Efficacy and safety of third-generation EGFR-TKI rechallenge therapy in advanced non-small cell lung cancer patients with EGFR mutation: a retrospective cohort study

Abstract

Background Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have become the standard treatment for EGFR-mutant non-small cell lung cancer (NSCLC), but acquired resistance remains inevitable. Current post-progression salvage regimens offer only modest clinical benefits, leaving an unmet need for effective late-line treatment strategies. This study evaluated the efficacy and safety of third-generation EGFR-TKI rechallenge as a potential salvage option for heavily pretreated resistant NSCLC patients. Methods We retrospectively analyzed 29 patients with advanced EGFR-mutant NSCLC who received third-generation EGFR-TKI rechallenge after progression on prior third-generation EGFR-TKI therapy between December 2019 and August 2025. All patients had pathologically confirmed EGFR-mutant lung adenocarcinoma and received multi-line subsequent treatment after third-generation EGFR-TKIs resistance. Baseline clinical data were extracted from electronic medical records, and follow-up chest CT evaluations were conducted every 6 to 8 weeks. Outcomes were standardized using RECIST version 1.1 for tumor responses and CTCAE version 5.0 for adverse events. Survival outcomes [progression-free survival (PFS), overall survival (OS)] were analyzed via Kaplan-Meier curves and log-rank tests. The primary endpoint was PFS. Secondary endpoints included OS and disease control rate (DCR). Results The median number of prior systemic treatment lines was 5 (range, 3–12). Third-generation EGFR-TKI rechallenge achieved a median progression-free survival (mPFS) of 6.0 months, a median overall survival (mOS) of 12.0 months. The DCR was 6/29 (20.7%). Treatment-related adverse events (TRAEs) occurred in 8/29 (27.6%) patients, with severe (grade ≥3) events in 3/29 (10.3%). Poorer baseline ECOG PS (3–4) was significantly associated with inferior PFS (median: 5.0 vs. 7.0 months, P=0.04) and OS (median: 10.0 vs. 25.0 months, P=0.005). Chemotherapy-containing interval therapy was associated with improved PFS (7.5 vs. 2.0 months, P=0.02). Conclusions Third-generation EGFR-TKI rechallenge may provide a feasible and well-tolerated salvage option for selected heavily pretreated patients with EGFR-mutant NSCLC. ECOG PS and prior treatment patterns may assist in patient selection for rechallenge therapy. However, these findings are strictly exploratory and require validation in larger, controlled prospective studies.