The Promise of Chemotherapy-Free Strategies in Advanced Driver-Negative NSCLC: A Systematic Review and Network Meta-Analysis of Antiangiogenic Combination Therapies.

Abstract

<h4>Background</h4>Antiangiogenic combination therapy-antiangiogenic agents combined with immune checkpoint inhibitors and/or chemotherapy-has become an important treatment strategy for advanced driver-negative non-small cell lung cancer (NSCLC). We conducted a network meta-analysis to compare efficacy and safety and identify optimal antiangiogenic combinations.<h4>Methods</h4>We searched PubMed, Embase, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) that evaluated antiangiogenic combination therapies. Primary outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and incidence of grade ≥ 3 treatment-related adverse events (TRAEs).<h4>Results</h4>Nine treatment regimens comprising 5954 patients were included. The network meta-analysis indicated that the chemotherapy-free regimen of sintilimab + anlotinib achieved the greatest progression-free survival (PFS) benefit, compared with chemotherapy (HR = 0.39, 95% CI 0.23-0.67), and the lowest incidence of grade ≥ 3 treatment-related adverse events (TRAEs) (RR = 0.57, 95% CI 0.32-0.95). Recombinant human endostatin (Endostar) + chemotherapy provided the largest overall survival (OS) benefit vs. chemotherapy (HR = 0.46, 95% CI 0.36-0.58). The triplet regimen of atezolizumab, bevacizumab, and chemotherapy yielded the largest improvement in objective response rate (ORR) vs. bevacizumab + chemotherapy (OR = 1.90, 95% CI 1.40-2.60). Across most subgroup analyses, regimens combining immunotherapy, an antiangiogenic agent, and chemotherapy conferred the greatest PFS and OS benefits.<h4>Conclusions</h4>This network meta-analysis demonstrates that antiangiogenic combinations improve outcomes in driver-negative advanced NSCLC. Endostar + chemotherapy offers the greatest OS benefit, atezolizumab-bevacizumab-chemotherapy improves ORR, and sintilimab-anlotinib provides superior PFS with lower toxicity. Treatment should be tailored based on clinical factors, with further validation in multiethnic trials.