Abstract 2487: KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma

Abstract PD-L1 protein expression is the most important predictive biomarker for immune checkpoint inhibition (ICI) in advanced non-small cell lung cancer (NSCLC), but has limited sensitivity and specificity. We analyzed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas of the Thoraxklinik Heidelberg who were negative for actionable EGFR and ALK/RET/ROS1 alterations. Two external cohorts of patients treated with immunotherapy (SU2C-ICI: n=247, MSK-ICI: n=135) and two external cohorts of surgical early stage patients were additionally analyzed (TCGA-LUAD: n=417, MSK-LUAD: n=394). Therapy benefit was assessed stratified by KRAS and TP53 mutations. RNA-Seq data of TCGA were analyzed to reveal the molecular characteristics of KRASmut/TP53mut tumors. Analyzing overall survival, an interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses (HR=0.56, p=0.0044 and HR=0.53, p=0.0021). KRASmut/TP53muts tumors performed better than tumors not harboring the dual mutation configuration (HR=0.71, CI 0.55-0.92). This observation could be confirmed in the external cohorts of immunotherapy patients (SU2C-ICI: HR=0.54, CI 0.28-1.03 and MSK-ICI: HR=0.35, CI 0.14-0.88), whereas KRASmut/TP53mut was not associated with prolonged survival in the surgical cohorts. Tumor mutational burden, proliferation (measured by TOP2A mRNA expression), and PD-L1 mRNA were significantly higher in TP53mut compared with TP53wt tumors, regardless of KRAS status. Genome-wide mRNA expression analysis revealed 64 genes including the chemokine CX3CL1 (fractalkine) as specific transcriptomic characteristic of KRASmut/TP53mut tumors. In summary, KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumor features. Further validation studies are warranted. Mutation testing of the two genes can be easily implemented using small gene panels or even single gene analyses. Citation Format: Jan Budczies, Eva Romanovsky, Martina Kirchner, Olaf Neumann, Miriam Blasi, Johannes Schnorbach, Rajiv Shah, Farastuk Bozorgmehr, Rajkumar Savai, Thorsten Stiewe, Solange Peters, Peter Schirmacher, Thomas Michael, Daniel Kazdal, Petros Christopoulos, Albrecht Stenzinger. KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2487.