WCLC 2025 - Posters & ePosters-EP.06.17 Immunological and Genetic Profile and Efficacy of Immunotherapy in NSCLC Patients With Mutations in KRAS and STK11 Genes

EP.06.17 Immunological and Genetic Profile and Efficacy of Immunotherapy in NSCLC Patients With Mutations in KRAS and STK11 Genes

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This study investigated the immunological and genetic profiles of non-small cell lung cancer (NSCLC) patients harboring mutations in KRAS and STK11 genes, focusing on their impact on the efficacy of immune checkpoint inhibitors (ICIs). KRAS mutations are common in NSCLC and often co-occur with STK11 mutations, a combination linked to resistance to ICIs. The study analyzed 20 NSCLC patients undergoing immunotherapy or chemoimmunotherapy using targeted next-generation sequencing and flow cytometry to assess peripheral blood immune cells before and during treatment.<br /><br />Three patients carried both KRAS and STK11 mutations, exhibiting varied responses to therapy. One patient (NK2) showed a durable response (26 months and ongoing) and also had mutations in RAD50, PMS2, JAK1, KDR, and NOTCH4 genes. Another (NK9) experienced short disease stabilization (4 months) with additional ATM, PMS2, and SMARCA4 mutations. The third (NK5) had rapid disease progression and carried mutations in PIK3CA, PDGFRA, H3-3A, and NOTCH4.<br /><br />Responders (NK2, NK9) had higher baseline levels of CD3 and CD4 T cells and lower CD8/PD-1 and regulatory T (Treg) cells compared to the non-responder (NK5). During therapy, responders showed increases in CD8, CD8/PD-1, CD4/EOMES, and Treg populations, while the non-responder exhibited increased T cells expressing exhaustion markers TIM-3 and LAG-3.<br /><br />The study identified mutations in DNA repair genes (PMS2, RAD50, ATM) as favorable predictors for immunotherapy, likely due to DNA repair deficiencies increasing tumor mutational burden and immunogenicity. Conversely, mutations in oncogenes like PIK3CA and PDGFRA were unfavorable predictors. Comprehensive immune profiling may enhance prediction of ICI treatment outcomes in NSCLC patients with KRAS/STK11 mutations.

Asset Subtitle

Michal Gil

Meta Tag

Speaker Michal Gil

Topic Pathology and Biomarkers

Keywords

non-small cell lung cancer

NSCLC

KRAS mutations

STK11 mutations

immune checkpoint inhibitors

immune profiling

DNA repair gene mutations

immunotherapy response

tumor mutational burden

immune exhaustion markers