance of broad NGS panel testing, including STK11 and KEAP1 mutations. Our findings based on real-world data indicate that in addition to the already known STK11/KEAP1/KRASconcomitant mutations, KEAP1/LOH mutations define a new subset of hard-to-treat genetic alterations. These patients represent a subgroup associated with primary therapy resistance, highlighting a new unmet need for tailored therapeutic strategies. Furthermore, our data emphasizes the benefit of upfront panel sequencing, including STK11/KEAP1 mutations and LOH, to identify at-need patients.