Real-world outcomes in EGFR subtypes and co- TP53 mutations in metastatic non-small cell lung cancer.

e20705 Background: EGFR mutations are key oncogenic drivers in non–small cell lung cancer (NSCLC) and predict response to EGFR tyrosine kinase inhibitors (TKIs). Despite therapeutic advances, outcomes vary by EGFR subtype, like exon 19 deletions and L858R substitutions, and co-mutations, like TP53 . However, the prognostic impact of these molecular features across generations of TKIs in real-world practice remains unclear. We investigated the impact of EGFR subtype and TP53 co-mutation on clinical outcomes within a real-world metastatic EGFR -mutant NSCLC cohort. Methods: We performed a retrospective study via chart review of patients with metastatic EGFR -mutant lung cancer treated within Northwell Health from 2018-2024. Clinical, demographic, molecular, and treatment data were collected. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan–Meier methods and compared by EGFR subtype ( exon 19 vs L858R ) and TP53 status using log-rank tests and Cox models. Results: Among the 185 patients within the cohort, 67% were female and never-smokers, with a median age of 69 years (IQR 60–78). Most presented with de novo stage IV disease (75%) and ECOG 0–1 (80%). EGFR alterations included exon 19 deletions (56%), L858R (28%), and atypical mutations (14%); TP53 co-mutation was present in 52%. Common metastatic sites were lung (88%), pleura (30%), bone (35%), brain (32%), and liver (13%). Metastatic distribution was largely comparable between exon 19 to L858R , though L858R was associated with higher rates of bone (47% vs 31%) and adrenal (11% vs 6%) involvement. At 3 months, 72% achieved a response, 17% had stable disease, and 11% experienced progression. At data cut-off, 83% had progressed and 44% had died. Median PFS did not differ between exon 19 and L858R (17.3 vs 15.3 months, p=0.48) or TP53 status (19.8 vs 15.2 months, p=0.09). Median OS was significantly longer with exon 19 versus L858R (62.8 vs 35.9 months, p<0.01) and for TP53 -mutant vs wild-type (29.7 vs 61.8 months, p<0.01) (Table 1). Conclusions: This study examined EGFR mutation subtype and TP53 co-mutation in a real-world metastatic EGFR -mutant NSCLC cohort across multiple TKI generations. While PFS did not differ significantly, OS was significantly longer in patients with exon 19 deletions compared with L858R mutations and in those without TP53 co-mutation. Sites of metastases between EGFR subtle were roughly even in distribution. These findings highlight the stability of EGFR subtype and TP53 -associated prognostic signals despite evolving therapeutic landscapes in metastatic EGFR -mutant NSCLC. Survival outcomes in EGFR -mutant metastatic NSCLC. EGFR Subtype Co-Mutation L858R (months) Exon 19 (months) P-value HR (95% CI) TP53 (months) Non- TP53 (months) P-value HR (95% CI) PFS 15.3 17.3 0.48 1.15 (0.78-1.70) 15.2 19.8 0.09 1.36 (0.96-1.94) OS 35.9 62.8 <0.01 2.07 (1.22-3.54) 29.7 61.8 <0.01 <jat