Class: Tyrosine kinase inhibitor (TKI), “switch-control” inhibitor
Mechanism of Action:
- Broad-spectrum KIT and PDGFRA inhibitor.
- Designed as a “switch-control” TKI, which locks the kinase in an inactive conformation and inhibits both primary and secondary mutations in KIT and PDGFRA.
- Overcomes resistance mutations seen with imatinib, sunitinib, and regorafenib in GIST.
Indication:
- FDA/EMA approved for adults with advanced gastrointestinal stromal tumor (GIST) who have received ≥3 prior kinase inhibitors (including imatinib).
- Essentially used as 4th-line therapy in GIST.
Dose:
- 150 mg orally once daily (with or without food).
- Continue until disease progression or unacceptable toxicity.
Metabolism & Elimination:
- CYP3A4 substrate (avoid strong inhibitors/inducers).
- Fecal elimination is primary route.
Adverse Effects:
- Common: Alopecia, fatigue, nausea, constipation, myalgia, palmar-plantar erythrodysesthesia (PPE).
- Serious: Hypertension, cardiac dysfunction (rare), secondary skin malignancies (SCC, melanoma).
Monitoring:
- Blood pressure (baseline, periodically).
- Dermatologic exams (risk of skin cancers).
- LVEF in patients with cardiac history.
- CBC and LFTs as clinically indicated.
Drug Interactions:
- CYP3A4 inducers ↓ ripretinib exposure.
- CYP3A4 inhibitors ↑ ripretinib exposure.
- Consider alternative agents if possible.
Key Clinical Trial: INVICTUS trial: Ripretinib improved median PFS (6.3 vs 1.0 months with placebo) and OS in heavily pretreated GIST.