TP53 Functional-Domain-Specific Mutations Define Distinct Clinical Outcomes in EGFR-Mutant Non-Small Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors

<b>Background:</b> In advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS). However, clinical outcomes vary according to EGFR mutation subtype and TP53 co-mutations. Most prior studies have evaluated TP53 status as binary, and the clinical relevance of domain-specific TP53 alterations remains insufficiently defined. <b>Methods:</b> We retrospectively analyzed patients with advanced NSCLC harboring sensitizing EGFR mutations who received first-line EGFR-TKI therapy at the National Cancer Centre Singapore between 22 November 2007, and 17 February 2022. EGFR mutations were classified as common (exon 19 deletion or L858R) or uncommon (all others). TP53 alterations were categorized into three groups: (i) DNA-binding domain (DBD)-involved mutations, including DBD-only mutations and those with additional oligomerization domain (OD) involvement; (ii) other TP53 mutations not involving the DBD or OD; and (iii) TP53 wild type (TP53-WT). The primary endpoint was PFS. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. <b>Results:</b> TP53 alterations were identified in approximately half of the cohort and were predominantly concentrated within the DBD. In the overall cohort, patients treated with third-generation EGFR-TKIs had longer PFS than those treated with first- or second-generation EGFR-TKIs, with this difference being more pronounced among patients with TP53-mutant tumors; no clear PFS difference by TKI generation was observed in the TP53-WT subgroup. Patients with common EGFR mutations experienced significantly longer PFS than those with uncommon mutations, particularly in the presence of TP53 co-mutations. Across multiple analyses, TP53 DBD-involved mutations were associated with shorter PFS compared with other TP53 mutations and TP53-WT, especially in patients treated with first- or second-generation EGFR-TKIs and in those with common EGFR mutations. <b>Conclusions:</b> In EGFR-mutant NSCLC treated with EGFR-TKIs, TP53 functional domain involvement provides prognostic information beyond TP53 mutation status alone. TP53 DBD-involved alterations define a high-risk subgroup with inferior PFS, particularly in treatment settings using first- or second-generation EGFR-TKIs. Incorporation of TP53 domain-based classification, together with EGFR mutation subtype, may improve risk stratification and help guide treatment planning in EGFR-mutant NSCLC.