Селективные ингибиторы RET стали стандартом лечения медуллярного рака щитовидной железы

Targeted therapies have reshaped the management of advanced medullary thyroid carcinoma (MTC), with selective RET inhibitors providing greater efficacy and improved tolerability than earlier multikinase inhibitors in RET-mutant disease, according to a review by Hameeda Arif Arain, MBBS, of the Department of Surgery, University of Alabama at Birmingham, published in The Oncologist. Vandetanib and cabozantinib established systemic treatment efficacy, but toxicity and acquired resistance remain important limitations. Emerging RET inhibitors, radioligand therapy, biomarkers and cellular therapies could further expand individualized treatment options. In the phase 3 ZETA trial (NCT00410761), vandetanib improved median progression-free survival (PFS) to approximately 30 months vs 19 months with placebo (hazard ratio [HR], 0.46; P <.001), with higher objective response rates (ORRs; 45% vs 13%) and disease control rates (87% vs 71%). Overall survival (OS) did not differ significantly (HR, 1.08; 95% CI, 0.72-1.61; P =.71), potentially reflecting crossover after progression. Real-world data showed an ORR of 42%, disease control rate of 83% and median PFS of 25.9 months. Cabozantinib similarly prolonged PFS in the phase 3 EXAM trial (NCT00704730), with median PFS of 11.2 vs 4.0 months with placebo (HR, approximately 0.28; P <.001) and an ORR of approximately 28% vs 0%. Median OS was not significantly different (26.6 vs 21.1 months; HR, 0.85; 95% CI, 0.64-1.12; P =.24), although patients with RET M918T had longer OS with cabozantinib (44.3 vs 18.9 months; HR, 0.60; 95% CI, 0.38-0.94; P =.03). Both multikinase inhibitors can cause substantial toxicities, including gastrointestinal adverse events, hypertension, and fatigue, with cabozantinib carrying warnings for perforation, hemorrhage, and fistula formation. Selective RET inhibition has subsequently shifted treatment toward molecularly directed therapy. In phase 1/2 LIBRETTO-001 (NCT03157128), selpercatinib produced ORRs of 77.6% in previously treated and 82.5% in treatment-naïve RET-mutant MTC, with median PFS of 41.4 months in previously treated patients. In phase 3 LIBRETTO-531 (NCT04211337), selpercatinib reduced the risk of progression or death vs cabozantinib or vandetanib (HR, 0.28; 95% CI, 0.16-0.48; P <.001), with higher ORR (69% vs 39%) and fewer treatment discontinuations due to adverse events (4.7% vs 26.8%). Resistance, particularly RET V804 gatekeeper and G810 solvent-front mutations, remains a major challenge. Next-generation agents including EP0031, BOS172738 and SY-5007 have demonstrated early activity against resistant disease, while 177Lu-DOTATATE peptide receptor radionuclide therapy has shown promise in somatostatin receptor–positive MTC. Emerging approaches also include GFRα4-directed CAR-T therapy and circulating cell-free DNA biomarkers. Emerging therapies, including newer selective RET inhibitors and [peptide receptor radionuclide therapy], show promising early results. For clinical management, molecular profiling should guide systemic therapy selection. Selpercatinib is preferred first-line treatment for RET-mutant advanced MTC, whereas vandetanib or cabozantinib remain options for RET-wild-type disease. Local therapies may be appropriate for isolated symptomatic or threatening lesions, and repeat tissue or liquid biopsy can help identify resistance after progression. Selpercatinib may also have a role in neoadjuvant treatment of RET-positive, progressive, unresectable locoregional disease. “Emerging therapies, including newer selective RET inhibitors and [peptide receptor radionuclide therapy], show promising early results,” explained Arain and colleagues. “Continued research is essential for addressing resistance and further improving patient outcomes in advanced MTC.” Disclosures: No funding was reported. The authors declare they have no conflicts of interest. This article originally appeared on Oncology Nurse Advisor