Multi-targeted tyrosine kinase inhibitors as third-line regimen in advanced non-small cell lung cancer: a network meta-analysis

Background: Four multi-targeted tyrosine kinase inhibitors (TKIs) including apatinib, anlotinib, fruquintinib and lenvatinib are currently available as third-line regimen for advanced non-small cell lung cancer (NSCLC) patients who failed at least two lines of systemic therapy. Limited evidence was provided to demonstrate the general efficacy and safety profile of these drugs as third-line treatment approach for NSCLC. Methods: Eligible literature was searched from electronic database. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), treatment related adverse event (TRAE), treatment related adverse event grade 3-5 (TRAE3-5), hypertension, proteinuria, hand-foot skin reaction (HFSR), elevated ALT/AST, nausea and vomiting, diarrhea were synthetically extracted. Multiple-treatments comparisons (MTCs) based on a Bayesian consistency model integrated the efficacy and toxicity outcomes. Rank probabilities of each regimen were assessed and clustered by the surface under the cumulative ranking curve. Results: Five phase II/III randomized trials involving 915 advanced NSCLC patients were enrolled. MTCs showed that four multi-targeted TKIs shared equivalent efficacy in terms of outcome measures, of which anlotinib stood out in ORR (OR = 39.26; 95% CI: 2.36-2,748.06), DCR (OR = 8.69; 95% CI: 1.70-50.18) and PFS (HR = 0.27; 95% CI: 0.10-0.78) when compared with placebo plus BSC. No significantly differences were observed among these TKIs and placebo with respect to OS, TRAE and TRAE 3-5. Fruquintinib and lenvatinib may relate to high rate of HFSR while anlotinib may relate to hypertension. Conclusions: Multi-targeted TKIs (apatinib, anlotinib, fruquintinib and lenvatinib) with acceptable efficacy and safety profile were options for advanced NSCLC in third-line setting.