Chemotherapy-Based Combination Regimens for Advanced EGFR-Mutant NSCLC After EGFR-TKI Failure: A Network Meta-Analysis
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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.
Submitted July 25, 2024; final revision received November 16, 2024; accepted for publication November 18, 2024. Published online March 13, 2025.
L.L. Pang, W.T. Zhuang, and Z.H. Chen are co-first authors.
W.F. Fang and Y.X. Zhang are co-last authors.
Author contributions: Conceptualization: Fang, Y.X. Zhang. Data curation: Pang, Chen. Formal analysis: Pang, Zhuang. Funding acquisition: Fang, Y.X. Zhang. Investigation & methodology: Pang, Y.X. Zhang. Project administration: Fang, Y.X. Zhang. Resources: Pang, Y.X. Zhang. Software: Pang. Supervision & validation: Fang, Y.X. Zhang. Visualization: All authors. Writing—original draft: All authors. Writing—review & editing: All authors.
Data availability statement: This study was a systematic review and meta-analysis. All the data were publicly available from clinical trials.
Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: This work was financially supported by the Chinese National Natural Science Foundation Project (82102872, Y.X. Zhang; 82173101 and 82373262, W. Fang), the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center, and the 308-Program for Clinical Research of Sun Yat-sen University Cancer Center.
Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2024.7092. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.
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