Ripretinib is an oral small‑molecule tyrosine‑kinase inhibitor (TKI) used in the treatment of advanced and metastatic gastrointestinal stromal tumors (GIST) that are resistant to prior therapies. It is marketed under the brand name Qinlock and was approved by the United States Food and Drug Administration (FDA) in May 2020 for patients who have received at least three prior lines of TKI therapy for GIST. The European Medicines Agency (EMA) granted similar approval in 2021.
Chemical and Pharmacological Profile
- IUPAC name: (E)-N‑[(3S,4R)-3‑hydroxy‑4‑(4‑fluorophenyl)‑1‑(2‑pyridyl)‑1‑oxo‑2‑propan-2‑yl]‑3‑(4‑morpholin-4-ylpyrimidin-5‑yl)‑2‑prop‑2‑enamide
- Molecular formula: C₃₁H₃₁F₁N₆O₄
- Molecular weight: 604.66 g·mol⁻¹
- Mechanism of action: Ripretinib functions as a “switch‑control” inhibitor of the KIT (CD117) and platelet‑derived growth factor receptor alpha (PDGFRA) kinases. It binds both the juxtamembrane and activation loop regions of these receptors, stabilizing them in an inactive conformation and thereby suppressing downstream signaling pathways involved in cell proliferation and survival. The drug exhibits activity against a broad spectrum of KIT and PDGFRA mutations, including those that confer resistance to earlier TKIs such as imatinib, sunitinib, and regorafenib.
Medical Use
Ripretinib is indicated for the treatment of adult patients with GIST who have progressed after treatment with at least three prior TKIs. It is administered orally at a standard dose of 150 mg once daily, taken with or without food. Dose adjustments may be required for patients with hepatic impairment or for management of adverse events.
Clinical Efficacy
The pivotal phase III INVICTUS trial evaluated ripretinib versus placebo in patients with advanced GIST who had received ≥3 prior TKIs. The study demonstrated a statistically significant improvement in median progression‑free survival (PFS) (6.3 months for ripretinib vs. 1.0 month for placebo) and an overall survival benefit, leading to its regulatory approval. Objective response rates were modest (≈9 % partial responses), but disease control rates were high due to durable stable disease.
Safety and Adverse Effects
Common adverse reactions (≥10 % incidence) reported in clinical trials include:
- Alopecia
- Fatigue
- Nausea and vomiting
- Diarrhea
- Decreased appetite
- Hand‑foot skin reaction
- Hypertension
- Elevated lipase and amylase
Serious but less frequent toxicities include hepatic enzyme elevations, pancreatitis, and cardiovascular events. Ripretinib is teratogenic in animal studies; therefore, pregnancy is contraindicated, and effective contraception is required during treatment and for at least 30 days after the last dose.
Pharmacokinetics
- Absorption: Peak plasma concentrations occur approximately 2–4 hours post‑dose.
- Distribution: Approximately 99 % bound to plasma proteins.
- Metabolism: Primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C8.
- Elimination: The mean terminal half‑life is approximately 15 hours; excretion is mainly fecal (≈70 %) with the remainder urinary.
Drug Interactions
Concomitant use of strong CYP3A4 inducers (e.g., rifampicin, carbamazepine) can reduce ripretinib plasma concentrations, potentially diminishing efficacy. Conversely, strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) may increase exposure and risk of toxicity; dose modifications are recommended.
Regulatory and Patent Status
Ripretinib is patented by Deciphera Pharmaceuticals, Inc., which holds exclusive rights in several jurisdictions. Post‑marketing surveillance continues to monitor long‑term safety and effectiveness.
Research Directions
Ongoing studies are assessing ripretinib in earlier lines of therapy for GIST, its combination with other targeted agents, and its activity in other KIT‑ or PDGFRA‑driven malignancies. Results from these investigations may expand its therapeutic indications.