Ripretinib — Drug Monograph

Brand names: Qinlock

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Ripretinib is an oral switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA, including wild-type and a wide spectrum of primary and secondary resistance mutations. It uses a dual mechanism of action, binding both the kinase switch pocket and the activation loop to lock the kinase in an inactive state. This switch-control design allows ripretinib to inhibit KIT mutations across exons 9, 11, 13, 14, 17 and 18 and PDGFRA mutations — the secondary resistance mutations that accumulate in heavily pretreated gastrointestinal stromal tumor (GIST) and that narrow-spectrum TKIs…

FDA Indications

• Advanced gastrointestinal stromal tumor (GIST) in adults who have received prior treatment with 3 or more kinase inhibitors, including imatinib (fourth-line and beyond) — approved May 2020 (INVICTUS trial)

Common Side Effects

• Alopecia (up to 52%)
• Fatigue (up to 42%)
• Nausea (up to 39%)
• Palmar-plantar erythrodysesthesia / hand-foot skin reaction (up to 21%)
• Myalgia (up to 32%)
• Diarrhea (up to 28%)
• Decreased appetite (up to 27%)
• Constipation (up to 21%)
• Weight loss
• Hypertension

Clinical Pearl

Ripretinib is the switch-control TKI that anchors fourth-line and beyond GIST: in INVICTUS it improved median progression-free survival to 6.3 vs. 1.0 months versus placebo in patients who had already received imatinib, sunitinib and regorafenib. Its broad coverage of secondary KIT resistance mutations (exons 13, 14, 17, 18) is what distinguishes it from the narrower-spectrum earlier-line agents. Note the negative INTRIGUE trial: ripretinib was not superior to sunitinib in the second line, so…

Related Therapies & Mechanisms

• Avapritinib (Ayvakit) — Tyrosine Kinase Inhibitor · GIST
• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor
• Alpelisib (Piqray) — Tyrosine Kinase Inhibitor