Comparative effectiveness of first-/second-generation EGFR-TKI combination therapy versus third-generation EGFR-TKI monotherapy in previously untreated advanced EGFR -mutant NSCLC: A real-world, retrospective study in China.

e20726 Background: At present, third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the combination of first-/second-generation EGFR-TKIs and chemotherapy or anti-angiogenic agents remains commonly used in real-world practice in China. This study aimed to compare the real-world effectiveness of these two first-line strategies. Methods: In this retrospective study, data were collected from Shanghai Chest Hospital from January 2017 to December 2023. Previously-untreated patients with stage III/IV EGFR-mutant NSCLC were enrolled and classified into two groups: those receiving first-line first-/second-generation EGFR-TKI combination therapy, and those receiving third-generation EGFR-TKI monotherapy. Propensity-score matching (PSM) (1:2 ratio) was performed to balance baseline characteristics. The primary endpoint was progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Results: A total of 512 eligible patients were enrolled and the median follow-up was 40.4 months. After PSM, 364 patients were included. The median PFS was significantly longer in the third-generation TKI monotherapy group (n = 130, PFS: 20.5 months; 95% confidence interval CI, 16.45-24.55) compared to the first-/second-generation TKI combination group (n = 234, median PFS: 16.0 months; 95% CI, 14.16-17.91; P < 0.001). Subgroup analysis of PFS consistently favored the third-generation EGFR-TKI across almost all variables. No significant difference in OS was observed between the two groups (46.1 months, 95%CI 39.64-52.49 vs. 41.6 months, 95%CI 38.51-45.14; P = 0.721). Besides, 165 (70.5%) patients in the combination group received third-generation EGFR-TKIs in later lines, and this subgroup demonstrated significantly longer OS than those who did not (45.4 vs 33.5 months, P = 0.017). Conclusions: This real-world study demonstrates that first-line third-generation EGFR-TKI monotherapy is associated with a significantly improved PFS compared to first-/second-generation EGFR-TKI combination therapy in EGFR-mutant NSCLC. The absence of OS difference may be attributed to the high proportion of patients in the combination group who subsequently received third-generation TKIs as a later-line therapy. These findings support the superior efficacy of third-generation EGFR-TKIs as the recommended first-line treatment and also indicate that the first-/second-generation EGFR-TKI combination therapy is a viable alternative in real-world practice.