Efficacy and safety of anti-VEGF/VEGFR monotherapy and combination with immune checkpoint inhibitors for advanced or metastatic renal cell carcinoma: A network meta-analysis

Background The treatment landscape for advanced/metastatic renal cell carcinoma (mRCC) has evolved to encompass anti-VEGF/VEGFR monotherapy as well as its combination with immune checkpoint inhibitors (ICIs). However, direct comparisons among all available regimens are currently lacking. This network meta-analysis (NMA) aims to evaluate their relative efficacy and safety to better inform clinical decision-making. Methods We conducted a Bayesian NMA of randomized controlled trials (RCTs) retrieved from PubMed, Embase, Web of Science, the Cochrane Library and Clinical Trials gov up to May 2025. Efficacy outcomes included overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR). Safety outcomes included grade ≥ 3 adverse events (≥ 3 AEs), treatment discontinuation due to AEs, and specific AEs. Treatments were ranked by calculating the surface under the cumulative ranking curve (SUCRA) probability. Results A total of 24 RCTs involving 10,271 patients were included. For OS, toripalimab plus axitinib ranked the highest (SUCRA = 0.849) and significantly outperformed tivozanib (HR = 2.14, 95% CI: 1.01–4.64), followed by bembelstobart plus anlotinib (SUCRA = 0.801) and pembrolizumab plus axitinib (SUCRA = 0.792). Lenvatinib plus pembrolizumab achieved the highest ranking for PFS (SUCRA = 0.939) and demonstrated superiority over most monotherapies (HR = 0.47, 95% CI: 0.34–0.65 vs. sunitinib). Bembelstobart plus anlotinib exhibited the highest ORR (SUCRA = 0.972). Anlotinib monotherapy presented the lowest risk of grade ≥ 3 AEs (SUCRA = 0.904) and hypertension (SUCRA = 0.727). Tivozanib and sunitinib (2-week-on/1-week-off regimens) displayed better tolerability for hand-foot syndrome and fatigue, respectively. Patients treated with bevacizumab plus atezolizumab had the lowest risk of treatment discontinuation due to adverse effects (AEs). Subgroup analyses confirmed the superiority of combination therapy in intermediate-/high-risk and Asian populations. Conclusion ICI-based combination therapies generally outperformed VEGF-targeted monotherapy (except cabozantinib) in efficacy but were associated with increased toxicity risks. Treatment strategies should be individualized based on risk stratification and patient preferences.