Comparative effectiveness of first-/second-generation EGFR-TKI combination therapy versus third-generation EGFR-TKI monotherapy in untreated locally advanced or metastatic EGFR-mutant NSCLC: a real-world, retrospective study in China

Third-generation (3G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are recommended first-line options for advanced EGFR -mutant non-small cell lung cancer (NSCLC). In real-world practice, first- or second-generation (1G/2G) EGFR-TKI combination strategies remain frequently used, particularly where access to 3G EGFR-TKIs is limited by cost or reimbursement. As of October 2024, first-line osimertinib was not routinely reimbursed in five Asian countries. Direct real-world comparisons of these two strategies are limited. This retrospective study enrolled previously-untreated patients with stage III/IV EGFR -mutant NSCLC from January 2017 to December 2023. Propensity-score matching (PSM, 1:2) balanced baseline characteristics between patients receiving 1G/2G EGFR-TKI combination therapy or 3G EGFR-TKI monotherapy. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Of 512 eligible patients, 364 were included after PSM. Median PFS was longer with 3G EGFR-TKI monotherapy than with 1G/2G TKI combination therapy (20.5 vs. 16.0 months; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50–0.80; P < 0.001). The PFS benefit was observed in both sexes, smoking statuses, and stages III/IV, and among the aged, those with an Eastern Cooperative Oncology Group performance status of 0–1, adenocarcinoma or EGFR exon 19 deletion, and no baseline brain metastases. Median OS did not differ significantly between 3G EGFR-TKI and 1G/2G TKI combination group (46.1 vs. 41.6 months; HR, 0.95; 95% CI, 0.72–1.26; P = 0.721). In the combination group, 165 patients (70.5%) received 3G EGFR-TKIs in later lines and had longer OS than those who did not. ORR (63.1% vs. 59.6%; P = 0.498) and DCR (99.2% vs. 99.5%; P = 0.903) were similar between groups. Adverse event-related discontinuation and dose reduction were more frequent with combination therapy. First-line 3G EGFR-TKI monotherapy was associated with longer PFS than 1G/2G EGFR-TKI combination therapy. The lack of statistically significant OS difference may partly reflect subsequent 3G EGFR-TKIs use after progression. These findings support 3G EGFR-TKIs as preferred first-line options when accessible. For selected patients, 1G/2G EGFR-TKI combination therapy may remain an alternative in settings with limited reimbursement or high costs.