Tyrosine Kinase Inhibitors in Metastatic Pheochromocytomas and Paragangliomas: An Updated Systematic Review and Meta-Analysis

Abstract Therapeutic options for metastatic pheochromocytomas/paragangliomas (mPPGLs) remain limited. Recent studies indicate tyrosine kinase inhibitors (TKIs) offer a promising treatment approach. This study aims to evaluate the efficacy and safety of TKIs for mPPGLs based on available evidence. A systematic search for studies investigating the treatment of TKIs for mPPGL was conducted across PubMed, Embase, and Web of Science from databases inception to February, 2026. Data were synthesized using fixed or random effects meta-analysis model. Subgroup analysis was conducted based on status of SDHB gene and subtypes of TKIs. A total of 11 studies, comprising 4 observational and 7 interventional studies, with 246 patients involved. The stable disease rate, objective response rate (ORR), and disease control rate (DCR) were 51.8%(95% CI, 44.6%-59.1%), 27.7%(95% CI, 21.6%-34.3%), and 84.2%(95% CI, 74.8%-91.9%), respectively. The proportion of discontinuation due to adverse events was 11.3%(95% CI, 5.4%-18.7%). The combined median progression-free survival and overall survival were 13.4 (95% CI, 7.9-14.7) and 26.7(95% CI, 24.9-49.4) months. Pooled ORR(36.8%[95% CI, 21.1%-53.8%] vs. 20.1%[95% CI, 10.8%-31.0%], P=0.06).and DCR (92.2%[95% CI, 79.6%-99.7%] vs. 78.5%[95% CI, 57.3%-94.5%]; P=0.269) were higher in patients with SDHB-related mPPGL than in those with non-SDHB mPPGL, although the differences were not statistically significant. Notably, sunitinib showed no therapeutic superiority over other TKI subtypes, with lower pooled ORR (21.2%[95% CI, 14.0%–29.4%] vs 36.9%[95% CI, 26.9%–47.4%]; P=0.04) and DCR (72.6%[95% CI, 63.9%–80.6%] vs 94.5%[95% CI, 87.2%–99.3%]; P=0.001). Consequently, TKIs show promising efficacy and manageable adverse event rates in mPPGL, supporting TKIs as components of the systematic treatment.