Pralsetinib — Drug Monograph

Brand names: Gavreto

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Selective RET kinase inhibitor targeting activating RET fusions and point mutations (including RET M918T, C634W gatekeeper mutations). Inhibits RET-driven oncogenic signaling in tumors with RET alterations. Exhibits intracranial activity. One of the first two FDA-approved selective RET inhibitors (alongside selpercatinib).

FDA Indications

• RET fusion-positive metastatic NSCLC in adults (FDA approved September 2020; ARROW: 72% ORR in treatment-naive patients)
• RET-mutant metastatic medullary thyroid cancer (MTC) in adults and pediatric patients ≥12 years requiring systemic therapy (ARROW: 60% ORR)
• RET fusion-positive thyroid cancer in adults and pediatric patients ≥12 years requiring systemic therapy and radioactive iodine refractory

Common Side Effects

• Constipation (35%)
• Hypertension (29%)
• Fatigue (27%)
• Musculoskeletal pain (32%)
• Edema (27%)
• Neutropenia (22%)
• Anemia
• Increased AST/ALT

Clinical Pearl

Pralsetinib and selpercatinib were the first two selective RET inhibitors approved, superseding multikinase inhibitors (cabozantinib, vandetanib) for RET-driven cancers. The key distinction is the need to avoid PPIs (take on an empty stomach) to ensure adequate bioavailability. Pneumonitis is the most critical serious toxicity requiring immediate evaluation.

Related Therapies & Mechanisms

• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC
• Larotrectinib (Vitrakvi) — Tyrosine Kinase Inhibitor · NSCLC
• Selpercatinib (Retevmo) — Tyrosine Kinase Inhibitor · NSCLC
• Trametinib (Mekinist) — Tyrosine Kinase Inhibitor · NSCLC