Avapritinib, a potent and selective inhibitor of platelet-derived growth factor receptor alpha (PDGFR-α), PDGFR-α with D842 mutations, and c-Kit with exon 11, 11/17, and 17 mutations, is an antineoplastic agent.1, 2, 4, 7, 9, 11
Avapritinib is used for the treatment of adults with unresectable or metastatic GI stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha ( PDGFR- ) exon 18 mutation, including PDGFR- D842V mutations.1, 2 The presence of PDGFR- exon 18 mutation should be confirmed prior to initiation of therapy.1 An FDA-approved diagnostic test for detection of PDGFR- exon 18 mutation is not currently available; however, in clinical studies, presence of PDGFR- exon 18 mutation was determined by a polymerase chain reaction (PCR) or next-generation sequencing (NGS) assay.1 Avapritinib has been designated an orphan drug by the Food and Drug Administration (FDA) for the treatment of this cancer.5
The current indication for avapritinib in the treatment of GIST is based principally on the results of a multicenter, open-label, phase 1 study (NAVIGATOR) in a cohort of 43 adults with unresectable or metastatic GIST harboring a PDGFR- exon 18 mutation.1, 2, 7, 12, 13, 14 PDGFR- exon 18 mutation was determined using PCR or NGS; 38 patients had PDGFR- D842V mutations and 5 patients had PDGFR- exon 18 non-D842V mutations.1, 2 In this study, an initial avapritinib dosage of 400 mg orally once daily was used; the protocol was subsequently amended to reduce the dosage to 300 mg following reports of increased toxicity with the higher dosage.1 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary efficacy end point was objective response rate (as evaluated by an independent review committee) according to the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodules within a preexisting tumor mass was considered progression; an additional outcome measure was duration of response.1, 7 Because the objective response rate was similar between patients receiving avapritinib 300 or 400 mg, the results for these patients were combined in the efficacy analysis.1 The median age of patients included in the PDGFR -α exon 18 mutation cohort was 64 years (range: 29-90 years); 67% were male, 67% were white, 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 98% had metastatic disease, 53% had a target lesion exceeding 5 cm, and 86% had undergone prior surgical resection.1 Patients received a median of 1 (range: 0-5) prior tyrosine kinase inhibitor.1
At a median follow-up of 10.6 months, the objective response rate in patients with PDGFR- exon 18 mutations or PDGFR- D842V mutations was 84 or 89%, respectively, and complete response was achieved in 7 or 8% of patients, respectively.1 Median duration of response had not been reached; however, 59-61% of the responders had a durable response of at least 6 months.1
Treatment selection in GIST is primarily based on the molecular subtype; molecular subtype may change following exposure to tyrosine kinase inhibition.15 The second most common molecular subtype of GIST is PDGFR-mutant GIST, with PDGFR- mutations occurring in 10% of GIST patients.15 Mutations in exon 18 of PDGFR- are the most common, and account for 8% of GIST.15 A large subset of PDGFR- mutant cases (70%) harbor PDGFR- exon 18 D842V mutations, which are resistant to imatinib (the typical first-line therapy).15
The National Cancer Institute and some experts have issued clinical practice guidelines on GIST.2020, 2021 The standard treatment of localized GIST is surgical excision.2020, 2021 In neoadjuvant GISTs sensitive to imatinib, imatinib is standard when resection with no tumor at the margin is not feasible; adjuvant imatinib is used in high-risk patients.2020, 2021 In cases of PDGFR- exon 18 D842V mutant GIST resistant to imatinib, neoadjuvant avapritinib treatment may be used.2021 Imatinib is recommended first-line in patients with unresectable or metastatic GIST.2020 Avapritinib is recommended first-line in metastatic disease in PDGFR- exon 18 D842V mutant disease.2021 Sunitinib is generally administered to patients with unresectable disease after progression on imatinib.2020, 2021 In the metastatic setting, therapy should be continued indefinitely until clinically relevant disease progression or intolerance.2020, 2021 Some experts recommend regorafenib as a third-line agent and ripretinib as a fourth-line agent for GIST.2021
Advanced Systemic Mastocytosis
Avapritinib is used for the treatment of adults with advanced systemic mastocytosis (AdvSM), which includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast-cell leukemia (MCL).1 Avapritinib has been designated an orphan drug by the FDA for the treatment of this cancer.5 Avapritinib is not recommended for use in patients with AdvSM with platelet counts <50,000/mm3.1
The safety and efficacy of avapritinib for AdvSM, including ASM, SM-AHN, and MCL were established based on results from 2 multicenter, single-arm, open-label studies; a phase 1 study (EXPLORER) and a phase 2 study (PATHFINDER).1, 16, 17 These 2 studies evaluated a total of 53 patients with AdvSM, including 2 patients with ASM, 40 patients with SM-AHN, and 11 patients with MCL.1 During EXPLORER, patients received doses of avapritinib ranging from 30 to 400 mg (0.15-2 times the recommended dose) once daily.1 In PATHFINDER, patients received a starting dose of 200 mg daily.1, 17 The primary efficacy endpoint was the overall response rate in patients who had received up to 200 mg avapritinib daily and per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria as adjudicated by an independent central committee.1 Response-evaluable patients included those with a confirmed diagnosis of AdvSM per World Health Organization (WHO) and deemed evaluable by modified IWG-MRT-ECNM criteria at baseline as adjudicated by an independent central committee, who received at least one dose of study drug, completed at least 2 post-baseline bone marrow assessments, and continued in either study for at least 24 weeks or completed an end of study visit.1 All enrolled patients had an ECOG performance status of 0-3, and 91% had a platelet count >50,000/mm3 prior to treatment initiation.1 The median age of the evaluated study population was 67 years (range: 37-85 years), 58% were male, and 98% were white.1 Ongoing corticosteroid therapy was present in 40% of patients, 66% had received prior antineoplastics, 47% had received prior midostaurin, and 94% had a D816V mutation.1 The median serum tryptase level was 255.8 ng/mL, the median bone marrow mast cell infiltrate was 50%, and the median KIT D816V mutant allele fraction was 12.2%.1
The median duration of follow-up was 11.6 months.1 The overall response rates for patients with ASM, SM-AHN, and MCL were 100, 58, and 45%, respectively, and complete remission was achieved in 50, 33, and 9% of patients, respectively.1 The overall response rate for patients with AdvSM (any type) was 57%, and 28% of patients achieved complete remission.1 For all evaluable patients, the median duration of response was 38.3 months, and the median time to response was 2.1 months.1
According to the 2016 WHO classification system, systemic mastocytosis (SM) is separated into 5 subcategories, which include indolent SM, smoldering SM, ASM, SM-AHN, and MCL.18 The treatment of adult SM is highly individualized.18 Advanced SM often requires mast cell-directed cytoreductive treatments to alleviate organ dysfunction; options for treatment include avapritinib, midostaurin, cladribine, imatinib, interferon-α, or allogeneic stem cell transplantation in refractory/relapsed disease.18
Indolent Systemic Mastocytosis
Avapritinib is used for the treatment of adults with indolent systemic mastocytosis (ISM), a clonal disease caused by mast-cell accumulation and activation, primarily driven by the KIT D816V mutation.1, 2023, 2024, 2025 Avapritinib has been designated an orphan drug by FDA for the treatment of this cancer.2022 Avapritinib is not recommended for use in patients with ISM with platelet counts <50,000/mm3.1
The efficacy of avapritinib for indolent systemic mastocytosis was demonstrated in a randomized, double-blind, placebo-controlled study (PIONEER).1, 2024 This study evaluated adult patients with ISM categorized by the World Health Organization (WHO) classification with moderate to severe symptoms despite receiving at least 2 symptom directed therapies.1, 2024 Patients were randomized to receive avapritinib 25 mg orally once daily and supportive care compared with placebo and supportive care over 24 weeks.1 The majority of patients who received avapritinib (99.3%) or placebo (100%) received concomitant best supportive care at baseline (median of 3 therapies in the avapritinib group and 4 in the placebo group).1 The most common therapies in patients receiving avapritinib were H1 antihistamines (97%), H2 antihistamines (66%), leukotriene inhibitors (35%), and cromolyn sodium (30%).1
The primary efficacy endpoint was the absolute mean change from baseline to week 24 in the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) total symptom score (TSS) based on a biweekly average.1 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, brainfog).1 Scores range from 0 ("none") to 10 ("worst imaginable").1 The item scores were summed to calculate a daily ISM-SAF TSS (range 0-110), with higher scores indicating greater symptom severity.1 An additional efficacy endpoint was the proportion of avapritinib-treated patients achieving ≥50% reduction from baseline through 24 weeks in TSS score compared with placebo.1
The absolute mean change from baseline to week 24 in the ISM-SAF TSS was 15.33 for patients receiving avapritinib and supportive care compared with 9.64 for patients receiving placebo and supportive care.1, 2025 The additional efficacy endpoint defining the proportion of avapritinib-treated patients achieving ≥50% reduction from baseline through 24 weeks was 25% for patients receiving avapritinib and supportive care compared with 10% for patients receiving placebo and supportive care.1, 2025
According to the 2016 WHO classification system, systemic mastocytosis (SM) is separated into 5 subcategories, which include ISM, smoldering SM, ASM, SM-AHN, and MCL.18 Current recommendations or management of ISM include treatment with a potent selective mutant KIT inhibitor such as avapritinib.2023
Avapritinib is administered orally once daily on an empty stomach (i.e., at least 1 hour before or 2 hours after a meal).1
If a dose of avapritinib is missed, the missed dose should be taken as soon as it is remembered unless the next dose is due within 8 hours.1 Do not take a missed dose within 8 hours of the next scheduled dose.1
If a dose is vomited, patients should not repeat the dose to make up for the vomited dose.1 The next dose should be taken at the regularly scheduled time.1
GIST Harboring PDGFR- Exon 18 Mutations
For the treatment of unresectable or metastatic GIST harboring PDGFR- exon 18 mutation, the recommended adult dosage of avapritinib is 300 mg orally once daily.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Advanced Systemic Mastocytosis
For the treatment of AdvSM, including aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL), the recommended adult dosage of avapritinib is 200 mg orally once daily.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Indolent Systemic Mastocytosis
For the treatment of ISM, the recommended adult dosage of avapritinib is 25 mg orally once daily.1
Dosage Modification for Toxicity
If adverse reactions occur during avapritinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of avapritinib should be reduced as described in Table 1.1
Dosage Reduction | GISTa | AdvSMb |
|---|---|---|
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 | Discontinue avapritinib | 25 mg once daily |
aPermanently discontinue avapritinib in patients with GIST unable to tolerate a dose of 100 mg daily.
bPermanently discontinue avapritinib in patients with AdvSM unable to tolerate a dose of 25 mg daily.
The following table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for adverse effects according to severity.1
Adverse Reaction and Severity | Dosage Modification |
|---|---|
Patients with GIST or AdvSM with intracranial hemorrhage | Any grade: Permanently discontinue therapy |
Patients with GIST or AdvSM with cognitive effects | Grade 1: Continue at same or reduced dosage, or withhold therapy until toxicity resolves or improves to baseline and then resume at same or reduced dosage Grade 2 or 3: Withhold therapy; when toxicity resolves or improves to baseline or grade 1, resume at same or reduced dosage Grade 4: Permanently discontinue therapy |
Patients with GIST or AdvSM with other toxicity | Grade 3 or 4: withhold therapy; when toxicity improves to grade 2 or less, resume at same or reduced dosage |
Patients with AdvSM with thrombocytopenia | Platelets <50,000/mm3: interrupt treatment until platelet count ≥50,000/mm3, then resume at reduced dosage. If platelet counts do not recover to ≥50,000/mm3, consider platelet support |
Dosage Modification with Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of avapritinib with drugs that are strong or moderate inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided.1 If concomitant use of a moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the initial dosage of avapritinib to 100 mg once daily (for GIST) or 50 mg once daily (for AdvSM).1 Avoid concomitant use of avapritinib with strong or moderate CYP3A inhibitors in patients with ISM.1
The manufacturer states that no dosage adjustment is necessary in patients with mild (total bilirubin concentration ≤ the upper limit of normal [ULN] with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration) or moderate (total bilirubin concentration exceeding 1.5 times the ULN, but no more than 3 times the ULN, with any AST concentration) hepatic impairment.1
Dosage adjustments are recommended in patients with severe hepatic impairment (Child-Pugh Class C).1 For patients with severe hepatic impairment receving avapritinib, the manufacturer recommends a dosage of 200 mg once daily (for patients with GIST), 100 mg once daily (for patients with AdvSM), and 25 mg every other day (for patients with ISM).1
The manufacturer states that no dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1
The effect of severe renal impairment or end-stage renal disease (creatinine clearance 29 mL/minute or less) on the pharmacokinetics of avapritinib has not been established, and the manufacturer makes no specific dosage recommendations for such patients.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
None.1
Intracranial hemorrhage (e.g., subdural hematoma, intracranial or cerebral hemorrhage) has been reported in patients with AdvSM or GIST receiving avapritinib, including fatalities in <1% of patients.1 In clinical trials, intracranial hemorrhage occurred in 2.9% of 749 patients receiving avapritinib for advanced systemic mastocytosis (AdvSM) or GI stromal tumor (GIST).1 Intracranial hemorrhage events were not reported in a clinical study of 246 patients with ISM who received any dose of avapritinib.1
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.1 Advise patients to seek immediate medical attention for signs or symptoms (headache, nausea, vomiting, vision changes, or altered mental status) of intracranial hemorrhage.1 Permanently discontinue avapritinib for occurrence of intracranial hemorrhage of any grade.1
In patients with AdvSM, a platelet count must be performed before initiating therapy.1 In patients with baseline platelets <50,000/mm3, avapritinib is not recommended.1 Following the initiation of treatment, monitor platelet counts every 2 weeks for the first 8 weeks; after 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently if clinically indicated) if platelets are <75,000/mm3, every 4 weeks if platelets are between 75,000/mm3 and 100,000/mm3, and as clinically indicated if platelets are >100,000/mm3.1
Thrombocytopenia is generally reversible with dosage reductions or interruptions in treatment.1 Manage platelet counts <50,000/mm3 by reducing avapritinib dosage or interrupting treatment as recommended; avapritinib is not recommended in patients with AdvSM or indolent systemic mastocytosis (ISM) with platelet counts of <50,000/mm3.1
Avapritinib can cause a broad spectrum of adverse CNS effects including cognitive impairment, dizziness, hallucinations, and sleep, speech, or mood disorders.1 In clinical trials of patients with GIST, AdvSM or ISM, cognitive effects have been reported in 33% of 995 patients receiving avapritinib.1 Overall, 10% led to dose interruptions, 7% led to dose reductions and 2.2% led to permanent discontinuation of treatment in patients with GIST, AdvSM or ISM.1
Memory impairment, cognitive disorder, confusional state, amnesia, or somnolence and speech disorder occurred in 21, 12, 6, 3, or 2%, respectively, of patients receiving avapritinib for GIST.1 The median time to first cognitive adverse reaction in GIST patients was 8.4 weeks (range: 1 day to 4 years).1 In patients experiencing adverse CNS effects, temporary interruption of avapritinib therapy, dosage reduction, or permanent discontinuance of therapy was necessary in 13.5, 8.5, or 2.7%, respectively, of patients receiving the drug for GIST.1
Memory impairment, cognitive disorder, or confusional state occurred in 16, 10, or 6%, respectively, of patients receiving avapritinib for AdvSM.1 The median time to initial onset of cognitive effects in AdvSM patients was 13.3 weeks (range: 1 day to 1.8 years).1 Out of the patients who received avapritinib for AdvSM, permanent discontinuance, dosage interruption, and dosage reduction was required in 2, 8.1, and 8.8% of patients, respectively.1
Cognitive effects occurred in 7.8% of patients with ISM who received avapritinib and best supportive care compared with 7% of patients who received placebo and best supportive care in a clinical study.1 The median time to initial onset of cognitive effects was 2.3 months (range: 0 to 5.4 months).1 Median time to improvement to Grade 1 or complete resolution was 2.1 months (range: 0.4 to 2.1 months).1
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of avapritinib may be necessary, depending on the severity of the adverse CNS effect.1
Avapritinib may cause photosensitivity reactions.1 These reactions occurred in 2.5% of all patients administered avapritinib in clinical trials.1 Patients should be advised to limit direct ultraviolet exposure during therapy and for 1 week after treatment discontinuation.1
Fetal/Neonatal Morbidity and Mortality
Avapritinib may cause fetal harm in humans based on its mechanism of action and animal findings; embryofetal toxicity and teratogenicity have been demonstrated in animals.1 There are no data regarding use of avapritinib in pregnant women.1
Pregnancy should be avoided during avapritinib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of avapritinib therapy in females of reproductive potential and that such patients should be advised to use effective contraceptive methods while receiving avapritinib and for 6 weeks after the last dose of the drug.1 In addition, males with such female partners should use effective contraceptive methods while receiving avapritinib and for 6 weeks after the last dose of the drug.1
Patients should be apprised of the potential hazard to the fetus if avapritinib is used during pregnancy.1
Avapritinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Embryofetal toxicity and teratogenicity have been demonstrated in animals.1 There are no data regarding use of avapritinib in pregnant women.1
Pregnancy should be avoided during avapritinib therapy.1 Patients should be apprised of the potential hazard to the fetus if avapritinib is used during pregnancy.1
It is not known whether avapritinib or its metabolites are distributed into human milk.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1
Because of the potential for serious adverse reactions to avapritinib in breast-fed infants, women should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
The manufacturer states that a pregnancy test should be performed prior to initiation of avapritinib therapy in females of reproductive potential and that such patients should be advised to use effective contraceptive methods while receiving avapritinib and for 6 weeks after the last dose of the drug.1 In addition, males with such female partners should use effective contraceptive methods while receiving avapritinib and for 6 weeks after the last dose of the drug.1
Based on animal studies, avapritinib may impair male and female fertility.1 Cystic degeneration of corpora lutea and hypospermatogenesis were observed in animals receiving avapritinib.1
Safety and efficacy of avapritinib have not been established in pediatric patients.1
In the NAVIGATOR, EXPLORER/PATHFINDER, and PIONEER studies, 40%,62%, and 6% of patients receiving avapritinib were ≥65 years of age, respectively, while 6%, 21%, and <1% were ≥75 years of age, respectively.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults.1 Population pharmacokinetic analysis suggests that age (range: 18-90 years) does not have a clinically important effect on the pharmacokinetics of avapritinib.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of avapritinib are not substantially altered in patients with mild (total bilirubin concentration ≤the upper limit of normal [ULN] with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration) or moderate (total bilirubin concentration exceeding 1.5 times the ULN, but no more than 3 times the ULN, with any AST concentration) hepatic impairment.1
Drug exposure was 61% higher in subjects with severe hepatic impairment (Child-Pugh Class C) as compared to matched healthy subjects with normal hepatic function.1 A lower starting dose is recommended in patients with severe hepatic impairment.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of avapritinib are not substantially altered in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1
The effect of severe renal impairment or end-stage renal disease (creatinine clearance 29 mL/minute or less) on the pharmacokinetics of avapritinib has not been established.1
The most common adverse reactions in clinical trials for GIST (occurring in ≥20% of patients receiving avapritinib) include edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness.1
The most common adverse reactions in clinical trials for AdvSM (occurring in ≥20% of patients receiving avapritinib) include: edema, diarrhea, nausea, and fatigue/asthenia.1
The most common adverse reactions in a clinical trial for ISM (occuring in ≥10% of patients receiving avapritinib) include: eye edema, dizziness, peripheral edema, and flushing.1
Avapritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, 3A5, and to a lesser extent by CYP2C9; the major circulating metabolites are a hydroxy glucuronide metabolite (M690) and an oxidative metabolite (M499).1, 7 Formation of M690 is catalyzed by UDP-glucuronosyltransferase (UGT) 1A3.1
In vitro, avapritinib demonstrates time-dependent inhibition and induction of CYP3A.1 In vitro, avapritinib inhibits CYP2C9, but does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C19, or 2D6 or induce CYP isoenzymes 1A2 or 2B6 at clinically relevant concentrations.1 In vitro, avapritinib is a substrate of CYP3A.1
In vitro, M499 inhibits CYP isoenzymes 3A, 2C8, and 2C9, but does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, and 2D6 at clinically relevant concentrations.1
In vitro studies indicate that avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal breast cancer resistance protein (BCRP), multidrug and toxic compound extrusion protein (MATE) 1, MATE2K, and bile salt export pump (BSEP).1 Avapritinib does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, and OCT2.1 Avapritinib also is not a substrate for P-gp or BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, and BSEP.1 The effect of M499 on transport systems is not known.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of avapritinib with potent or moderate inhibitors of CYP3A may result in increased systemic exposure to avapritinib and increased risk of avapritinib toxicity.1 Simulations using physiologically based pharmacokinetic models suggest concomitant use of avapritinib (300 mg once daily) and the potent CYP3A inhibitor itraconazole (200 mg once daily) or moderate CYP3A inhibitor fluconazole (200 mg once daily) may increase steady-state AUC of avapritinib by 600 or 210%, respectively.1
Concomitant use of avapritinib with potent (e.g., itraconazole) or moderate (e.g., erythromycin, fluconazole, verapamil)7 CYP3A inhibitors should be avoided.1 If concomitant use of a moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the initial dosage of avapritinib to 100 mg once daily (for GI stromal tumor [GIST]) or 50 mg once daily (for advanced systemic mastocytosis [AdvSM]).1
Concomitant use of avapritinib with potent or moderate inducers of CYP3A may result in decreased systemic exposure to avapritinib and reduced avapritinib efficacy.1 When the potent CYP3A inducer rifampin (600 mg once daily) was administered concomitantly with avapritinib (single 400-mg dose), AUC or peak plasma concentration of avapritinib decreased by 92 or 74%, respectively.1 Simulations using physiologically based pharmacokinetic models suggest concomitant use of avapritinib (300 mg once daily) and the moderate CYP3A inducer efavirenz (600 mg once daily) may decrease AUC or peak plasma concentration of avapritinib at steady-state by 62 or 55%, respectively.1
Concomitant use of avapritinib with potent (e.g., rifampin) or moderate (e.g., efavirenz) CYP3A inducers should be avoided.1
Drugs Affecting Gastric Acidity
Concomitant administration of avapritinib and proton-pump inhibitors had no clinically important effects on the pharmacokinetics of avapritinib in patients with GI stromal tumor (GIST) or AdvSM.1, 7
Avapritinib, a potent and selective inhibitor of platelet-derived growth factor receptor alpha (PDGFR-α), PDGFR-α with D842 mutations, and c-Kit with exon 11, 11/17, and 17 mutations, is an antineoplastic agent.1, 2, 4, 7, 9, 11 Some mutations in PDGFR -α and c-Kit increase autophosphorylation and activation, independent of ligand binding, of the tyrosine kinase receptor resulting in increased cell proliferation and survival in GI stromal tumors (GIST) harboring these mutations.1, 9 In cellular assays, avapritinib inhibits autophosphorylation of PDGFR-α D842V and c-Kit D816V mutations associated with resistance to other tyrosine kinase inhibitors (e.g., imatinib, regorafenib, sunitinib).1, 7 In cellular assays, avapritinib inhibited the proliferation in KIT mutant cell lines that included murine mastocytoma cell lines and human mast cell leukemia cell lines.1 In vivo, avapritinib demonstrated antitumor activity in patient-derived xenograft models of imatinib-resistant GIST harboring c-Kit exon 11/17 mutations.1, 9
Systemic exposure to avapritinib increases in a dose proportional manner over a dosage range of 25-400 mg daily.1 Following oral administration, the median time to peak plasma concentrations of avapritinib is 2-4 hours.1 Following repeated daily dosing, steady-state concentrations of the drug are attained in 15 days with a mean accumulation ratio of 3.82, 4.06, and 6.41 in GIST, ISM, and systemic mastocytosis, respectively.1 Administration of avapritinib with a high-fat, high-calorie meal (i.e., approximately 909 calories, 56 g of fat) increases the area under the concentration-time curve (AUC) and peak plasma concentration of avapritinib by 29 and 59%, respectively, compared with administration in the fasted state.1 Avapritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, CYP3A5, and to a lesser extent by CYP2C9.1 The main circulating metabolites are M690 (a hydroxy glucuronide metabolite) and M499 (an oxidative metabolite).1, 7 Following administration of avapritinib 300 mg once daily, M499 accounts for approximately 80% of systemic exposure to the drug at steady state but is unlikely to contribute significantly to the activity of avapritinib at the recommended dose.1, 7 Following oral administration of a single radiolabeled dose of avapritinib, 70% of the radioactivity was recovered in feces (11% of the dose as unchanged drug) and 18% was recovered in urine (0.23% of the dose as unchanged drug).1 In vitro, avapritinib is 98.8% bound to plasma proteins, and binding is independent of avapritinib concentration.1 The mean elimination half-life of the drug is 32-57 hours in patients with GIST, 20-39 hours in patients with AdvSM, and 38-45 hours in patients with ISM.1
The pharmacokinetics of avapritinib do not appear to be affected substantially by age (18-90 years), sex, race, and body weight (39.5-156.3 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Avapritinib is available only from designated specialty pharmacies.6 The manufacturer should be contacted for additional information.6
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 25 mg | Blueprint Medicines | |
50 mg | Ayvakit® | Blueprint Medicines | ||
100 mg | Ayvakit® | Blueprint Medicines | ||
200 mg | Ayvakit® | Blueprint Medicines | ||
300 mg | Ayvakit® | Blueprint Medicines |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Blueprint Medicines Corporation. Ayvakit® (avapritinib) tablets prescribing information. Cambridge, MA: 2023 May.
2. Heinrich M, Jones, RL, von Mehren M et al. Clinical response to avapritinib by RECIST and Choi Criteria in ≥ 4th line and PDGFRA exon 18 gastrointestinal stromal tumors (GIST). Oral presentation at 2019 Annual Meeting of the Connective Tissue Oncology Society. Tokyo, Japan: 2019 Nov 14. Accessed from manufacturer website on 2020 Jun 26. [Web]
3. Heinrich M, Jones, RL, von Mehren, M et al. Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST). J Clin Oncol . 2019; 37(Suppl):11022.
4. Joseph C, Abaricia S, Angelis M et al. Avapritinib for the treatment of GIST: Analysis of efficacy, safety, and patient management strategies at the recommended phase 2 dose. Poster presented at 2019 Annual Meeting of the Connective Tissue Oncology Society. Tokyo, Japan: 2019 Nov 14. Accessed from manufacturer website on 2020 Jun 26. [Web]
5. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2020 Mar 8. [Web]
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