QINLOCK

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 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 patients in the pooled safety population included cardiac ischemic events (1.1%) (including acute coronary syndrome and fatal cardiac arrest or myocardial infarction). Photosensitivity occurred in 0.6% [see Warnings and Precautions ( 5.6 )] .

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION 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 C 24 H 21 BrFN 5 O 2 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. Figure

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 discontinuation of the moderate CYP3A inducer. [ see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 ) ].

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 )

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 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism 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. 12.2 Pharmacodynamics Exposure-Response Relationships Ripretinib exposure-response relationships and the time course of pharmacodynamics have not been fully characterized. Cardiac Electrophysiology No large mean increase in QTc interval (i.e. >20 ms) was detected following treatment with QINLOCK at the recommended dose of 150 mg taken orally once daily. 12.3 Pharmacokinetics The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were characterized in clinical studies. In patients with advanced malignancies, ripretinib AUC 0-24h increased proportionally over a dose range of 20-250 mg (0.13 to 1.67 times the recommended dose), but C max was less than dose proportional; DP-5439 C max and AUC 0-24h 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 C max and AUC 0-24h 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 . Table 5: Pharmacokinetic Parameters of Ripretinib and DP-5439 a. Estimated based on cycle 1, day 15 b. After a single oral dose of 150 mg CV=coefficient of variation; C max =maximum plasma concentration; AUC 0-12h =area under the plasma concentration-time curve from time zero to 12 hours; AUC 0-24h =area under the plasma concentration-time curve from time zero to 24 hours; T max =time to maximum concentration Parameter Ripretinib DP-5439 General Information Steady state exposure following QINLOCK 150 mg once daily [Mean (CV%)] C max (ng/mL) 761 (32) 804 (46) AUC 0-12h (ng•h/mL) 5678 (32) 7138 (44) Time to steady state [Days] 14 14 Accumulation ratio (AUC 0-12h ) [Mean (CV%)] a 1.7 (55) 5.29 (49) Absorption T max [Median in hours] b 4 15.6 Distribution Plasma protein binding (in vitro) Human serum albumin 99.8% 99.7% α-1 acid glycoprotein 99.4% >99.8% Steady state apparent volume of distribution, L [Mean (CV%)] b 307 (39) 507 (51) Elimination Apparent clearance, L/hr [Mean (CV%)] b 15.3 (45) 17.5 (63) Half-life, hours [Mean (CV%)] b 14.8 (30) 17.8 (23) Metabolism Metabolic pathways Major CYP3A4 CYP3A4 Minor CYP2C8 and CYP2D6 CYP2C8, CYP2E1 and CYP2D6 Excretion Excretion pathways Feces 34% 6% Urine 0.02% 0.1% 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) on the pharmacokinetics of ripretinib have not been studied. Patients with Hepatic Impairment In subjects with mild hepatic impairment, there were no clinically significant changes in AUC 0-last and C max when compared to matched healthy subjects. In subjects with moderate hepatic impairment, ripretinib AUC 0-last increased 2-fold while C max was unchanged when compared to matched healthy subjects. The combined AUC 0-last of ripretinib and DP-5439 increased 1.5-fold. In subjects with severe hepatic impairment, ripretinib AUC 0-last increased 2.6-fold and C max decreased by 24% when compared to matched healthy subjects. The combined AUC 0-last of ripretinib and DP-5439 increased by 1.4-fold. The observed magnitude of increase in ripretinib and the combination of ripretinib and DP-5439 exposures in subjects with hepatic impairment is unlikely to be clinically relevant based on the known safety profile of ripretinib. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Coadministration of QINLOCK with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib C max by 36% and AUC 0-inf by 99% and also increased DP-5439 AUC 0-inf by 99% with no change in its C max . Strong CYP3A Inducers: Coadministration of QINLOCK with rifampin (a strong CYP3A inducer) decreased ripretinib C max by 18% and AUC 0-inf by 61% and also decreased DP-5439 AUC 0-inf by 57% with increased C max by 37%. Moderate CYP3A Inducers: Coadministration of QINLOCK with efavirenz (a moderate CYP3A inducer) was predicted to decrease ripretinib C max by 24% and decrease AUC 0-inf by 56%. Proton Pump Inhibitors: No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observed when QINLOCK was coadministered with pantoprazole (a proton pump inhibitor). In Vitro Studies CYP Enzymes: Ripretinib and DP-5439 are inhibitors of CYP2C8. Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Ripretinib is an inhibitor of P-gp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein). DP-5439 is a substrate for P-gp and BCRP. DP-5439 is an inhibitor of BCRP and MATE1 (Multidrug And Toxin Extrusion Protein 1).

12.1 Mechanism 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.

12.2 Pharmacodynamics Exposure-Response Relationships Ripretinib exposure-response relationships and the time course of pharmacodynamics have not been fully characterized. Cardiac Electrophysiology No large mean increase in QTc interval (i.e. >20 ms) was detected following treatment with QINLOCK at the recommended dose of 150 mg taken orally once daily.

12.3 Pharmacokinetics The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were characterized in clinical studies. In patients with advanced malignancies, ripretinib AUC 0-24h increased proportionally over a dose range of 20-250 mg (0.13 to 1.67 times the recommended dose), but C max was less than dose proportional; DP-5439 C max and AUC 0-24h 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 C max and AUC 0-24h 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 . Table 5: Pharmacokinetic Parameters of Ripretinib and DP-5439 a. Estimated based on cycle 1, day 15 b. After a single oral dose of 150 mg CV=coefficient of variation; C max =maximum plasma concentration; AUC 0-12h =area under the plasma concentration-time curve from time zero to 12 hours; AUC 0-24h =area under the plasma concentration-time curve from time zero to 24 hours; T max =time to maximum concentration Parameter Ripretinib DP-5439 General Information Steady state exposure following QINLOCK 150 mg once daily [Mean (CV%)] C max (ng/mL) 761 (32) 804 (46) AUC 0-12h (ng•h/mL) 5678 (32) 7138 (44) Time to steady state [Days] 14 14 Accumulation ratio (AUC 0-12h ) [Mean (CV%)] a 1.7 (55) 5.29 (49) Absorption T max [Median in hours] b 4 15.6 Distribution Plasma protein binding (in vitro) Human serum albumin 99.8% 99.7% α-1 acid glycoprotein 99.4% >99.8% Steady state apparent volume of distribution, L [Mean (CV%)] b 307 (39) 507 (51) Elimination Apparent clearance, L/hr [Mean (CV%)] b 15.3 (45) 17.5 (63) Half-life, hours [Mean (CV%)] b 14.8 (30) 17.8 (23) Metabolism Metabolic pathways Major CYP3A4 CYP3A4 Minor CYP2C8 and CYP2D6 CYP2C8, CYP2E1 and CYP2D6 Excretion Excretion pathways Feces 34% 6% Urine 0.02% 0.1% 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) on the pharmacokinetics of ripretinib have not been studied. Patients with Hepatic Impairment In subjects with mild hepatic impairment, there were no clinically significant changes in AUC 0-last and C max when compared to matched healthy subjects. In subjects with moderate hepatic impairment, ripretinib AUC 0-last increased 2-fold while C max was unchanged when compared to matched healthy subjects. The combined AUC 0-last of ripretinib and DP-5439 increased 1.5-fold. In subjects with severe hepatic impairment, ripretinib AUC 0-last increased 2.6-fold and C max decreased by 24% when compared to matched healthy subjects. The combined AUC 0-last of ripretinib and DP-5439 increased by 1.4-fold. The observed magnitude of increase in ripretinib and the combination of ripretinib and DP-5439 exposures in subjects with hepatic impairment is unlikely to be clinically relevant based on the known safety profile of ripretinib. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Coadministration of QINLOCK with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib C max by 36% and AUC 0-inf by 99% and also increased DP-5439 AUC 0-inf by 99% with no change in its C max . Strong CYP3A Inducers: Coadministration of QINLOCK with rifampin (a strong CYP3A inducer) decreased ripretinib C max by 18% and AUC 0-inf by 61% and also decreased DP-5439 AUC 0-inf by 57% with increased C max by 37%. Moderate CYP3A Inducers: Coadministration of QINLOCK with efavirenz (a moderate CYP3A inducer) was predicted to decrease ripretinib C max by 24% and decrease AUC 0-inf by 56%. Proton Pump Inhibitors: No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observed when QINLOCK was coadministered with pantoprazole (a proton pump inhibitor). In Vitro Studies CYP Enzymes: Ripretinib and DP-5439 are inhibitors of CYP2C8. Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Ripretinib is an inhibitor of P-gp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein). DP-5439 is a substrate for P-gp and BCRP. DP-5439 is an inhibitor of BCRP and MATE1 (Multidrug And Toxin Extrusion Protein 1).

20230111

6

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

QINLOCK Ripretinib Ripretinib Ripretinib hypromellose acetate succinate 06081224 (3 MM2/S) microcrystalline cellulose lactose monohydrate crospovidone silicon dioxide magnesium stearate white to off-white OVAL DC1

13.1 Carcinogenesis, 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).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, 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).

NDA213973

QINLOCK

Ripretinib

73207-101

HUMAN PRESCRIPTION DRUG

ORAL

Principal Display Panel - 90 Tablet Carton Label NDC: 73207-101-30 Rx only QINLOCK™ (ripretinib) tablets 50 mg Dispense the enclosed Patient Information Leaflet to each patient. 90 TABLETS Principal Display Panel - 90 Tablet Carton Label

Warnings and Precautions, Photosensitivity ( 5.6 ) 09/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Palmar-Plantar Erythrodysesthesia Syndrome Advise patients to contact their healthcare provider immediately if they experience severe skin changes [see Warnings and Precautions ( 5.1 )] . New Primary Cutaneous Malignancies Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions [see Warnings and Precautions ( 5.2 )] . Hypertension Advise patients that hypertension may develop during treatment with QINLOCK and that blood pressure should be monitored regularly during treatment [ see Warnings and Precautions ( 5.3 )] . Cardiac Dysfunction Advise patients that cardiac failure may develop during treatment with QINLOCK and that signs or symptoms of cardiac failure should be regularly monitored during treatment. Advise patients to contact their healthcare provider immediately for signs or symptoms of cardiac dysfunction [see Warnings and Precautions ( 5.4 )] . Risk of Impaired Wound Healing Advise patients that QINLOCK may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions ( 5.5 )] . Photosensitivity Inform patients that there is a potential risk of photosensitivity reactions with QINLOCK. Advise patients to limit direct ultraviolet exposure by using sunscreen or protective clothing during treatment with QINLOCK [see Warnings and Precautions ( 5.6 )]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with QINLOCK and for 1 week after the last dose [see Use in Specific Populations ( 8.3 )]. 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 ( 8.3 ), Nonclinical Toxicology ( 13.1 )] . Lactation Advise females not to breastfeed during treatment with QINLOCK and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )] . Infertility Advise males of reproductive potential that QINLOCK may impair fertility [see Use in Specific Populations ( 8.3 ), Nonclinical Toxicology ( 13.1 ) ] . Drug Interactions Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions ( 7.1 )] . Dosage and Administration Instruct patients to take QINLOCK at the same time each day (once daily) with or without food. Advise patients to swallow tablets whole. Inform patients about what to do in the event they miss a dose or vomit after taking a dose of QINLOCK [see Dosage and Administration ( 2.1 ) ] . Storage Instructions Store QINLOCK in the original container at room temperature between 20ºC to 25ºC (68ºF to 77ºF). Manufactured for and marketed by: Deciphera Pharmaceuticals, LLC 200 Smith Street, Waltham, MA 02451

14 CLINICAL 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. Efficacy results from INVICTUS are summarized in Table 6 . Table 6: Efficacy Results of INVICTUS BICR=Blinded Independent Central Review; CI=Confidence Interval a. Assessed per BICR. b. p-value is based on 2-sided stratified log-rank test. c. Hazard ratio is based on Cox proportional regression model. This model includes treatment and randomization stratification factors as fixed factors. d. Based on Fisher's exact test. The p-value is not statistically significant. e. Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints of ORR and OS. QINLOCK (N=85) Placebo (N=44) Progression-Free Survival a Number of events (%) 51 (60) 37 (84) Progressive disease 46 (54) 32 (73) Deaths 5 (6) 5 (11) Median PFS (months) (95% CI) 6.3 (4.6, 6.9) 1.0 (0.9, 1.7) Hazard ratio (95% CI) c 0.15 (0.09, 0.25) p-value b < 0.0001 Overall Response Rate a Overall Response Rate (%) 9 0 (95% CI) (4.2, 18) (0, 8) p-value d 0.0504 Overall Survival e Number of deaths (%) 26 (31) 26 (59) Median OS (months) (95% CI) 15.1 (12.3, 15.1) 6.6 (4.1, 11.6) Hazard ratio (95% CI) c 0.36 (0.21, 0.62) Figure 1: Kaplan-Meier Curve of Progression-Free Survival in INVICTUS Figure 2: Kaplan-Meier Curve of Overall Survival in INVICTUS Figure 1 Figure 2

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.

8.4 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.

8.1 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 USE IN SPECIFIC POPULATIONS 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 )] .

16 HOW 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 to patient 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] .