Qinlock - Drug Monograph

Introduction

Qinlock (ripretinib) is an oral kinase inhibitor approved by the FDA in May 2020 for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib. It represents a significant advancement in the management of heavily pretreated GIST patients, offering a novel mechanism of action that targets a broad spectrum of KIT and PDGFRA mutations.

Mechanism of Action

Ripretinib functions as a switch-control kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. Unlike earlier kinase inhibitors, ripretinib binds to the kinase in both its active and inactive conformations, effectively blocking both wild-type and mutant forms of KIT and PDGFRA. It specifically targets the kinase switch pocket, stabilizing the kinase in its inactive state and preventing downstream signaling pathways that drive tumor proliferation and survival.

Indications

Qinlock is indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib.

Dosage and Administration

• Standard dosing: 150 mg orally once daily with or without food
• Administration: Swallow tablets whole; do not crush or chew
• Missed dose: Take as soon as remembered unless next dose is due within 12 hours
• Special populations:

- Renal impairment: No dosage adjustment recommended for mild to moderate impairment - Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment - Elderly patients: No dosage adjustment recommended - Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Median Tmax approximately 4 hours post-dose
• Distribution: Apparent volume of distribution ~765 L; >99% protein bound
• Metabolism: Primarily via CYP3A4 and CYP2C8; also undergoes flavin-containing monooxygenase (FMO) metabolism
• Elimination: Half-life ~14.8 hours; primarily excreted in feces (94%) with minimal renal excretion
• Food effect: No clinically significant effect on exposure

Contraindications

• History of hypersensitivity to ripretinib or any component of the formulation

Warnings and Precautions

• Palmar-plantar erythrodysesthesia syndrome: Monitor for skin reactions; may require dose modification
• Hypertension: Monitor blood pressure regularly; manage with antihypertensive therapy as needed
• Cardiac dysfunction: Assess left ventricular ejection fraction (LVEF) at baseline and during treatment
• Dermatologic reactions: Including hair color changes, alopecia, and rash
• Embryo-fetal toxicity: Can cause fetal harm; advise patients of reproductive potential of risks and need for contraception

Drug Interactions

• Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin): May increase ripretinib exposure; consider alternative agents or monitor for adverse reactions
• Strong CYP3A inducers (e.g., rifampin, carbamazepine): May decrease ripretinib exposure; avoid concomitant use
• CYP3A substrates: Ripretinib may increase exposure to sensitive CYP3A substrates

Adverse Effects

• Alopecia (52%)
• Fatigue (42%)
• Nausea (38%)
• Abdominal pain (36%)
• Constipation (33%)
• Myalgia (31%)
• Diarrhea (28%)
• Decreased appetite (27%)
• Palmar-plantar erythrodysesthesia syndrome (21%)
• Vomiting (21%)

• Palmar-plantar erythrodysesthesia syndrome (7%)
• Hypertension (5%)
• Abdominal pain (3%)

Monitoring Parameters

• Baseline: Complete blood count, comprehensive metabolic panel, LVEF assessment, blood pressure
• Ongoing:

- Blood pressure monitoring every 2 weeks for first 2 months, then monthly - LVEF assessment every 3 months - Dermatologic examinations for skin reactions - Routine assessment of renal and hepatic function - Monitoring for signs and symptoms of cardiac dysfunction

Patient Education

• Take medication at approximately the same time each day
• Report any skin changes, particularly on palms and soles
• Monitor blood pressure regularly as directed by healthcare provider
• Report symptoms of cardiac dysfunction (shortness of breath, edema, fatigue)
• Use effective contraception during treatment and for at least 1 week after final dose
• Do not crush, chew, or split tablets
• Inform all healthcare providers about Qinlock use before starting new medications
• Report any new or worsening symptoms promptly

References

1. FDA Approval Letter: Qinlock (ripretinib). May 2020 2. Blay JY, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(7):923-934 3. Qinlock [package insert]. Waltham, MA: Deciphera Pharmaceuticals, LLC; 2023 4. Smith BD, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(5):738-751 5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma. Version 2.2023