Chemotherapy-Based Combination Regimens for Advanced EGFR-Mutant NSCLC After EGFR-TKI Failure: A Network Meta-Analysis

Background: Traditional chemotherapy provides restricted benefits for advanced EGFR -mutant non–small cell lung cancer (NSCLC) after failure of EGFR-tyrosine kinase inhibitors (EGFR-TKIs), necessitating the combined treatment. However, it remains controversial which is the optimal regimen. Methods: Eligible randomized controlled trials (RCTs) comparing various platinum-based chemotherapy (Chemo) regimens in patients with EGFR -mutated NSCLC who experienced disease progression on EGFR-TKIs were included. A Bayesian random-effects network meta-analysis was performed. Progression-free survival (PFS) was analyzed using the logarithm of hazard ratio (HR) and its standard error, whereas objective response rate (ORR) and treatment-related adverse events (TRAEs) were analyzed using odds ratio (OR) and 95% confidence intervals. Results: A total of 9 RCTs involving 2,534 patients with EGFR-TKI resistance, published between 2022 and 2024, were included in the meta-analysis. The analyzed regimens were summarized into 5 arms: platinum-based doublet chemotherapy (“Chemo”); immunotherapy + chemotherapy (“Chemo_IO”); bevacizumab + chemotherapy (“Chemo_Bev”), immunotherapy combined with bevacizumab (or bispecific antibody against PD-1/PD-L1 and VEGF) + chemotherapy (“Chemo_anti–PD-1/PD-L1_anti-VEGF”), and amivantamab + chemotherapy (“Chemo_Ami”). Compared with “Chemo,” both “Chemo_Ami” and “Chemo_anti–PD-1/PD-L1_anti-VEGF” significantly prolonged PFS (HR, 0.48 [95% CI, 0.32–0.71] and HR, 0.51 [95% CI, 0.41–0.62], respectively) and improved ORR (OR, 3.13 [95% CI, 1.64–5.96] and OR, 2.17 [95% CI, 1.51–3.11], respectively). “Chemo_Bev” also significantly reduced the risk of progression (HR, 0.66 [95% CI, 0.45–0.98]). In contrast, “Chemo_IO” failed to improve ORR (OR, 1.25 [95% CI, 0.89–1.81]) and provided a modest PFS benefit (HR, 0.78 [95% CI, 0.64–0.95) compared with “Chemo.” Furthermore, compared with “Chemo_IO,” both “Chemo_Ami” and “Chemo_anti–PD-1/PD-L1_anti-VEGF” significantly prolonged PFS (HR, 0.62 [95% CI, 0.39–0.95] and HR, 0.65 [95% CI, 0.52–0.81], respectively) and improved ORR (OR, 2.51 [95% CI, 1.17–5.14] and OR, 1.73 [95% CI, 1.13–2.60], respectively). No statistically significant difference in PFS was observed among “Chemo_Ami,” “Chemo_anti–PD-1/PD-L1_anti-VEGF,” and “Chemo_Bev.” Additionally, “Chemo_Ami” was associated with a significantly higher incidence of grade 3–5 TRAEs (OR, 3.71 [95% CI, 1.08–12.7]) compared with “Chemo,” whereas no significant differences in TRAEs were observed among the other regimens. Conclusions: Antiangiogenic agents may create a therapeutic window for immunotherapy in advanced NSCLC after progression on prior EGFR-TKI treatment. Based on their superior efficacy, “Chemo_anti–PD-1/PD-L1_anti-VEGF” and “Chemo_Ami” are recommended as preferred treatment options for patients who experienced disease progression on EGFR-TKIs. Our study highlights and updated therapeutic approach for advanced EGFR -mutant NSCLC.