1.1 PDGFRA Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST)

AYVAKIT® is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations [see Dosage and Administration (2.2)].

1.2 Advanced Systemic Mastocytosis (AdvSM)

AYVAKIT is indicated for the treatment of adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

1.3 Indolent Systemic Mastocytosis (ISM)

AYVAKIT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM).

2.1 Recommended Administration

Administer AYVAKIT orally on an empty stomach, at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)].

Do not make up for a missed dose within 8 hours of the next scheduled dose.

Do not repeat dose if vomiting occurs after AYVAKIT but continue with the next scheduled dose.

2.2 GIST Harboring PDGFRA Exon 18 Mutations

Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation [see Clinical Studies (14.1)]. Information on the FDA-approved test for the detection of PDGFRA D842V mutations is available at: http://www.fda.gov/CompanionDiagnostics.

The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST. Continue treatment until disease progression or unacceptable toxicity.

2.3 Advanced Systemic Mastocytosis

The recommended dosage of AYVAKIT is 200 mg orally once daily in patients with AdvSM. Continue treatment until disease progression or unacceptable toxicity.

2.4 Indolent Systemic Mastocytosis

The recommended dosage of AYVAKIT is 25 mg orally once daily in patients with ISM.

2.5 Dosage Modifications for Adverse Reactions

The recommended dosage reductions and modifications for adverse reactions are provided in Tables 1 and 2.

2.6 Concomitant Use of Strong and Moderate CYP3A Inhibitors

Avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the starting dosage of AYVAKIT is as follows [see Drug Interactions (7.1)]:

• GIST: 100 mg orally once daily
• AdvSM: 50 mg orally once daily

For ISM, avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors.

2.7 Dosage Modifications for Severe Hepatic Impairment

A modified starting dosage of AYVAKIT is recommended for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7)]:

• GIST: 200 mg orally once daily
• AdvSM: 100 mg orally once daily
• ISM: 25 mg orally every other day

5.1 Intracranial Hemorrhage

Serious intracranial hemorrhage may occur with AYVAKIT treatment; fatal events occurred in less than 1% of patients. Overall, intracranial hemorrhage (e.g., subdural hematoma, intracranial hemorrhage, and cerebral hemorrhage) occurred in 2.9% of the 749 patients with GIST or AdvSM who received AYVAKIT in clinical trials. No events of intracranial hemorrhage occurred in the 246 patients with ISM who received any dose of AYVAKIT in the PIONEER study.

Monitor patients closely for risk factors of intracranial hemorrhage which may include history of vascular aneurysm, intracranial hemorrhage or cerebrovascular accident within the prior year, concomitant use of anticoagulant drugs, or thrombocytopenia.

Symptoms of intracranial hemorrhage may include headache, nausea, vomiting, vision changes, or altered mental status. Advise patients to seek immediate medical attention for signs or symptoms of intracranial hemorrhage.

Permanently discontinue AYVAKIT if intracranial hemorrhage of any grade occurs [see Dosage and Administration (2.5)].

5.2 Cognitive Effects

Cognitive adverse reactions can occur in patients receiving AYVAKIT. These cognitive adverse reactions occurred in 33% of the 995 patients with GIST, AdvSM or ISM who received AYVAKIT in clinical trials. These adverse reactions were managed with dose interruption and/or reduction when needed.

Overall, 10% led to dose interruptions, 7% led to dose reductions and 2.2% led to permanent discontinuation of AYVAKIT treatment in patients with GIST, AdvSM or ISM.

Depending on the severity and indication, withhold AYVAKIT and then resume at the same dose or at a reduced dose upon improvement, or permanently discontinue AYVAKIT [see Dosage and Administration (2.5)].

5. 3 Photosensitivity

AYVAKIT may cause photosensitivity reactions. In all patients treated with AYVAKIT in clinical trials (n=1049), photosensitivity reactions occurred in 2.5% of patients. Advise patients to limit direct ultraviolet exposure during treatment with AYVAKIT and for one week after discontinuation of treatment.

5.4 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, AYVAKIT can cause fetal harm when administered to pregnant women. Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 31.4, 6.3 and 2.7 times the human exposure based on area under the curve (AUC) at the 25 mg, 200 mg, and 300 mg dose, respectively.

Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.1, 8.3)].

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.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to AYVAKIT at 25 mg to 600 mg orally once daily in 995 patients enrolled in one of five clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER, PATHFINDER and PIONEER [see Clinical Studies (14.1, 14.2, 14.3)]. These patients included 601 patients with GIST, 148 patients with AdvSM and 246 patients with ISM. Among the 995 patients receiving AYVAKIT, 54% were exposed for 6 months or longer and 26% were exposed for greater than 1 year.

7.1 Effects of Other Drugs on AYVAKIT

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of AYVAKIT in pediatric patients have not been established.

8.5 Geriatric Use

Of the 204 patients with unresectable or metastatic GIST who received AYVAKIT in NAVIGATOR, 40% were 65 years or older, while 6% were 75 years and older. Of the 131 patients with AdvSM who received AYVAKIT in EXPLORER and in PATHFINDER, 62% were 65 years or older, while 21% were 75 years and older. Of the 141 patients with ISM who received AYVAKIT in PIONEER, 6% were 65 years or older, while <1% were 75 years and older. No overall differences in safety or efficacy were observed between these patients and younger adult patients.

8.6 Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated by Cockcroft-Gault]. The recommended dose of AYVAKIT has not been established for patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (CLcr <15 mL/min) [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with mild [total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 times ULN and any AST], or moderate [total bilirubin >1.5 to 3 times ULN and any AST] hepatic impairment. Unbound AUC0-INF was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function. A lower starting dose is recommended in patients with severe hepatic impairment [see Dosage and Administration (2.7)].

12.1 Mechanism 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 (IC50s) 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 IC50 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 IC50 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Avapritinib Cmax 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.

13.1 Carcinogenesis, 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.

13.2 Animal 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.

14.1 Gastrointestinal 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).

14.2 Advanced 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 × 109/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 daily. The efficacy of AYVAKIT in the treatment of AdvSM was based on overall response rate (ORR) in 53 patients with AdvSM dosed at up to 200 mg daily per modified IWG-MRT-ECNM criteria as adjudicated by the central committee. Additional efficacy outcome measures were duration of response (DOR), time to response, and changes in individual measures of mast cell burden.

The median duration of follow up for these patients was 11.6 months (95% confidence interval: 9.9, 16.3).

The study population characteristics were median age of 67 years (range: 37 to 85 years), 58% were male, 98% were White, 68% had an ECOG PS of 0-1, 32% had an ECOG PS of 2-3, 40% had ongoing corticosteroid therapy use for AdvSM at baseline, 66% had prior antineoplastic therapy, 47% had received prior midostaurin, and 94% had a D816V mutation. The median bone marrow mast cell infiltrate was 50%, the median serum tryptase level was 255.8 ng/mL, and the median KIT D816V mutant allele fraction was 12.2%.

Efficacy results in patients with AdvSM enrolled in EXPLORER and PATHFINDER are summarized in Table 12.

For all evaluable patients, the median duration of response was 38.3 months (95% confidence interval: 19, not estimable) and the median time to response was 2.1 months.

In the subgroup of patients with MCL, the efficacy of AYVAKIT was based on complete remission (CR).

14.3 Indolent Systemic Mastocytosis

The efficacy of AYVAKIT was demonstrated in PIONEER (NCT03731260), a randomized, double-blind, placebo-controlled trial conducted in adult patients with Indolent Systemic Mastocytosis (ISM) based on World Health Organization (WHO) classification. Enrolled patients had moderate to severe symptoms despite receiving at least 2 symptom directed therapies. Patients were randomized to receive 25 mg AYVAKIT orally once daily with best supportive care versus placebo with best supportive care. The treatment duration was over a 24-week period, during the randomized portion of the study.

Efficacy was based on the absolute mean change from baseline to Week 24 in the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) total symptom score (TSS). The ISM-SAF is a patient-reported outcome measure assessing ISM signs and symptoms: abdominal pain, nausea, diarrhea, spots, itching, flushing, bone pain, fatigue, dizziness, headache, brain fog. Scores ranged from 0 ("none") to 10 ("worst imaginable"). The item scores were summed to calculate a daily ISM-SAF TSS (range 0-110), with higher scores indicating greater symptom severity. A biweekly average ISM-SAF TSS was used to evaluate efficacy endpoints.

Additional supportive results included the proportion of AYVAKIT-treated patients achieving ≥50% reduction from baseline through Week 24 in TSS compared to placebo. Objective measures of mast cell burden were assessed including the proportion of AYVAKIT-treated patients with a ≥50% reduction from baseline through Week 24 in serum tryptase, peripheral blood KIT D816V allele fraction and bone marrow mast cells.

The median age of the patients who received AYVAKIT was 50 years (range: 18 to 77 years), 71% were female, 77% were White, <1% were Asian, 3% had other race and 19% had missing race. Ethnicities included 4% Hispanic or Latino. KIT D816V mutations were identified in 93% of patients. At baseline, the mean TSS was 50.17 (standard deviation: 19.15), the median serum tryptase level was 38.40 ng/mL, the median KIT D816V mutant allele fraction was 0.39% by ddPCR and the median bone marrow mast cell infiltrate was 7%. Study population characteristics were similar in the placebo group.

The majority of patients who received AYVAKIT (99.3%) or placebo (100%) received concomitant best supportive care at baseline (median of 3 therapies in the AYVAKIT group and 4 in the placebo group). The most common therapies in the AYVAKIT group were H1 antihistamines (97%), H2 antihistamines (66%), leukotriene inhibitors (35%) and cromolyn sodium (30%).

Efficacy results are summarized in Tables 13 and 14.

To aid in the interpretation of the ISM-SAF TSS absolute mean change from baseline results, the proportion of patients reporting less than or equal to any particular level of change in the ISM-SAF TSS from baseline to Week 24 is depicted in a cumulative distribution function plot as shown in Figure 1.

Figure 1: Cumulative Proportion of Patients with ISM in PIONEER Reporting Change in ISM-SAF TSS From Baseline to Week 24

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Intracranial Hemorrhage

Advise patients to contact their healthcare provider immediately if experiencing neurological signs and symptoms that may be associated with intracranial hemorrhage (i.e., severe headache, vomiting, drowsiness, dizziness, confusion, slurred speech, or paralysis) [see Warnings and Precautions (5.1)].

Inform patients with AdvSM of the need to monitor platelet counts before and during treatment [see Warnings and Precautions (5.1)].

Cognitive Effects

Advise patients and caretakers to notify their healthcare provider if they experience new or worsening cognitive symptoms. Advise patients not to drive or operate hazardous machinery if they are experiencing cognitive adverse reactions [see Warnings and Precautions (5.2)].

Photosensitivity

Inform patients that there is a potential risk of photosensitivity reactions with AYVAKIT. Advise patients to limit direct ultraviolet exposure by using sunscreen and protective clothing during treatment with AYVAKIT [see Warnings and Precautions (5.3)].

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 (5.4), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Lactation

Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that AYVAKIT may impair fertility at 200 mg or 300 mg [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Advise males of reproductive potential that AYVAKIT may decrease sperm production at 200 mg or 300 mg [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Drug Interactions

Advise patients and caregivers 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)].

Administration

Advise patients to take AYVAKIT on an empty stomach, at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.1)].