Advanced Thyroid Cancer — RET-Altered

Sequencing for RET-altered advanced thyroid cancer (RET-mutant medullary and RET fusion-positive differentiated): a selective RET inhibitor (selpercatinib preferred, or pralsetinib) first line, then a multikinase tyrosine kinase inhibitor (cabozantinib or vandetanib) on progression, then a clinical trial.

RET alteration and histology

• RET-mutant medullary thyroid cancer → Selective RET inhibitor (selpercatinib preferred, or pralsetinib)
• RET fusion-positive differentiated thyroid cancer → Selective RET inhibitor (selpercatinib preferred, or pralsetinib)

1L: Selective RET inhibitor (selpercatinib preferred, or pralsetinib)

Preferred first line for both RET-mutant medullary thyroid cancer and RET fusion-positive differentiated thyroid cancer; LIBRETTO-531 showed selpercatinib superior to multikinase TKIs in RET-mutant MTC. Selpercatinib: monitor hypertension, transaminitis, QTc, and hypersensitivity. Pralsetinib: monitor cytopenias and pneumonitis.

• Progression → Multikinase TKI (cabozantinib or vandetanib)

2L: Multikinase TKI (cabozantinib or vandetanib)

On progression after a selective RET inhibitor. Cabozantinib and vandetanib are both FDA-approved in medullary thyroid cancer; manage hypertension, hand-foot skin reaction, and (vandetanib) QTc prolongation. For differentiated thyroid cancer, a VEGFR multikinase TKI (e.g., lenvatinib/sorafenib) is an alternative per histology.

• Progression → Clinical trial or best supportive care

3L+: Clinical trial or best supportive care

After selective RET and multikinase TKI therapy, prioritize a clinical trial (e.g., next-generation RET inhibitors for acquired solvent-front resistance) or best supportive care.