e20506 Background: Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in most patients with EGFR- mutant advanced non-small-cell lung cancer (NSCLC). In cases of systematic progression with unknown resistance mechanisms, post-TKI options vary, but the lack of direct comparisons hinders decision-making. We evaluated the efficacy and safety of subsequent-line treatments to identify optimal strategies. Methods: A systematic review and network meta-analysis (NMA) were conducted by searching PubMed, Embase, and the Cochrane Library up to October 10, 2025, plus conference abstracts from ASCO, ESMO, and WCLC (2015–2025). Randomized controlled trials of post-TKI treatments in EGFR -mutant NSCLC were included. Primary outcomes were progression-free survival (PFS) and overall survival (OS); secondary outcomes included objective response rate (ORR) and grade ≥3 adverse events (≥3 AEs). A Bayesian framework was employed to estimate hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs), and the surface under the cumulative ranking curve (SUCRA) was used to rank treatments. Subgroup analyses were conducted by EGFR mutation subtypes and clinicopathological features. The protocol is registered with PROSPERO (CRD420251232072). Results: Ten RCTs (3,820 patients, 13 regimens) were analyzed. Compared with chemotherapy alone, amivantamab plus lazertinib and chemotherapy (AMI+Lazer+CT) showed the best PFS (HR 0.44, 95% CI 0.35–0.56). For OS, the TROP2 antibody-drug conjugate (ADC) sacituzumab tirumotecan (SACTMT) ranked first (HR 0.60, 95% CI 0.44–0.82). Atezolizumab plus bevacizumab and chemotherapy (ATE+BEV+CT) yielded the highest ORR (OR 3.26, 95% CI 1.79–5.94). Amivantamab-based regimens were associated with elevated toxicity; AMI+Lazer+CT had the highest risk of ≥ 3 AEs (OR 14.59, 95% CI 8.99–24.94). AMI+CT was optimal for L858R mutation (HR 0.30, 95% CI 0.17–0.54), whereas SACTMT was superior for 19DEL (HR 0.42, 95% CI 0.31–0.57). ATE+BEV+CT provided the best PFS benefit (HR 0.44) for T790M-negative patients, while ivonescimab plus chemotherapy (IVO+CT) ranked first for T790M-positive (HR 0.21). AMI+Lazer+CT ranked first for PFS in patients aged ≥ 65 years (HR 0.41), smokers (HR 0.45), and those without brain metastases (HR 0.42). Conversely, ATE+BEV+CT significantly improved PFS in patients with brain metastases (HR 0.32, 95% CI 0.19–0.53). Conclusions: AMI+Lazer+CT and SACTMT are the optimal regimens for PFS and OS for EGFR -mutant NSCLC after TKIs progression, respectively, though the toxicity of amivantamab-based regimens requires management. SACTMT and AMI+CT are preferred for 19DEL and L858R, while ATE+BEV+CT and IVO+CT are the respective treatments for patients with and without brain metastases, highlighting the need for personalized treatment.
Wang et al. (Thu,) studied this question.