Ripretinib

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. QINLOCK is a kinase inhibitor 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. ( 1 )

Tablets: 50 mg, white to off-white, oval shaped, debossed with “DC1” on one side. Tablets: 50 mg. ( 3 )

None. None. ( 4 )

Palmar-Plantar Erythrodysesthesia Syndrome : Based on severity, withhold QINLOCK and resume at same or reduced dose. ( 2.2 , 5.1 ) New Primary Cutaneous Malignancies : Perform dermatologic evaluations when initiating QINLOCK and routinely during treatment. ( 5.2 ) Hypertension : Do not initiate QINLOCK in patients with uncontrolled hypertension and monitor blood pressure during treatment. Based on severity, withhold QINLOCK and then resume at same or reduced dose or permanently discontinue. ( 2.2 , 5.3 ) Cardiac Dysfunction : 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. ( 2.2 , 5.4 ) Risk of Impaired Wound Healing : Withhold QINLOCK for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of QINLOCK after resolution of wound healing complications has not been established. ( 5.5 ) Photosensitivity : May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )

5.1 Palmar-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 )] .

5.2 New 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.

5.3 Hypertension 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 )] .

5.4 Cardiac 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 1.3% 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 1.9% 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 )] .

5.5 Risk 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 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.

5.7 Embryo-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 )].

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 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Deciphera Pharmaceuticals, LLC, at 1-888-724-3274 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical 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. Gastrointestinal Stromal Tumor Patients Who Received Prior Treatment with Imatinib, Sunitinib and Regorafenib The safety of QINLOCK was evaluated in INVICTUS [see Clinical Studies ( 14 )] . Patients received QINLOCK 150 mg taken orally once daily (n=85) or placebo (n=43). Among the patients who received QINLOCK, 46% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. Serious adverse reactions occurred in 31% of patients who received QINLOCK. Serious adverse reactions that occurred in >2% of patients were abdominal pain (4.7%), anemia (3.5%), nausea (2.4%), and vomiting (2.4%). Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received QINLOCK. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included general physical health deterioration (2.4%), anemia (1.2%), cardiac failure (1.2%), PPES (1.2%), and vomiting (1.2%). Dosage interruptions due to an adverse reaction occurred in 24% of patients who received QINLOCK. Adverse reactions requiring dosage interruption in >2% of patients included nausea (3.5%), increased blood bilirubin (2.4%), and PPES (2.4%). Dose reductions due to an adverse reaction occurred in 7% of patients who received QINLOCK. Adverse reactions resulting in a dose reduction in ≥1.2% of patients were abdominal pain, agitation, alopecia, arthritis, dermatosis, gastrointestinal disorder, hyperesthesia, myalgia, PPES, and decreased weight. The most common adverse reactions (≥20%), were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, PPES, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥4%) were increased lipase and decreased phosphate. Table 2 summarizes the adverse reactions in INVICTUS. Table 2: Adverse Reactions (≥10%) in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK in INVICTUS Adverse Reaction QINLOCK (N=85) Placebo (N=43) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Skin and subcutaneous tissue Alopecia 52 0 4.7 0 Palmar-plantar erythrodysesthesia syndrome 21 0 0 0 Dry skin 13 0 7 0 Pruritus 11 0 4.7 0 General Fatigue 42 3.5 23

2.3 Peripheral edema 17 1.2 7 0 Asthenia 13 1.2 14

4.7 Gastrointestinal Nausea 39 3.5 12 0 Abdominal pain 36 7 30

4.7 Constipation 34 1.2 19 0 Diarrhea 28 1.2 14

2.3 Vomiting 21 3.5 7 0 Stomatitis 11 0 0 0 Musculoskeletal and connective tissue Myalgia 32 1.2 12 0 Arthralgia 18 0 4.7 0 Muscle spasms 15 0 4.7 0 Metabolism and nutrition Decreased appetite 27 1.2 21

2.3 Investigations Decreased weight 19 0 12 0 Nervous system Headache 19 0 4.7 0 Vascular Hypertension 14 7 4.7 0 Respiratory, thoracic and mediastinal Dyspnea 13 0 0 0 Table 3 summarizes the laboratory abnormalities in INVICTUS. Table 3: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients with Gastrointestinal Stromal Tumor Who Received QINLOCK with a Difference Between Arms of >5% Compared to Placebo in INVICTUS CPK=creatine phosphokinase; INR=international normalized ratio; AST=aspartate aminotransferase; ALT=alanine aminotransferase a. The denominator used to calculate the rate varied from 82 to 83 for QINLOCK and 34 to 40 for placebo based on the number of patients with a baseline value and at least one post-treatment value. b. Only includes Grade 3 laboratory abnormalities. Laboratory Abnormality QINLOCK a (N=85) Placebo a (N=43) Grades 1-4 Grades 3-4 b Grades 1-4 Grades 3-4 Hematology Increased activated partial thromboplastin time 35 0 9 0 Increased INR 21 3.8 15 0 Decreased neutrophil count 10 0 2.5 0 Chemistry Increased lipase 32 7 13 8 Decreased phosphate 26 4.9 2.5 0 Increased triglycerides 26 2.4 23 0 Decreased calcium 23 0 8 0 Increased blood bilirubin 22 0 5

2.5 Increased CPK 21 1.2 10 0 Decreased sodium 17 2.4 10

2.5 Increased creatinine 16 0 18 0 Increased serum amylase 13 1.2 5 0 Increased ALT 12 1.2 5 0 Other Adverse Reactions Clinically relevant adverse reactions that occurred in <10% of QINLOCK-treated patients in INVICTUS included peripheral sensory neuropathy, dermatitis acneiform, and rash. Clinically relevant adverse reactions that occurred in <10% of patients in the pooled safety population included cardiac ischemic events (including acute coronary syndrome and fatal cardiac arrest or myocardial infarction). Photosensitivity occurred in 0.6% [see Warnings and Precautions ( 5.6 )] .

Strong CYP3A Inhibitors : Monitor more frequently for adverse reactions. ( 7.1 ) Strong CYP3A Inducers : Avoid concomitant use of strong CYP3A inducers. ( 7.1 ) Moderate CYP3A Inducers : Avoid concomitant use of moderate CYP3A inducers. If a moderate CYP inducer cannot be avoided, increase ripretinib dose frequency to twice daily. ( 2.3 , 7.1 )

7.1 Effect of Other Drugs on QINLOCK Table 4 includes drug interactions that affect the pharmacokinetics of ripretinib. Table 4: Drug Interactions that Affect QINLOCK Strong CYP3A Inhibitors Clinical Impact 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 [see Clinical Pharmacology ( 12.3 )]. Prevention or Management Monitor patients more frequently for adverse reactions. Strong and Moderate CYP3A Inducers Clinical Impact Coadministration of QINLOCK with a strong CYP3A inducer decreased the exposure of ripretinib and its active metabolite (DP-5439), which may decrease QINLOCK anti-tumor activity [see Clinical Pharmacology ( 12.3 )] . Coadministration of QINLOCK with moderate CYP3A inducers is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease QINLOCK anti-tumor activity [see Clinical Pharmacology ( 12.3 )] . Prevention or Management Avoid concomitant use of QINLOCK with strong CYP3A inducers. Avoid concomitant use of QINLOCK with moderate CYP3A inducers. If a moderate CYP3A inducer cannot be avoided, increase 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 [see Dosage and Administration ( 2.3 )] .

Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , QINLOCK can cause fetal harm when administered to a pregnant woman. There are no available data on the use of QINLOCK in pregnant women to inform a drug-associated risk. 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, reduced fetal body weight, and increased post-implantation loss at maternal exposures that were approximately equal to the human exposure at the recommended dose of 150 mg (see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In an embryo-fetal development study investigating daily doses of ripretinib administered during the period of organogenesis in rats, ripretinib resulted in malformations primarily associated with the cardiovascular and skeletal systems, including interrupted or retroesophageal aortic arch and retroesophageal subclavian artery, fusion of the exoccipital bone to the first cervical vertebra, branched and fused ribs, anomalies of the cervical, thoracic, caudal, and sacral vertebrae, absent forepaw phalanges, and absent metacarpals at a dose of 20 mg/kg/day (approximately one half of the human exposure at the recommended dose of 150 mg). An increased incidence of anatomic variations were also observed at 20 mg/kg/day. Variations included malpositioned carotid and subclavian artery origins, malpositioned subclavian artery, absent or elongated innominate artery, misshapen and nodulated ribs, bipartite, incompletely ossified, or unossified vertebral centra, small or misshapen vertebral arches, and reductions in ossified forelimb and hindlimb phalanges, hindlimb metatarsals, and caudal vertebrae. In a preliminary embryo-fetal development study investigating the administration of ripretinib in rabbits during the period of organogenesis, ripretinib resulted in total loss of pregnancy at doses of 150 mg/kg (approximately 3.5 times the human exposure at the recommended dose of 150 mg). At a dose of 40 mg/kg (approximately 2.1 times the human exposure at the recommended dose of 150 mg), toxicities included increased post-implantation loss and decreased fetal body weights.

8.2 Lactation Risk Summary 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. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with QINLOCK and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential QINLOCK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to the initiation of QINLOCK [see Use in Specific Populations ( 8.1 )] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. Infertility Based on findings from animal studies, QINLOCK may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use The safety and effectiveness of QINLOCK in pediatric patients have not been established. Animal Toxicity Data In 13-week repeat-dose studies in rats there were dose-dependent findings of increased osteoblastic surface and decreased trabeculae of the femur at doses ≥30 mg/kg/day (approximately one half of the human exposure at the recommended dose of 150 mg). There were additional findings of missing or discolored teeth that were accompanied by dose-dependent incisor degeneration at doses ≥30 mg/kg/day.

8.5 Geriatric 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.

8.6 Hepatic Impairment No dose adjustment is recommended in patients with hepatic impairment (Child-Pugh A, B, or C) [see Clinical Pharmacology ( 12.3 )] .

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.