De novo vs recurrent metastatic presentation and outcomes with first-line EGFR TKI in <i>EGFR</i> -mutant NSCLC.

Abstract

e20766 Background: Approximately 20% of EGFR-mutant metastatic non-small cell lung cancer (NSCLC) presents as recurrent disease in real-world practice. Whether metastatic presentation (de novo vs recurrent) influences treatment durability and disease control on first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) is unknown. Methods: We conducted a retrospective cohort study of patients with EGFR-mutant metastatic NSCLC treated with 1L EGFR TKI from 2012-2025 at Northwell Health. Recurrent disease was defined as metastatic progression after prior curative intent therapy. The primary outcome was time to treatment discontinuation (TTD). Secondary outcomes included early discontinuation (&lt; 6 months) and progression-free survival (PFS), defined as time from 1L TKI to disease progression or death with censoring at last follow up. Multivariable Cox models adjusted for EGFR subtype, TKI agent, performance status, age, and brain metastases. Early discontinuation (&lt; 6 months) was evaluated using Poisson regression with robust standard errors, adjusted for same covariates. Results: Among 152 patients (117 TTD events; 133 PFS events), 79% presented with de novo metastatic disease and 21% with recurrent metastatic disease. EGFR subtype distribution was similar between groups (de novo vs recurrent: Ex19del 64% vs 54%, L858R 28% vs 31%, Other 8% vs 15%). In adjusted cox models, recurrent presentation was associated with a trend toward longer TTD (median 30.4 vs 16.8 months, HR 0.68; 95% CI 0.44-1.04) and significantly longer PFS (median 28.0 vs 15.2 months; HR 0.52; 95% CI 0.34-0.80) compared with de novo presentation. L858R was associated with shorter TTD (HR 1.49; 95% CI 0.94-2.34) and PFS (HR 1.63; 95% CI 1.08-2.46) relative to Ex19del. Erlotinib (HR 1.88; 95% CI 1.21-2.94) and afatinib (HR 1.85; 95% CI 1.02-3.33) were associated with shorter TTD compared with osimertinib, with similar patterns for PFS. Early treatment discontinuation did not differ by metastatic presentation (RR 1.02; 95% CI 0.44-2.47), EGFR subtype, or TKI agent. ECOG ≥2 was the only significant predictor of early discontinuation (RR 2.34; 95% CI 1.01-5.21; p = 0.04). Conclusions: In this real-world cohort, recurrent metastatic presentation was associated with significantly longer PFS and a consistent trend toward longer treatment durability on 1L EGFR TKI, independent of mutation subtype and TKI agent. As early discontinuation rates were similar, the differences in TTD and PFS in recurrent disease appear to reflect differences in tumor biology rather than early treatment failure. If validated, metastatic presentation may inform prognostic counseling and therapeutic expectations. Prospective validation in larger, multi-institutional cohorts is warranted.