Ayvakit Drug Information
Generic name: AVAPRITINIB
Kinase Inhibitor [EPC]
Uses of Ayvakit
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).
Dosage & Administration of Ayvakit
Recommended Administration Administer
AYVAKIT orally on an empty stomach, at least 1 hour before or 2 hours after a meal. 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.
GIST Harboring PDGFRA Exon 18 Mutations
Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation. An FDA-approved test for the detection of exon 18 mutations is not currently available. The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST.
Continue treatment until disease progression or unacceptable toxicity.
Advanced Systemic Mastocytosis
The recommended dosage of AYVAKIT is 200 mg orally once daily in patients with AdvSM.
Indolent Systemic Mastocytosis
The recommended dosage of AYVAKIT is 25 mg orally once daily in patients with ISM.
Dosage Modifications for Adverse Reactions
The recommended dosage reductions and modifications for adverse reactions are provided in Tables 1 and 2. Table 1: Recommended Dosage Reductions for AYVAKIT for
Concomitant Use of Strong and Moderate CYP3A Inhibitors
Avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors.
Dosage Modifications for Severe Hepatic Impairment
A modified starting dosage of AYVAKIT is recommended for patients with severe hepatic impairment (Child-Pugh Class C): GIST: 200 mg orally once daily AdvSM: 100 mg orally once daily ISM: 25 mg orally every other day
| Dose Reduction Level | Dosage in patients with GIST Permanently discontinue AYVAKIT in patients with GIST who are unable to tolerate a dose of 100 mg once daily. | Dosage in patients with AdvSM Permanently discontinue AYVAKIT in patients with AdvSM who are unable to tolerate a dose of 25 mg once daily. |
|---|---|---|
| First dose reduction | 200 mg once daily | 100 mg once daily |
| Second dose reduction | 100 mg once daily | 50 mg once daily |
| Third dose reduction | - | 25 mg once daily |
| Adverse Reaction | Severity Severity as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 | Dosage Modification |
|---|---|---|
| Patients with GIST or AdvSM | ||
| Intracranial Hemorrhage [see Warnings and Precautions (5.1) ] | Any grade | Permanently discontinue AYVAKIT. |
| Cognitive Effects [see Warnings and Precautions (5.2) ] | Grade 1 | Continue AYVAKIT at same dose or reduced dose or withhold until improvement to baseline or resolution. Resume at same dose or reduced dose. |
| Grade 2 or Grade 3 | Withhold AYVAKIT until improvement to baseline, Grade 1, or resolution. Resume at same dose or reduced dose. | |
| Grade 4 | Permanently discontinue AYVAKIT. | |
| Other [see Adverse Reactions (6.1) ] | Grade 3 or Grade 4 | Withhold AYVAKIT until improvement to less than or equal to Grade 2. Resume at same dose or reduced dose, as clinically appropriate. |
| Patients with AdvSM | ||
| Thrombocytopenia [see Warnings and Precautions (5.1) ] | <50 × 10 9 /L | Interrupt AYVAKIT until platelet count is ≥ 50 × 10 9 /L, then resume at reduced dose (per Table 1). If platelet counts do not recover above 50 × 10 9 /L, consider platelet support. |
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.
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. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7). Serious adverse reactions occurred in 52% of patients receiving AYVAKIT.
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.
Table 6. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with GIST Receiving AYVAKIT in NAVIGATOR 1 Advanced Systemic Mastocytosis The safety of AYVAKIT in patients with AdvSM was evaluated in EXPLORER and PATHFINDER. Among patients receiving AYVAKIT, 70% were treated for 6 months or longer and 37% were exposed for greater than one year.
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.
Of patients receiving 200 mg once daily, subdural hematoma was the only adverse reaction requiring permanent discontinuation in more than one patient. 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. Median time to dose reduction was 1.7 months.
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.
Table 8. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER 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.
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.
Table 9.
| Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 | 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 | 0.5 |
| 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 | 1.5 |
| 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 | 4.9 |
| 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 | 2.9 |
| 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 | 2.1 |
| Hair color changes | 21 | 0.5 |
| Alopecia | 13 | 0 |
| Respiratory, thoracic and mediastinal | ||
| Dyspnea | 17 | 2.5 |
| Pleural effusion | 12 | 2 |
| Investigations | ||
| Weight decreased | 13 | 1 |
| 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 | 0.5 |
| Increased INR | 24 | 0.6 |
| Increased activated partial thromboplastin time | 13 | 0 |
| Chemistry | ||
| Increased bilirubin | 69 | 9 |
| Increased aspartate aminotransferase | 51 | 1.5 |
| 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 | 0.5 |
| Increased alkaline phosphatase | 14 | 1 |
| Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 | 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 |
| 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 |
| 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 5.0 | 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 |
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. 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.
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). 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. 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.
Memory impairment occurred in 16% of patients; all events were Grade 1 or 2. 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. 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. 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.
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. 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 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.
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. 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 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 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. Ethnicities included 4% Hispanic or Latino.
KIT D816V mutations were identified in 93% of patients. Study population characteristics were similar in the placebo group. Efficacy results are summarized in Tables 13 and 14.
Table 13. Efficacy Results for Patients with ISM in PIONEER at Week 24 Table 14. Efficacy Results Related to Mast Cell Burden for Patients with ISM in PIONEER at Week 24 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.
| 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%) |
| 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 (42, 70) | N=2 100 (16, 100) | N=40 58 (41, 73) | N=11 45 (17, 77) |
| 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 |
| 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 (17.9, 32.8) | 10 (4.1, 19.3) | 0.009 |
| 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 53.9 (45.3, 62.3) | N=71 0 (0.0, 5.1) | <0.0001 |
| % of patients with a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable (95% CI) | N=118 67.8 (58.6, 76.1) | N=63 6.3 (1.8, 15.5) | <0.0001 |
| % of patients with a ≥50% reduction in bone marrow mast cells or no aggregates (95% CI) | N=106 52.8 (42.9, 62.6) | N=57 22.8 (12.7, 35.8) | <0.0001 |
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.
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