Abstract 3310: The impact of TP53 mutations on immunotherapy efficacy and the immune microenvironment in NSCLC patients

Abstract Background TP53 mutations are common in non-small cell lung cancer (NSCLC), but no targeted therapies for these mutations are approved. Immunotherapy is the standard treatment for NSCLC with negative driver mutations. Understanding how TP53 mutation status influences immunotherapy efficacy and the tumor immune microenvironment (TIME) is essential. Methods This study included 6, 148 Chinese NSCLC patients who underwent next-generation sequencing (NGS); 158 also received multiplex immunohistochemistry (mIHC) to assess immune cell infiltration in the TIME. We analyzed the relationship between TP53 mutation status and progression-free survival (PFS) in NSCLC patients receiving immunotherapy from two public cohorts (Rizvi 2015 and Hellmann 2018). Results Among 6, 148 NSCLC patients, 3, 023 (49.17%) had TP53 mutations. The TP53 mutation distribution showed a "long tail" phenomenon, with 293 sites and 897 distinct variants, and no hotspot mutations. The most common mutations were R273X (14.6%) and R248X (13.0%). Concurrent TP53 mutations occurred in 47.89% of KRAS mutation patients (317/662) and 46.20% of EGFR mutation patients (1, 458/3, 156). TP53 mutant patients had a significantly higher tumor mutation burden (TMB) than wild-type patients (median TMB: 6.24 vs. 3.12 Muts/Mb, p<0.01). In the Rizvi 2015 and Hellmann 2018 cohorts, median PFS for wild-type versus mutant TP53 was 6.5 vs. 7.8 months (HR=1.43; 95% CI, 0.89-2.28; P=0.12). Patients with TP53 and KRAS co-mutations exhibited higher median PFS than those with KRAS mutations alone (HR=0.28; 95% CI, 0.12-0.64; P<0.01). No significant difference in median PFS was found between patients with TP53 and EGFR co-mutations and those with EGFR mutations alone (HR=1.69; 95% CI, 0.54-5.27; P=0.36). Among 158 patients who underwent both NGS and mIHC, TP53 mutant NSCLC had a higher proportion of total infiltrating T cells (CD3+) in the tumor parenchyma than wild-type patients (median: 7.12% vs. 4.79%, p=0.03). This included CD8+ T cells (median: 1.19% vs. 0.66%, p=0.02), CD8+PD-1+ T cells (median: 0.05% vs. 0.01%, p<0.01), and Foxp3+ T cells (median: 1.16% vs. 0.67%, p<0.01). Additionally, TP53 mutant NSCLC showed higher PD-L1+CD68+ macrophage infiltration in both tumor parenchyma and stroma (p<0.01). Compared to single EGFR mutation patients, those with TP53 and EGFR co-mutations had significantly higher CD8+PD-1+ T cell densities in the tumor parenchyma (median: 4.00 vs. 0.26 cells/mm2, p<0.01) and stroma (median: 5.37 vs. 0.39 cells/mm2, p=0.01). Due to the low number of KRAS mutation patients, adequate analysis of TIME infiltration was not possible. Conclusion These findings suggest that TP53 mutations may enhance immunotherapy efficacy by improving the tumor immune microenvironment, warranting further research. This study provides new insights and potential targets for personalized immunotherapy in TP53 mutant NSCLC. Citation Format: Guangshun Wang, Hui Xie, Ning Gao, Ding Zhang, Wencheng Zhang. The impact of TP53 mutations on immunotherapy efficacy and the immune microenvironment in NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3310.