Background: Despite the availability of several validated therapies, the optimal second-line regimen for EGFR-mutant non-small cell lung cancer (NSCLC) after tyrosine kinase inhibitor (TKI) failure remains uncertain.
Methods: The protocol was registered in PROSPERO (CRD420251157131). We systematically searched MEDLINE, Embase, CENTRAL, and conference proceedings (to Oct 20, 2025) for phase III randomized controlled trials (RCTs). A Bayesian network meta-analysis was performed. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS) and the incidence of grade ≥3 treatment-related adverse events (TRAEs).
Results: Eleven RCTs (3,650 patients, seven regimens) were included. Compared to chemotherapy, sacituzumab tirumotecan (SacTMT), amivantamab plus chemotherapy (Chemo-Ami), and chemo-immunotherapy plus anti-angiogenic agent (Chemo-IO-anti-VEGF) demonstrated superior PFS (HR 0.49, 0.48, 0.53, respectively) and OS (HR 0.60, 0.73, 0.83, respectively). SacTMT also significantly improved OS over chemo-immunotherapy (HR 0.68, 95 % CrI 0.48 to 0.95). Regarding safety, Chemo-Ami carried higher grade ≥3 TRAEs risk (OR 2.83, 95 % CrI 1.01 to 7.90) versus chemotherapy, while SacTMT and Chemo-IO-anti-VEGF demonstrated toxicity comparable to chemotherapy.
Conclusions: SacTMT, Chemo-Ami, and Chemo-IO-anti-VEGF offer superior efficacy over chemotherapy for EGFR-mutant NSCLC after TKI progression. SacTMT and Chemo-IO-anti-VEGF may have more favorable safety profiles than Chemo-Ami. This comparative evidence helps to inform clinical decision-making.
Keywords: Acquired resistance; Amivantamab; Antibody-drug conjugates; EGFR mutation; Immunotherapy; Network meta-analysis; Non-small-cell lung cancer.
Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.