Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis

BACKGROUND: Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements. METHODS: We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS). RESULTS: We included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, with second-and third- generation TKIs showing the greatest benefit (HR=0.25, 95%CI 0.15-0.40). Overall PFS was also improved compared to conventional chemotherapy (HR=0.47, 95%CI 0.36-0.61). In EGFR-mutant patients, osimertinib showed the greatest benefit in iPFS (HR=0.32, 95%CI 0.15-0.69) compared to conventional chemotherapy, while gefitinib + chemotherapy showed the greatest overall PFS benefit (HR=0.26, 95%CI 0.10-0.70). All ALKi improved overall PFS compared to conventional chemotherapy, with alectinib having the greatest benefit (HR=0.13, 95%CI 0.07-0.24). CONCLUSIONS: In patients with NSCLC BMs and EGFR/ALK mutations, targeted TKIs improve intracranial and overall PFS compared to conventional modalities such as chemotherapy, with greater efficacy seen using newer generations of TKIs. This data is important for treatment selection and patient counseling, and highlights areas for future RCT research. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=179060.