Selpercatinib — Drug Monograph
Brand names: Retevmo
Drug class: Tyrosine Kinase Inhibitor
Mechanism of Action
First-in-class, highly selective, ATP-competitive RET (rearranged during transfection) kinase inhibitor. RET is a receptor tyrosine kinase that, when activated by oncogenic fusions (CCDC6-RET, KIF5B-RET, NCOA4-RET, and others) or point mutations (C634W, M918T in MEN2B/sporadic MTC), drives constitutive downstream MAPK, PI3K/AKT, and JAK/STAT signaling. Selpercatinib was designed to selectively inhibit RET with minimal off-target kinase activity (particularly avoids VEGFR2, avoiding the hypertension and other vascular effects of multi-kinase inhibitors like cabozantinib/vandetanib). Active…
FDA Indications
- RET fusion-positive NSCLC — locally advanced or metastatic (first-line and previously treated — LIBRETTO-001)
- RET-mutant medullary thyroid carcinoma (MTC) — advanced or metastatic adults and pediatric patients ≥12 years — first-line preferred over cabozantinib/vandetanib (LIBRETTO-001/LIBRETTO-531)
- RET fusion-positive thyroid cancer (DTC, PTC) — locally advanced or metastatic, RAI-refractory
- RET fusion-positive solid tumors — locally advanced or metastatic, adults and pediatric patients ≥2 years, after prior systemic therapy (tumor-agnostic)
Common Side Effects
- Hypertension (35–40%)
- Fatigue
- Edema
- Rash
- Nausea
- Dry mouth
- Diarrhea
- Constipation
- Headache
- QTc prolongation
Clinical Pearl
Selpercatinib is now the preferred first-line targeted therapy for RET-mutant MTC (LIBRETTO-531: superior PFS vs. cabozantinib/vandetanib as first-line; HR 0.28). Unlike multi-kinase inhibitors (cabozantinib, vandetanib), selpercatinib's high RET selectivity translates to a much better-tolerated toxicity profile — significantly less hypertension and GI toxicity. RET testing should be performed by NGS (not FISH alone) to capture the diverse fusion partners. For RET fusions in NSCLC,…
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