Selpercatinib versus multi-kinase inhibitors for advanced medullary thyroid cancer: A network meta-analysis of RET-targeted therapies

Background – Several RET-targeted agents, including highly selective RET inhibitors (SRIs) and multi-kinase inhibitors (MKIs), have been approved for the treatment of advanced medullary thyroid cancer (MTC). Despite these agents targeting the same pathway, direct comparative data is lacking. This study aims to evaluate the relative efficacy and safety of these agents via network meta-analysis (NMA). Methods – We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and CNKI (up to March 2026) for RCTs evaluating RET-targeted therapies for advanced MTC. The primary outcome was progression-free survival (PFS); secondary outcomes included objective response rate (ORR) and ≥Grade 3 adverse events (AEs). A frequentist random-effects model was employed, and treatments were ranked using P-scores. The study was registered in PROSPERO (CRD420261342793). Results – Five RCTs (n = 1, 076) were included. Selpercatinib demonstrated the most significant PFS benefit (HR = 0.10, 95% CI: 0.05–0.18; P-score = 0.999), outperforming cabozantinib (HR = 0.28) and vandetanib (HR = 0.46). It also ranked first for ORR (OR = 122.6, 95% CI: 34.5–435.6). Regarding safety, selpercatinib showed no significant difference in ≥Grade 3 AEs compared to placebo (OR = 1.34), whereas anlotinib exhibited the highest toxicity (OR = 12.00). Although selpercatinib was associated with hepatotoxicity (OR = 4.20), it avoided the off-target toxicities typical of MKIs, such as hypertension and diarrhea. Conclusion – This network meta-analysis demonstrates that selpercatinib exhibits superior efficacy (PFS and ORR) and a more favorable safety profile compared to MKIs for advanced MTC. These results support its role as a recommended first-line option for advanced MTC. However, due to the heterogeneity of included populations (mixed RET mutation status and therapy lines), clinicians should interpret these findings with caution regarding the generalizability to strictly defined RET-mutant populations. Clinical decisions should be individualized. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261342793, identifier CRD420261342793.