Front-line therapy for brain metastases and non-brain metastases in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: a network meta-analysis
Authors: Zhu Yixiang , Liu Chengcheng , Xu Ziyi , Zou Zihua , Xie Tongji , Xing Puyuan , Wang Le , Li Junling 
Published: May 2023

Abstract

Background:
The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR-mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR-mutated NSCLC patients with different BM statuses.

Methods:
Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR-mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework.

Results:
This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17–0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20–0.90; HR = 0.46, 95% CI: 0.31–0.68; HR = 0.51, 95% CI: 0.34–0.77; HR = 0.50, 95% CI: 0.38–0.66; HR = 0.62, 95% CI: 0.43–0.89; HR = 0.64, 95% CI: 0.44–0.94; HR = 0.61, 95% CI: 0.48–0.76; HR = 0.71, 95% CI: 0.50–1.00), PbCT (HR = 0.29, 95% CI: 0.11–0.74; HR = 0.31, 95% CI: 0.15–0.62; HR = 0.34, 95% CI: 0.17–0.69; HR = 0.34, 95% CI: 0.18–0.64; HR = 0.42, 95% CI: 0.21–0.82; HR = 0.43, 95% CI: 0.22–0.87; HR = 0.41, 95% CI: 0.22–0.74; HR = 0.48, 95% CI: 0.31–0.75), and PfCT (HR = 0.14, 95% CI: 0.06–0.32; HR = 0.15, 95% CI: 0.09–0.26; HR = 0.17, 95% CI: 0.09–0.29; HR = 0.16, 95% CI: 0.10–0.26; HR = 0.21, 95% CI: 0.12–0.35; HR = 0.21, 95% CI: 0.12–0.39; HR = 0.20, 95% CI: 0.12–0.31; HR = 0.23, 95% CI: 0.16–0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22–0.92) and PfCT (HR = 0.21, 95% CI: 0.12–0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42–1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84–2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06–4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06–0.32). For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively.

Conclusion:
Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR-mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.