Brand Name
Qinlock
Generic Name
Ripretinib
View Brand Information FDA approval date: May 15, 2020
Classification: Kinase Inhibitor
Form: Tablet
What is Qinlock (Ripretinib)?
QINLOCK is indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with 3 or more kinase inhibitors, including imatinib. QINLOCK is a kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with 3 or more kinase inhibitors, including imatinib.
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Brand Information
QINLOCK (Ripretinib)
1INDICATIONS AND USAGE
QINLOCK is indicated 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.
2DOSAGE AND ADMINISTRATION
2.1Recommended Dosage
The recommended dosage of QINLOCK is 150 mg orally once daily with or without food until disease progression or unacceptable toxicity.
Instruct patients to swallow tablets whole.
Advise patients to take QINLOCK at the same time each day.
Advise patients to take a missed dose if less than 8 hours have passed since the missed scheduled dose.
Advise patients not to take an additional dose if vomiting occurs after taking QINLOCK and to continue with their next scheduled dose.
2.2Dosage Modifications for Adverse Reactions
The recommended dose reduction for adverse reactions is:
- QINLOCK 100 mg orally once daily.
Permanently discontinue QINLOCK in patients who are unable to tolerate 100 mg orally once daily.
2.3Dose Modifications for Moderate CYP3A Inducers
Avoid concomitant use of moderate CYP3A inducers during QINLOCK treatment.
If a moderate CYP3A inducer cannot be avoided, increase the QINLOCK dosing frequency from the recommended dose of 150 mg once daily to 150 mg twice daily during the co-administration period. Monitor for clinical response and tolerability. If the concomitant moderate CYP3A inducer is discontinued, resume QINLOCK dosage back to 150 mg once daily 14 days after the discontinuation of the moderate CYP3A inducer [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
For patients concomitantly using a moderate CYP3A inducer with QINLOCK (taking QINLOCK twice daily) who missed a dose:
- If less than 4 hours have passed since the missed scheduled dose, advise the patient to take the missed dose as soon as possible and then take the next dose at the regularly scheduled time.
- If more than 4 hours have passed since the missed scheduled dose, advise the patient to skip the missed dose and then take the next dose at the regularly scheduled time. [see Drug Interactions (7.1)].
3DOSAGE FORMS AND STRENGTHS
Tablets: 50 mg, white to off-white, oval shaped, debossed with “DC1” on one side.
4CONTRAINDICATIONS
None.
5WARNINGS AND PRECAUTIONS
5.1Palmar-Plantar Erythrodysesthesia Syndrome
In INVICTUS, Grade 1-2 palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 21% of the 85 patients who received QINLOCK [see Adverse Reactions (6.1)]. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients.
Based on severity, withhold QINLOCK and then resume at same or reduced dose [see Dosage and Administration (2.2)].
5.2New Primary Cutaneous Malignancies
In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received QINLOCK, with a median time to event of 4.6 months (range: 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of patients, respectively.
In INVICTUS, melanoma occurred in 2.4% of the 85 of patients who received QINLOCK. In the pooled safety population, melanoma occurred in 0.9% of patients.
Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue QINLOCK at the same dose.
5.3Hypertension
In INVICTUS, Grade 1-3 hypertension occurred in 14% of the 85 patients who received QINLOCK, including Grade 3 hypertension in 7% [see Adverse Reactions (6.1)].
Do not initiate QINLOCK in patients with uncontrolled hypertension. Adequately control blood pressure prior to initiating QINLOCK. Monitor blood pressure as clinically indicated during treatment with QINLOCK, and initiate or adjust antihypertensive therapy as appropriate. Based on severity, withhold QINLOCK and then resume at same or reduced dose or permanently discontinue [see Dosage and Administration (2.2)].
5.4Cardiac Dysfunction
In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received QINLOCK. In the pooled safety population, cardiac dysfunction (including cardiac failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7% of patients, including Grade 3 adverse reactions in 1.1%.
In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram. In the pooled safety population, Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients who received QINLOCK and who had a baseline and at least one post-baseline echocardiogram.
In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received QINLOCK. The safety of QINLOCK has not been assessed in patients with a baseline ejection fraction below 50%.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating QINLOCK and during treatment, as clinically indicated. Permanently discontinue QINLOCK for Grade 3 or 4 left ventricular systolic dysfunction [see Dosage and Administration (2.2)].
5.5Risk of Impaired Wound Healing
Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, QINLOCK has the potential to adversely affect wound healing.
Withhold QINLOCK for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of QINLOCK after resolution of wound healing complications has not been established.
5.6>5.6 Photosensitivity
QINLOCK may cause photosensitivity reactions. In all patients treated with QINLOCK in clinical trials (n=621), photosensitivity reactions occurred in 0.6% of patients.
Advise patients to limit direct ultraviolet exposure during treatment with QINLOCK and for at least one week after discontinuation of treatment.
5.7Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, QINLOCK can cause fetal harm when administered to a pregnant woman. Oral administration of ripretinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations primarily associated with the cardiovascular and skeletal systems, anatomic variations, decreased fetal body weight, and increased post-implantation loss at exposures approximately one half of the recommended dose of 150 mg once daily based on area under the curve (AUC).
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with QINLOCK and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with QINLOCK and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
6ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
- Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions (5.1)]
- New Primary Cutaneous Malignancies [see Warnings and Precautions (5.2)]
- Hypertension [see Warnings and Precautions (5.3)]
- Cardiac Dysfunction [see Warnings and Precautions (5.4)]
- Photosensitivity [see Warnings and Precautions (5.6)]
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to QINLOCK as a single agent in 351 patients with advanced solid tumors enrolled in either an open-label dose finding with cohort expansion trial or INVICTUS. Among the patients who received QINLOCK in these trials, 52% were exposed for 6 months or longer and 21% were exposed for greater than one year.
7DRUG INTERACTIONS
7.1Effect of Other Drugs on QINLOCK
Table 4 includes drug interactions that affect the pharmacokinetics of ripretinib.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.2Lactation
8.3Females and Males of Reproductive Potential
QINLOCK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
8.4Pediatric Use
The safety and effectiveness of QINLOCK in pediatric patients have not been established.
8.5Geriatric Use
Of the 85 patients in INVICTUS who received QINLOCK 150 mg orally once daily, 24% were between 65 to 74 years of age and 9% were 75 years of age or older. Clinical studies of QINLOCK did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
8.6Hepatic Impairment
No dose adjustment is recommended in patients with hepatic impairment (Child-Pugh A, B, or C) [see Clinical Pharmacology (12.3)].
9DESCRIPTION
Ripretinib is a kinase inhibitor. The chemical name of ripretinib is 1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl)-3-phenylurea. The molecular formula is C24H21BrFN5O2 and the molecular weight is 510.36 g/mol. The chemical structure of ripretinib is shown below:
Ripretinib is a white to off-white crystalline solid. Ripretinib is a lipophilic, weak base, and practically insoluble in aqueous media.
QINLOCK is available as a white to off-white, oval tablets for oral use containing 50 mg of ripretinib. The tablet is debossed with “DC1” on one side. Each tablet contains the following inactive ingredients: crospovidone, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and silicon dioxide.
10CLINICAL PHARMACOLOGY
10.1Mechanism of Action
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. Ripretinib also inhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF.
10.2Pharmacodynamics
10.3Pharmacokinetics
The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were characterized in clinical studies. In patients with advanced malignancies, ripretinib AUC0-24h increased proportionally over a dose range of 20-250 mg (0.13 to 1.67 times the recommended dose), but Cmax was less than dose proportional; DP-5439 Cmax and AUC0-24h were less than dose proportional within the dose range of 50-250 mg (0.33 to 1.67 times the recommended dose).
No clinically significant differences in the Cmax and AUC0-24h were observed between administration of QINLOCK with a high-fat meal (150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively) and under fasted conditions. The pharmacokinetic parameters of ripretinib and DP-5439 are summarized in Table 5.
11NONCLINICAL TOXICOLOGY
11.1Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with ripretinib.
Ripretinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either an in vitro human lymphocyte culture micronucleus assay or an in vivo rat bone marrow micronucleus assay.
Dedicated fertility studies in male animals were not conducted with ripretinib. Findings in male reproductive organs occurred in repeat-dose toxicity studies and included degeneration of the testes and cellular debris of the epididymis in males administered ≥30 mg/kg/day (approximately one half of the human exposure at the recommended dose of 150 mg).
12CLINICAL STUDIES
The efficacy of QINLOCK was evaluated in INVICTUS, an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (NCT03353753). Eligible patients had unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST) and had received prior treatment with imatinib, sunitinib, and regorafenib. Randomization was stratified by prior lines of therapy (3 versus ≥4) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1 or 2). Patients received QINLOCK 150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Tumor response assessments were performed every 28 days through for the first 4 months and then every 56 days thereafter. 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 efficacy outcome measures included objective response rate (ORR) by BICR and overall survival (OS). Patients randomized to receive placebo could be treated with QINLOCK at the time of disease progression.
A total of 129 patients were randomized, 85 to QINLOCK and 44 to placebo.
Patient characteristics of the intent-to-treat (ITT) population in INVICTUS were median age of 60 years (range: 29 to 83 years), with 39% aged ≥65 years; 57% were male; 75% were White; and 92% had an ECOG performance status of 0 or 1. Sixty-three percent (63%) of patients received 3 prior therapies and 37% received 4 or more prior therapies. Sixty-six percent (66%) of patients randomized to placebo switched to QINLOCK after disease progression.
Figure 1: Kaplan-Meier Curve of Progression-Free Survival in INVICTUS
Figure 2: Kaplan-Meier Curve of Overall Survival in INVICTUS
13HOW SUPPLIED/STORAGE AND HANDLING
QINLOCK 50 mg tablets are white to off-white, oval shaped, and debossed with “DC1” on one side.
- 90-count bottles NDC 73207-101-30
Dispense in original container only. Store in the original container with the desiccant to protect from moisture and light. Replace cap securely each time after opening. Do not discard desiccant.
Store at 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
14PATIENT COUNSELING INFORMATION
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