Efficacy and safety of third-generation EGFR-TKIs combined with local consolidative therapy as first-line treatment for EGFR-mutated stage IIIB–IV NSCLC: a retrospective study

Although third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and aumolertinib, can improve prognosis as first-line treatment, most patients inevitably develop resistance and disease progression (PD). Local consolidative therapy (LCT) combined with TKIs can enhance therapeutic efficacy, but the existing evidence is mainly based on first- and second-generation TKIs. This retrospective case-control study aimed to evaluate whether the combination of LCT with third-generation EGFR-TKIs treatment can improve the efficacy and safety in the management of advanced NSCLC compared with TKIs monotherapy. This retrospective study enrolled patients diagnosed with EGFR-mutant NSCLC. The experimental group received EGFR-TKIs combined with LCT, and the control group received EGFR-TKIs monotherapy. The primary endpoints were progression-free survival (PFS) and duration of objective response (DOR), which were compared using the Kaplan‑Meier method and log‑rank test; hazard ratios (HR) were analyzed by the Cox proportional hazards model. Subgroup analyses were conducted to investigate the heterogeneity. The patterns of PD and adverse events were summarized. A total of 49 patients were enrolled in this study (combination therapy group: n = 27; monotherapy group: n = 22). The median PFS was significantly longer in the combination therapy group than in the monotherapy group (32.0 vs. 21.0 months; HR = 0.39, P = 0.012). The DOR was also superior in the combination therapy group (29.0 vs. 17.0 months; HR = 0.36, 95% CI: 0.16–0.78, P = 0.006). Subgroup analyses showed that significant PFS benefit from combination therapy can be observed in patients with extrathoracic metastasis and those who achieved partial response after TKI treatment. Multivariate Cox regression analysis identified combination local therapy (HR = 0.29, 95% CI: 0.12–0.70) and ≤ 5 metastatic lesions (HR = 0.12, 95% CI: 0.02–0.56) as independent prognostic factors for PFS. Analysis of disease progression patterns revealed that 87.5% of progression events in the combination therapy group occurred at sites not treated with LCT, while 80% of progression events in the monotherapy group arose from baseline pre-existing lesions. No statistically significant difference was found in the incidence of grade 1–2 and grade 3 adverse events between the two groups (all P > 0.05). Third-generation EGFR-TKIs combined with LCT can significantly prolong PFS and DOR in patients with advanced EGFR-mutant NSCLC, with manageable safety.