Ayvakit Drug Information
Generic name: AVAPRITINIB
Kinase Inhibitor [EPC]
Uses of Ayvakit
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 .
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). Limitations of Use : AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 × 10 9 /L .
Indolent Systemic Mastocytosis (ISM)
AYVAKIT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM). Limitations of Use : AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 × 10 9 /L .
Dosage & Administration of Ayvakit
| First dose reduction | 200 mg once daily |
|---|---|
| Second dose reduction | 100 mg once daily |
| Third dose reduction | - |
Side Effects of Ayvakit
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. 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. Gastrointestinal Stromal Tumors Unresectable or Metastatic GIST The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR . The trial excluded patients with history of cerebrovascular accident or transient ischemic attacks, known risk of intracranial bleeding, and metastases to the brain.
Patients received AYVAKIT 300 mg or 400 mg orally once daily (n = 204). Among patients receiving AYVAKIT, 56% were exposed for 6 months or longer and 44% were exposed for greater than one year. The median age of patients who received AYVAKIT was 62 years (range: 29 to 90 years), 60% were <65 years, 62% were male, and 69% were White. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7). Serious adverse reactions occurred in 52% of patients receiving AYVAKIT. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%), and tumor hemorrhage (1%). Fatal adverse reactions occurred in 3.4% of patients.
Fatal adverse reactions that occurred in more than one patient were sepsis and tumor hemorrhage (1% each). Permanent discontinuation due to adverse reactions occurred in 16% of patients who received AYVAKIT. Adverse reactions requiring permanent discontinuation in more than one patient were fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy. Dosage interruptions due to an adverse reaction occurred in 57% of patients who received AYVAKIT. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain. Dose reduction due to an adverse reaction occurred in 49% of patients who received AYVAKIT. Median time to dose reduction was 9 weeks.
Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea, and periorbital edema. The most common adverse reactions (≥ 20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, increased lacrimation, abdominal pain, constipation, rash, dizziness, and hair color changes. Table 5 summarizes the adverse reactions observed in NAVIGATOR. Table 5. Adverse Reactions (≥ 10%) in Patients with GIST Receiving AYVAKIT in NAVIGATOR Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and
AYVAKIT N=204 All Grades % Grade ≥ 3 % General Edema Edema
includes face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema. 72 2 Fatigue/asthenia 61 9 Pyrexia 14
Gastrointestinal Nausea 64 2.5 Vomiting 38 2 Diarrhea 37 4.9 Abdominal pain
Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort. 31 6 Constipation 23
Dyspepsia 16 0 Nervous System Cognitive impairment Cognitive impairment includes memory impairment
cognitive disorder, confusional state, disturbance in attention, amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, mental disorder, and retrograde amnesia. 48
Dizziness 22 0.5 Headache 17 0.5 Sleep disorders Sleep disorders includes insomnia
somnolence, and sleep disorder. 16 0 Taste effects Taste effects include dysgeusia and ageusia. 15 0 Mood disorders Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered, nervousness, personality change, and suicidal ideation. 13 1 Metabolism and nutrition Decreased appetite 38
Eye Increased lacrimation 33 0 Skin and subcutaneous tissue Rash Rash includes
rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular. 23
Hair color changes 21 0.5 Alopecia 13 0 Respiratory, thoracic and mediastinal
Dyspnea 17
Pleural effusion 12 2 Investigations Weight decreased 13 1 Clinically relevant adverse
reactions occurring in <10% of patients were: Vascular: hypertension (8%) Endocrine: thyroid disorders (hyperthyroid, hypothyroid) (3%) Skin and subcutaneous: palmar-plantar erythrodysesthesia (1%) Table 6 summarizes the laboratory abnormalities observed in NAVIGATOR. Table 6. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with GIST Receiving AYVAKIT in NAVIGATOR Laboratory Abnormality AYVAKIT The denominator used to calculate the rate varied from 154 to 201 based on the number of patients with a baseline value and at least one post-treatment value. N=204 All Grades (%) Grade ≥ 3 (%) Hematology Decreased hemoglobin 81 28 Decreased leukocytes 62 5 Decreased neutrophils 43 6 Decreased platelets 27
Increased
INR 24
Increased activated partial thromboplastin time 13 0 Chemistry Increased bilirubin 69 9
Increased aspartate aminotransferase 51
Decreased phosphate 49 13 Decreases potassium 34 6 Decreased albumin 31 2
Decreased magnesium 29 1 Increased creatinine 29 0 Decreased sodium 28 7 Increased alanine aminotransferase 19
Increased alkaline phosphatase 14 1 Advanced Systemic Mastocytosis
The safety of AYVAKIT in patients with AdvSM was evaluated in EXPLORER and PATHFINDER . Patients received a starting dose of AYVAKIT ranging from 30 mg to 400 mg orally once daily (n = 131), including 80 patients who received the recommended starting dose of 200 mg once daily. Among patients receiving AYVAKIT, 70% were treated for 6 months or longer and 37% were exposed for greater than one year. The median age of patients who received AYVAKIT was 68 years (range: 31 to 88 years), 38% were <65 years, 57% were male, and 88% were White.
Serious adverse reactions occurred in 34% of patients receiving the recommended starting dose of 200 mg once daily and in 50% of patients receiving AYVAKIT at all doses. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (5%), subdural hematoma (4%), pleural effusion, ascites and pneumonia (3% each), acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each). Fatal adverse reactions occurred in 2.5% of patients receiving the recommended starting dose of 200 mg once daily and in 5.3% of patients receiving AYVAKIT at all doses. No specific adverse reaction leading to death was reported in more than one patient.
Permanent discontinuation due to adverse reactions occurred in 10% of patients receiving the recommended starting dose of 200 mg once daily and in 15% of patients who received AYVAKIT at all doses. Of patients receiving 200 mg once daily, subdural hematoma was the only adverse reaction requiring permanent discontinuation in more than one patient. Dosage interruptions due to an adverse reaction occurred in 60% of patients receiving the recommended starting dose of 200 mg once daily and in 67% of patients who received AYVAKIT at all doses.
Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, neutrophil count decreased, platelet count decreased, anemia, white blood cell decreased, cognitive disorder, blood alkaline phosphatase increased, and edema peripheral. Dose reduction due to an adverse reaction occurred in 68% of patients receiving the recommended starting dose of 200 mg once daily and 70% of patients who received AYVAKIT at all doses. Median time to dose reduction was 1.7 months.
Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, edema peripheral, neutrophil count decreased, platelet count decreased, periorbital edema, cognitive disorder, anemia, fatigue, arthralgia, blood alkaline phosphatase increased, and white blood cell count decreased. The most common adverse reactions (≥ 20%) at all doses were edema, diarrhea, nausea, and fatigue/asthenia. Table 7 summarizes the adverse reactions observed in EXPLORER and PATHFINDER. Table 7. Adverse Reactions (≥ 10%) in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and
AYVAKIT (200 mg once daily) N=80 All Grades % Grade ≥ 3
% General Edema Edema includes face swelling, eyelid edema, orbital edema, periorbital edema, face edema, peripheral edema, edema, generalized edema, and peripheral swelling. 79 5 Fatigue/asthenia 23 4 Gastrointestinal Diarrhea 28 1 Nausea 24 1 Vomiting 18 3 Abdominal pain Abdominal pain includes abdominal pain, upper abdominal pain, and abdominal discomfort. 14 1 Constipation 11 0 Nervous system Headache 15 0 Cognitive effects Cognitive effects include memory impairment, cognitive disorder, confusional state, delirium, and disorientation. 14 1 Taste effects Taste effects include dysgeusia. 13 0 Dizziness 13 0 Musculoskeletal and connective tissue Arthralgia 10 1 Respiratory, thoracic and mediastinal Epistaxis 11 0 Clinically relevant adverse reactions occurring in <10% of patients were: Cardiac : cardiac failure (2.5%), and cardiac failure congestive (1.3%) Gastrointestinal: ascites (5%), gastrointestinal hemorrhage (1.3%), and large intestine perforation (1.3%) Hepatobiliary: cholelithiasis (1.3%) Infections and infestations: upper respiratory tract infection (6%), urinary tract infection (6%), and herpes zoster (2.5%) Vascular: flushing (3.8%), hypertension (3.8%), hypotension (3.8%), and hot flush (2.5%) Nervous : insomnia (6%) Musculoskeletal and connective tissue : pain in extremity (6%) Respiratory, thoracic and mediastinal : dyspnea (9%), and cough (2.5%) Skin and subcutaneous tissue : rash Grouped terms (8%), alopecia (9%), pruritus (8%), and hair color changes (6%) Metabolism and nutrition : decreased appetite (8%) Eye : lacrimation increased (9%) Laboratory abnormality: decreased phosphate (9%) Rash includes rash and rash maculo-papular Table 8 summarizes the laboratory abnormalities observed in EXPLORER and PATHFINDER. Table 8. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER Laboratory Abnormality AYVAKIT (200 mg once daily) N=80 All Grades (%) Grade ≥ 3 (%) Hematology Decreased platelets 64 21 Decreased hemoglobin 55 23 Decreased neutrophils 54 25 Decreased lymphocytes 34 11 Increased activated partial thromboplastin time 14 1 Increased lymphocytes 10 0 Chemistry Decreased calcium 50 3 Increased bilirubin 41 3 Increased aspartate aminotransferase 38 1 Decreased potassium 26 4 Increased alkaline phosphatase 24 5 Increased creatinine 20 0 Increased alanine aminotransferase 18 1 Decreased sodium 18 1 Decreased albumin 15 1 Decreased magnesium 14 1 Increased potassium 11 0 Other Clinically Relevant Adverse Reactions in <10% of patients In the pooled GIST and AdvSM safety populations, photosensitivity occurred in 2.5% of patients. Indolent Systemic Mastocytosis The safety of AYVAKIT in patients with ISM was evaluated in PIONEER . Patients received AYVAKIT 25 mg orally once daily with best supportive care (n = 141) or placebo once daily with best supportive care (n = 71). Serious adverse reactions occurred in 1 patient (0.7%) who received AYVAKIT due to pelvic hematoma. Permanent discontinuation of AYVAKIT due to an adverse reaction occurred in 1 patient (0.7%) due to dyspnea and dizziness.
Dosage interruptions of AYVAKIT due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dosage interruption included dizziness, blood alkaline phosphatase increased, dyspnea, face edema, pelvic hematoma, liver transaminase increased and respiratory tract infection (1 patient each). Table 9 summarizes the frequency of adverse reactions in the PIONEER study. The most common adverse reactions (≥ 10%) in the AYVAKIT group were eye edema, dizziness, peripheral edema and flushing.
Of all adverse reactions, 55% were Grade 1, 38% were Grade 2 and 7% were Grade 3. Among patients with edema adverse reactions, 95% were Grade 1 and 5% were Grade 2. Among patients with hemorrhage adverse reactions, 86% were Grade 1 and 14% were Grade 2. Table 9. Adverse Reactions Occurring in AYVAKIT-Treated Patients with Indolent Systemic Mastocytosis During PIONEER Trial Adverse Reactions Adverse reactions that occurred in ≥5% of AYVAKIT-treated patients and ≥2% more than placebo-treated patients., Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version
AYVAKIT (25 mg once daily) +
BSC N=141 % Placebo + BSC N=71 % Abbreviations: BSC=best supportive care Eye edema Eye edema includes periorbital edema, eye edema, swelling of eyelid, orbital edema, eye swelling, eyelid edema and eyelid ptosis. 13 7 Dizziness Term includes several similar terms. 13 10 Peripheral edema 12 6 Flushing 11 4 Respiratory tract infection Respiratory tract infection includes pneumonia, upper respiratory tract infection, bronchitis and respiratory tract infection. 8 1 Face edema 7 1 Rash 6 4 Liver transaminase increased 6 3 Insomnia 6 3 Hematoma Hematoma includes contusion, hematoma and pelvic hematoma. 6 1 Blood alkaline phosphatase increased 6 1 Hemorrhage Hemorrhage includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, retinal hemorrhage. 5 3 Clinically relevant adverse reactions occurring in <5% of patients were: Skin and subcutaneous tissue: photosensitivity (2.8%)
Warnings & Cautions for Ayvakit
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 . Gastrointestinal Stromal Tumors Intracranial hemorrhage occurred in 3 of 267 patients (1.1%). Two (0.7%) of the events were Grade ≥ 3 and resulted in discontinuation of study drug. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating AYVAKIT. Advanced Systemic Mastocytosis In patients with AdvSM who received AYVAKIT at 200 mg daily, intracranial hemorrhage occurred in 2 of 75 patients (2.7%) who had platelet counts ≥ 50 × 10 9 /L prior to initiation of therapy and in 3 of 80 patients (3.8%) regardless of platelet counts. In patients with AdvSM, a platelet count must be performed prior to initiating therapy; AYVAKIT is not recommended in patients with AdvSM with platelet counts < 50 × 10 9 /L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count.
After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically indicated) if values are less than 75 × 10 9 /L, every 4 weeks if values are between 75 and 100 × 10 9 /L, and as clinically indicated if values are greater than 100 × 10 9 /L. Manage platelet counts of < 50 × 10 9 /L by treatment interruption or dose-reduction of AYVAKIT. Platelet support may be necessary . Dose-interruptions and dose-reductions for thrombocytopenia occurred in 20% and 22% of AYVAKIT-treated patients, respectively. Thrombocytopenia was generally reversible by reducing or interrupting AYVAKIT.
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 . Indolent Systemic Mastocytosis Cognitive adverse reactions occurred in 7.8% of patients with ISM who received AYVAKIT + best supportive care versus 7% of patients who received placebo + best supportive care in the PIONEER study; <1% were Grade 3. The median time to onset of the first cognitive adverse reaction was 2.3 months (range: 0 to 5.4 months). Median time to improvement to Grade 1 or complete resolution was 2.1 months (range: 0.4 to 2.1 months). Gastrointestinal Stromal Tumors Cognitive adverse reactions occurred in 41% of 601 patients with GIST who received AYVAKIT; 5% were Grade ≥ 3. Memory impairment occurred in 21% of patients; <1% of these events were Grade 3. Cognitive disorder occurred in 12% of patients; 1.2% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Amnesia occurred in 3% of patients; <1% of these events were Grade 3. Somnolence and speech disorder occurred in 2% of patients; none of these events were Grade 3. Other events occurred in less than 2% of patients.
The median time to onset of the first cognitive adverse reaction was 8.4 weeks (range: 1 day to 4 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 7.9 weeks. Overall, 2.7% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 13.5% required a dosage interruption, and 8.5% required dose reduction. Advanced Systemic Mastocytosis Cognitive adverse reactions occurred in 28% of 148 patients with AdvSM who received AYVAKIT; 3% were Grade ≥ 3. Memory impairment occurred in 16% of patients; all events were Grade 1 or 2. Cognitive disorder occurred in 10% of patients; <1% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Other events occurred in less than 2% of patients.
The median time to onset of the first cognitive adverse reaction was 13.3 weeks (range: 1 day to 1.8 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 8.1 weeks. Overall, 2% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 8.1% required a dosage interruption, and 8.8% required dose reduction. 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.
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 .
Drug Interactions with Ayvakit
Effects of Other Drugs on
AYVAKIT Strong and Moderate CYP3A Inhibitors Coadministration of AYVAKIT with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate CYP3A inhibitor cannot be avoided, reduce the dose of AYVAKIT. Strong and Moderate CYP3A Inducers Coadministration of AYVAKIT with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations , which may decrease efficacy of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers.
Effects of
AYVAKIT on Other Drugs Coadministration of AYVAKIT with ethinyl estradiol-containing contraceptives may increase the exposure of ethinyl estradiol, which may lead to increased risk of ethinyl estradiol-associated adverse reactions . If the patient is unable to use or tolerate an effective nonhormonal contraceptive or an effective hormonal contraceptive without estrogen, use a formulation of ethinyl estradiol containing 20 mcg or less unless a higher dose is necessary.
Pregnancy Safety for Ayvakit
Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action , AYVAKIT can cause fetal harm when administered to a pregnant woman. There are no available data on AYVAKIT use in pregnant women. Oral administration of avapritinib to pregnant rats during the period of organogenesis was teratogenic and embryotoxic at exposure levels approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively (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 2-4% and 15-20%, respectively. Data Animal Data In a reproductive toxicity study, administration of avapritinib to rats during the period of organogenesis resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses greater than or equal to 10 mg/kg/day (approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively).
Pediatric Use of Ayvakit
Pediatric Use The safety and effectiveness of AYVAKIT in pediatric patients have not been established.
Clinical Studies of Ayvakit
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). 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 (
Denotes ongoing response, 20.3 ) NR Patients with
DOR ≥ 6-months, n (%) 11 patients with an ongoing response were followed < 6 months from onset of response. 22 (61%) 20 (59%)
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 × 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 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. Table 12. Efficacy Results for Patients with AdvSM in EXPLORER and PATHFINDER All evaluable patients ASM SM-AHN MCL Abbreviations: CI=confidence interval; CR=complete remission; CRh=complete remission with partial recovery of peripheral blood counts; PR=partial remission Overall Response Rate Overall Response Rate (ORR) per modified IWG-MRT-ECNM is defined as patients who achieved a CR, CRh or PR (CR + CRh + PR), % per modified IWG-MRT-ECNM (95% CI Clopper–Pearson confidence interval ) N=53 57 N=2 100 N=40 58 N=11 45 Complete Remission with full or partial hematologic recovery, % 28 50 33 9 Partial Remission, % 28 50 25 36 Clinical Improvement, % 15 0 20 0 Stable Disease, % 19 0 13 45 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).
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. Table 13. Efficacy Results for Patients with ISM in PIONEER at Week 24 Efficacy Parameter AYVAKIT (25 mg once daily) + BSC N=141 Placebo + BSC N=71 2-sided p-value Abbreviations: BSC=best supportive care; CI=confidence interval; ISM-SAF= Indolent Systemic Mastocytosis-Symptom Assessment Form TSS=Total Symptom Score Absolute Mean change in the ISM-SAF TSS Markov chain Monte Carlo simulation was used to impute the missing values at Baseline or C7D1. Change from baseline (95% CI) -15.33 (-18.36, -12.31) -9.64 (-13.61, -5.68) 0.012 Difference from placebo (95% CI) -5.69 (-10.16, -1.23) % of patients achieving ≥50% reduction in the ISM-SAF TSS Patients with missing values at Baseline or C7D1 were counted in the denominator but not numerator. (95% CI) 25 10 0.009 Table 14. Efficacy Results Related to Mast Cell Burden for Patients with ISM in PIONEER at Week 24 Efficacy Parameter AYVAKIT (25 mg once daily) + BSC Placebo + BSC 2-sided p-value Abbreviations: BSC=best supportive care; CI=confidence interval % of patients with a ≥50% reduction in serum tryptase (95% CI) N=141
N=71 0 <0.0001 % of patients with a ≥50% reduction in peripheral
blood KIT D816V allele fraction or undetectable (95% CI) N=118
N=63 6.3 <0.0001 % of patients with a ≥50% reduction in bone
marrow mast cells or no aggregates (95% CI) N=106
N=57 22.8 <0.0001 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 Figure 1
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
Ready to save on Ayvakit?
Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.
Compare Ayvakit Prices