QINLOCK

1 INDICATIONS 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. 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 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage : 150 mg orally once daily with or without food. ( 2.1 ) 2.1 Recommended 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. 2.2 Dosage 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. The recommended dosage modifications of QINLOCK for adverse reactions are provided in Table 1 . Table 1: Recommended Dosage Modifications for QINLOCK for Adverse Reactions Adverse Reaction Severity a QINLOCK Dosage Modifications a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). Palmar-Plantar Erythrodysesthesia Syndrome (PPES) [see Warnings and Precautions ( 5.1 )] Grade 2 Withhold QINLOCK until Grade ≤1 or baseline. If recovered within 7 days, resume QINLOCK at same dose; otherwise resume at reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. If PPES recurs, withhold QINLOCK until Grade ≤1 or baseline and then resume QINLOCK at a reduced dose regardless of time to improvement. Grade 3 Withhold QINLOCK for at least 7 days or until Grade ≤1 or baseline (maximum 28 days). Resume QINLOCK at a reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. Hypertension [see Warnings and Precautions ( 5.3 )] Grade 3 If symptomatic, withhold QINLOCK until symptoms have resolved and blood pressure is controlled. If blood pressure is controlled to Grade ≤1 or baseline, resume QINLOCK at the same dose; otherwise, resume QINLOCK at reduced dose. If Grade 3 hypertension recurs, withhold QINLOCK until symptoms have resolved and blood pressure is controlled. Resume QINLOCK at a reduced dose. Grade 4 Permanently discontinue QINLOCK. Left Ventricular Systolic Dysfunction [see Warnings and Precautions ( 5.4 )] Grade 3 or 4 Permanently discontinue QINLOCK. Arthralgia or Myalgia [see Adverse Reactions ( 6.1 )] Grade 2 Withhold QINLOCK until Grade ≤1 or baseline. If recovered within 7 days, resume QINLOCK at same dose; otherwise resume QINLOCK at reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. If arthralgia or myalgia recurs, withhold QINLOCK until Grade ≤1 or baseline and then resume QINLOCK at a reduced dose regardless of time to improvement. Grade 3 Withhold QINLOCK for at least 7 days or until Grade ≤1 or baseline (maximum of 28 days). Resume QINLOCK at a reduced dose. Consider re-escalating QINLOCK if maintained at Grade ≤1 or baseline for at least 28 days. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Withhold QINLOCK until Grade ≤1 or baseline (maximum 28 days), and then resume QINLOCK at a reduced dose; otherwise permanently discontinue. Consider re-escalating QINLOCK if no recurrence of the adverse reaction for at least 28 days. If Grade 3 or 4 recurs, permanently discontinue QINLOCK. 2.3 Dose 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 discontinua…

5 WARNINGS AND PRECAUTIONS 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 ha…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 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 )] .

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.

6 ADVERSE 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 )] 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 conn…