Ayvakit avapritinib 200 mg Tablet, Film Coated, 30-count — NDC 72064-120-30 (Billing 72064-0120-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V, PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC 50s ) less than 25 nM in biochemical assays. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors which can contribute to tumor and mast cell proliferation. Other potential targets for avapritinib include wild type KIT, PDGFRB, and CSFR1.

In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V with an IC 50 of 4 nM, approximately 48-fold lower concentration than wild-type KIT. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with KIT exon 17 mutation.

Avapritinib inhibited the autophosphorylation of PDGFRA D842V, a mutation associated with resistance to approved kinase inhibitors, with an IC 50 of 30 nM. Avapritinib also had anti-tumor activity in mice implanted with an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/17 mutations.

12.2Pharmacodynamics Exposure-Response Relationships Gastrointestinal Stromal Tumors or Advanced Systemic Mastocytosis Based on the data from four clinicals trials conducted in patients with advanced malignancies and AdvSM, including NAVIGATOR, EXPLORER, and PATHFINDER, higher exposure was associated with increased risk of Grade ≥ 3 related adverse effects, any Grade pooled cognitive adverse effects, Grade ≥ 2 pooled cognitive adverse effects, and Grade ≥ 2 pooled edema adverse effects over the dose range of 30 mg to 400 mg (0.1 to 1.33 times the recommended dose for GIST and 0.15 to 2 times the recommended dose for AdvSM) once daily.

Based on exposure and efficacy data from EXPLORER and PATHFINDER (n=84), higher avapritinib exposure was associated with faster time to response over the dose range of 30 mg to 400 mg (0.15 to 2 times the recommended dose for AdvSM) once daily. Cardiac Electrophysiology The effect of AYVAKIT on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered doses of 300 mg or 400 mg (12 to 16 times the lowest recommended 25 mg dose, 1.33 times the highest recommended 300 mg dose) once daily.

No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (C max ) of 899 ng/mL.

12.3Pharmacokinetics Avapritinib C max and AUC increased approximately proportionally over the dose range of 25 mg to 400 mg once daily. Steady state concentrations of avapritinib were reached prior to day 15 following daily dosing. Steady state pharmacokinetic parameters per recommended dosing regimen are described in Table 10.

Table 10. Steady State Pharmacokinetic Parameters of AYVAKIT Following Different Dosing Regimen Pharmacokinetic Parameters 25 mg once daily (ISM) 200 mg once daily (AdvSM) 300 mg once daily (GIST) Abbreviations: CV%=coefficient of variation C max (ng/mL) Geometric Mean (CV%) 70.2 (47.8 %, n=9) 377 (62%, n=18) 813 (52%, n=110) AUC 0-24h (h∙ng/mL) Geometric Mean (CV%) 1330 (49.5 %, n = 9) 6600 (54%, n=16) 15400 (48%, n=110) Mean accumulation ratio of AUC 0-24h 4.06 (n=9) 6.41 (n=9) 3.82 (n=34) Absorption The median time to peak concentration (T max ) ranged from 2 to 4 hours following single doses of avapritinib.

Effect of Food The C max of avapritinib was increased by 59% and the AUC 0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state. Distribution The mean (CV %) apparent volume of distribution of avapritinib is 1310 L (51.5%) at 300 mg in patients with GIST,… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Avapritinib is a tyrosine kinase inhibitor that targets KIT D816V, PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC 50s ) less than 25 nM in biochemical assays. Certain mutations in PDGFRA and KIT can result in the autophosphorylation and constitutive activation of these receptors which can contribute to tumor and mast cell proliferation. Other potential targets for avapritinib include wild type KIT, PDGFRB, and CSFR1.

In cellular assays, avapritinib inhibited the autophosphorylation of KIT D816V with an IC 50 of 4 nM, approximately 48-fold lower concentration than wild-type KIT. In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines, including a murine mastocytoma cell line and a human mast cell leukemia cell line. Avapritinib also showed growth inhibitory activity in a xenograft model of murine mastocytoma with KIT exon 17 mutation.

Avapritinib inhibited the autophosphorylation of PDGFRA D842V, a mutation associated with resistance to approved kinase inhibitors, with an IC 50 of 30 nM. Avapritinib also had anti-tumor activity in mice implanted with an imatinib-resistant patient-derived xenograft model of human GIST with activating KIT exon 11/17 mutations.

12.3Pharmacokinetics Avapritinib C max and AUC increased approximately proportionally over the dose range of 25 mg to 400 mg once daily. Steady state concentrations of avapritinib were reached prior to day 15 following daily dosing. Steady state pharmacokinetic parameters per recommended dosing regimen are described in Table 10.

Table 10. Steady State Pharmacokinetic Parameters of AYVAKIT Following Different Dosing Regimen Pharmacokinetic Parameters 25 mg once daily (ISM) 200 mg once daily (AdvSM) 300 mg once daily (GIST) Abbreviations: CV%=coefficient of variation C max (ng/mL) Geometric Mean (CV%) 70.2 (47.8 %, n=9) 377 (62%, n=18) 813 (52%, n=110) AUC 0-24h (h∙ng/mL) Geometric Mean (CV%) 1330 (49.5 %, n = 9) 6600 (54%, n=16) 15400 (48%, n=110) Mean accumulation ratio of AUC 0-24h 4.06 (n=9) 6.41 (n=9) 3.82 (n=34) Absorption The median time to peak concentration (T max ) ranged from 2 to 4 hours following single doses of avapritinib.

Effect of Food The C max of avapritinib was increased by 59% and the AUC 0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state. Distribution The mean (CV %) apparent volume of distribution of avapritinib is 1310 L (51.5%) at 300 mg in patients with GIST, 1900 L (43.2%) at 200 mg in patients with AdvSM, and 1400 L (59.1%) at 25 mg in patients with ISM. In vitro protein binding of avapritinib is 98.8% and is independent of concentration.

The blood-to-plasma ratio is 0.95. Elimination The mean plasma elimination half-life of avapritinib was 32 to 57 hours in patients with GIST, 20 to 39 hours in patients with AdvSM, and 38 to 45 hours in patients with ISM. The steady state mean (CV%) apparent oral clearance of avapritinib is

21.8L/h (54.9%) at 300 mg in patients with GIST,

40.3L/h (86.0%) at 200 mg in patients with AdvSM, and

21.6L/h (58.1%) at 25 mg in patients with ISM. Metabolism Avapritinib is primarily metabolized by CYP3A4, CYP3A5 and to a lesser extent by CYP2C9 in vitro. Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds.

The formation of the glucuronide M690 is catalyzed mainly by UGT1A3. Following oral administration of AYVAKIT 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.

Excretion Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CL cr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment.

In a dedicated hepatic impairment study following a single oral dose administration of 100 mg avapritinib, the mean unbound AUC was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. The effect of severe renal impairment (CL cr 15 to 29 mL/min) and end-stage renal disease (CL cr < 15 mL/min) on the pharmacokinetics of avapritinib is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong and Moderate CYP3A Inhibitors on Avapritinib: Coadministration of AYVAKIT 300 mg once daily with itraconazole 200 mg… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Exposure-Response Relationships Gastrointestinal Stromal Tumors or Advanced Systemic Mastocytosis Based on the data from four clinicals trials conducted in patients with advanced malignancies and AdvSM, including NAVIGATOR, EXPLORER, and PATHFINDER, higher exposure was associated with increased risk of Grade ≥ 3 related adverse effects, any Grade pooled cognitive adverse effects, Grade ≥ 2 pooled cognitive adverse effects, and Grade ≥ 2 pooled edema adverse effects over the dose range of 30 mg to 400 mg (0.1 to 1.33 times the recommended dose for GIST and 0.15 to 2 times the recommended dose for AdvSM) once daily.

Based on exposure and efficacy data from EXPLORER and PATHFINDER (n=84), higher avapritinib exposure was associated with faster time to response over the dose range of 30 mg to 400 mg (0.15 to 2 times the recommended dose for AdvSM) once daily. Cardiac Electrophysiology The effect of AYVAKIT on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered doses of 300 mg or 400 mg (12 to 16 times the lowest recommended 25 mg dose, 1.33 times the highest recommended 300 mg dose) once daily.

No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (C max ) of 899 ng/mL.

14 CLINICAL STUDIES

14.1Gastrointestinal Stromal Tumors The efficacy of AYVAKIT was demonstrated in NAVIGATOR (NCT02508532), a multi-center, single-arm, open-label clinical trial. Eligible patients were required to have a confirmed diagnosis of GIST and an ECOG performance status (PS) of 0 to 2. Patients received AYVAKIT 300 mg or 400 mg (1.33 times the recommended dose) orally once daily until disease progression or unacceptable toxicity.

The trial initially enrolled patients at a starting dose of 400 mg, which was later reduced to the recommended dose of 300 mg due to toxicity. As there was no apparent difference in overall response rate (ORR) between patients who received 300 mg daily compared to those who received 400 mg daily, these patients were pooled for the efficacy evaluation. The major efficacy outcome measure was ORR based on disease assessment by independent radiological review using modified RECIST v1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodules within a pre-existing tumor mass was progression.

An additional efficacy outcome measure was duration of response (DOR). Patients with GIST Harboring a PDGFRA Exon 18 Mutation Patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation were identified by local or central assessment using a PCR- or NGS-based assay. The assessment of efficacy was based on a total of 43 patients, including 38 patients with PDGFRA D842V mutations.

The median duration of follow up for patients with PDGFRA exon 18 mutations was 10.6 months (range: 0.3 to 24.9 months). The study population characteristics were median age of 64 years (range: 29 to 90 years), 67% were male, 67% were White, 93% had an ECOG PS of 0-1, 98% had metastatic disease, 53% had largest target lesion >5 cm, and 86% had prior surgical resection. The median number of prior kinase inhibitors was 1 (range: 0 to 5).

Efficacy results in patients with GIST harboring PDGFRA exon 18 mutations including the subgroup of patients with PDGFRA D842V mutations enrolled in NAVIGATOR are summarized in Table 11. Table 11. Efficacy Results for Patients with GIST Harboring PDGFRA Exon 18 Mutations in NAVIGATOR Efficacy Parameter PDGFRA exon 18 Exon 18 mutations other than D842V included in this population are: deletion of D842_H845 (n=3); D842Y (n=1); and deletion of D842_H845 with insertion of V (n=1).

N = 43 PDGFRA D842V N = 38 Abbreviations: CI=confidence interval; NR=not reached Overall Response Rate (95% CI) 84% (69%, 93%) 89% (75%, 97%) Complete Response, n (%) 3 (7%) 3 (8%) Partial Response, n (%) 33 (77%) 31 (82%) Duration of Response n=36 n=34 Median in months (range) NR (1.9 Denotes ongoing response , 20.3 ) NR (1.9 , 20.3 ) Patients with DOR ≥ 6-months, n (%) 11 patients with an ongoing response were followed < 6 months from onset of response. 22 (61%) 20 (59%)

14.2Advanced Systemic Mastocytosis The efficacy of AYVAKIT was demonstrated in EXPLORER (NCT02561988) and PATHFINDER (NCT03580655), two multi-center, single-arm, open-label clinical trials. Response-evaluable patients include those with a confirmed diagnosis of AdvSM per World Health Organization (WHO) and deemed evaluable by modified international working group-myeloproliferative neoplasms research and treatment-European competence network on mastocytosis (IWG-MRT-ECNM) criteria at baseline as adjudicated by an independent central committee, who received at least 1 dose of AYVAKIT, had at least 2 post-baseline bone marrow assessments, and had been on study for at least 24 weeks, or had an end of study visit.

All enrolled patients had an ECOG performance status (PS) of 0 to 3 and 91% had a platelet count of ≥ 50 × 10 9 /L prior to initiation of therapy. Patients enrolled in EXPLORER received a starting dose of AYVAKIT ranging from 30 mg to 400 mg (0.15 – 2 times the recommended dose) orally once daily. In PATHFINDER, patients were enrolled at a starting dose of 200 mg orally once d… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day. Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Avapritinib was positive in the in vitro chromosome aberration test in human peripheral blood lymphocytes but negative in the in vivo rat bone marrow micronucleus test, and overall non-genotoxic.

There were no direct effects on fertility in rats of either sex in a dedicated fertility and early embryonic development study. Avapritinib may impair spermatogenesis and adversely affect early embryogenesis. Reduction in sperm production and testicular weight were observed in rats and hypospermatogenesis in dogs administered avapritinib at exposure of 8.7 times and 0.5 time the 300 mg human dose, respectively.

Avapritinib partitioned into seminal fluids up to 0.2 times the concentration found in human plasma at 300 mg. In female rats there was an increase in pre-implantation loss at exposure of 5.4 times the human exposure at 300 mg and in early resorptions at exposure 2.7 times the human exposure at 300 mg with an overall decrease in viable embryos. Cystic degeneration of corpora lutea and vaginal mucification was also observed in female rats administered avapritinib for up to 6 months at exposure 1.3 times the human exposure based on AUC at the 300 mg dose.

13.2Animal Toxicology and/or Pharmacology In repeat dose toxicology studies, administration of avapritinib to rats for up to 28 days and to dogs for up to 3 months resulted in tremors at doses greater than or equal to 100 mg/kg/day or 30 mg/kg/day (approximately 8 and 1.5 times the human exposure based on AUC at the 300 mg dose). Hemorrhage in the brain and spinal cord occurred in dogs at doses greater than or equal to 15 mg/kg/day (approximately 9.0, 1.8, or 0.8 times the human exposure based on AUC at the 25 mg, 200 mg. or 300 mg dose, respectively) and choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.

An in vitro phototoxicity study in 3T3 mouse fibroblasts and an in vivo phototoxicity study in pigmented rats demonstrated that avapritinib has a slight potential for phototoxicity.