**Background:** Thyroid cancer incidence has risen globally, with an estimated 586,202 new cases in 2020. While differentiated thyroid cancer (DTC) has a favorable prognosis (5-year survival ~98%), advanced or metastatic disease, particularly medullary thyroid carcinoma (MTC) and radioiodine-refractory DTC, carries poor outcomes. RET alterations—activating mutations in MTC (45-50% sporadic, 95-98% hereditary) and RET fusions in papillary thyroid cancer (10-20%)—are key oncogenic drivers. Multikinase inhibitors (MKIs) like vandetanib, cabozantinib, sorafenib, and lenvatinib have been standard therapies but are limited by off-target toxicity, high dose reduction rates (35-79%), and discontinuation rates (12-19%). Selective RET inhibitors (selpercatinib, pralsetinib) have emerged as more potent and better-tolerated alternatives.
**Methods:** This is a narrative review summarizing clinical trial data, guideline recommendations, and current challenges in managing advanced RET-driven thyroid cancer in Europe. Key data sources include phase III MKI trials (ZETA, EXAM, DECISION, SELECT, COSMIC-311) and phase I/II trials of selective RET inhibitors (LIBRETTO-001 for selpercatinib, ARROW for pralsetinib). The review also discusses molecular testing methods, imaging modalities, and future directions including ongoing head-to-head trials and resistance mechanisms.
**Key Results:** In the ZETA trial, vandetanib improved median progression-free survival (PFS) versus placebo in advanced MTC (30.5 vs 19.3 months; HR 0.46; p<0.001), with objective response rate (ORR) 45% vs 13%. Cabozantinib in the EXAM trial showed PFS 11.2 vs 4.0 months (HR 0.28; p<0.001) and ORR 28% vs 0%. For RAI-refractory DTC, sorafenib (DECISION) improved PFS (10.8 vs 5.8 months; HR 0.59; p<0.0001), lenvatinib (SELECT) showed PFS 18.3 vs 3.6 months (HR 0.21; p<0.001) with ORR 64.8% vs 1.5%, and cabozantinib (COSMIC-311) as second-line therapy yielded PFS not reached vs 1.9 months (HR 0.22; p<0.0001). Selective RET inhibitors demonstrated superior efficacy: selpercatinib (LIBRETTO-001) achieved ORR 73.5% in previously treated RET-mutant MTC (median PFS 34 months) and 81.0% in treatment-naïve MTC (median PFS not reached); in RET fusion-positive thyroid cancer, ORR was 77.3%. Pralsetinib (ARROW) showed ORR 52.2% in previously treated MTC (median PFS 25.8 months), 71.6% in treatment-naïve MTC, and 84.0% in RET fusion-positive thyroid cancer (median PFS 25.4 months). Both selective inhibitors had favorable safety profiles with low discontinuation rates (4-7% for selpercatinib, 6-7% for pralsetinib) compared to MKIs.
**Clinical Implications:** The review recommends that genetic testing for RET alterations should be performed before initiating systemic therapy, with DNA-based NGS for mutations and RNA-based NGS or RT-PCR for fusions. With EMA approval of selpercatinib for first-line treatment of advanced RET-mutant MTC (September 2022), selective RET inhibitors should be considered first-line therapy for these patients. For RET fusion-positive DTC, selpercatinib is approved after prior sorafenib and/or lenvatinib. The improved tolerability of selective inhibitors may allow earlier treatment initiation and better quality of life. Ongoing trials (e.g., LIBRETTO-531 comparing selpercatinib vs cabozantinib/vandetanib) will further define optimal sequencing. Challenges include resistance mechanisms (e.g., RET G180 solvent front mutations, MAPK pathway reactivation), need for multidisciplinary team management, and regulatory heterogeneity across European countries. Future directions include second-generation RET inhibitors (TPX-0046, LOXO-260) and combination therapies targeting alternative pathways.