FDA Approves QINLOCK (Ripretinib) for the Treatment of Adult Patients with Advanced Gastrointestinal Stromal Tumor who Have Received Prior Treatment with 3 or More Kinase Inhibitors, Including Imatinib
On May 15, 2020, the U.S. Food and Drug Administration (FDA) approved QINLOCK (ripretinib) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib. The approved recommended dosage of QINLOCK is 150 mg orally once daily with or without food until disease progression or unacceptable toxicity. Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about palmar-plantar erythrodysesthesia syndrome, new primary cutaneous malignancies, hypertension, cardiac dysfunction, risk of impaired wound healing, or embryo-fetal toxicity can be found in the full prescribing information linked below.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Ripretinib is a tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet derived growth factor receptor A (PDGFRA) kinase, including wild type, primary, and secondary mutations.
General PK: The general pharmacokinetics of ripretinib and its active metabolite, DP-5439, are presented below.
- Ripretinib: The mean (CV%) steady state Cmax and AUC0-12h was 761 ng/mL (32%) and 5678 ng•h/mL (32%), respectively. Ripretinib AUC0-24h increased proportionally over a dose range of 20 mg to 250 mg (0.13 to 1.67 times the recommended dose), but Cmax was less than dose proportional. The time to steady state of ripretinib was 14 days with a mean accumulation ratio (AUC0-12h) of 1.7 (55%).
- DP-5439: The mean (CV%) steady state Cmax and AUC0-12h was 804 ng/mL (46%) and 7138 ng•h/mL (44%), respectively. DP-5439 Cmax and AUC0-24h were less than dose proportional within the dose range of 50 mg to 250 mg (0.33 to 1.67 times the recommended dose). The time to steady state of DP-5439 was 14 days with a mean accumulation ratio (AUC0-12h) of 5.3 (49%).
Absorption: The median Tmax of ripretinib and DP-5439 was 4 hours and 15.6 hours, respectively.
Distribution: The mean (CV%) apparent volume of distribution ripretinib and DP-5439 at steady-state was 307 L (39%) and 507 L (51%), respectively. The plasma protein binding of ripretinib and DP-5439 was 99.8% and 99.7% to human serum albumin and 99.4% and > 99.8% to α-1 acid glycoprotein, respectively.
Elimination: The mean (CV%) half-life of ripretinib and DP-5439 was 14.8 hours (30%) and 17.8 hours (23%), respectively. The mean apparent clearance of ripretinib and DP-5439 was 15.3 L/hr (45%) and 17.5 L/hr (63%), respectively.
Metabolism: Ripretinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8 and CYP2D6. DP-5439 is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2E1, and CYP2D6.
Excretion: After a single oral ripretinib 150 mg dose, 34% of the dose was excreted in feces as ripretinib and 6% as DP-5439, whereas 0.02% was excreted in urine as ripretinib and 0.1% as DP-5439.
Strong CYP3A Inhibitors: Monitor patients more frequently for adverse reactions. Coadministration of QINLOCK with a strong CYP3A inhibitor increased the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions.
Strong CYP3A Inducers: Avoid concomitant use of QINLOCK with strong CYP3A inducers. Coadministration of QINLOCK with a strong CYP3A inducer may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease QINLOCK anti-tumor activity.
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of ripretinib were observed based on age (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), tumor (GIST or other solid tumors), prior gastrectomy, mild to moderate renal impairment (CLcr 30 to <90 mL/min estimated by Cockcroft-Gault), and mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 × ULN and AST any). The effects of severe renal impairment (CLcr 15 to 29 mL/min) or moderate to severe hepatic impairment (total bilirubin >1.5 × ULN, AST any) on the pharmacokinetics of ripretinib have not been studied.
Lactation: Advise women not to breastfeed during treatment with QINLOCK and for at least 1 week after the final dose because of the potential for serious adverse reactions in the breastfed child. There are no data regarding the presence of ripretinib or its metabolites in either human milk or its effects on a breastfed child or on milk production.
Efficacy and Safety
Efficacy of QINLOCK was demonstrated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial that enrolled patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST) and had received prior treatment with imatinib, sunitinib, and regorafenib. The major efficacy outcome measure was progression-free survival (PFS) based on disease assessment by blinded independent central review (BICR) using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.
The most common adverse reactions (≥20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.