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Gastrointestinal Stromal Tumors
Unresectable or Metastatic GIST
The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR [see Clinical Studies (14.1)]. 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, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Table 3 summarizes the adverse reactions observed in NAVIGATOR.
Table 3. Adverse Reactions (≥ 10%) in Patients Receiving AYVAKIT in NAVIGATOR
|Grade ≥ 3|
|*Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0|
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.
Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort.
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.
Sleep disorders includes insomnia, somnolence, and sleep disorder.
Taste effects include dysgeusia and ageusia.
Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered, nervousness, personality change, and suicidal ideation.
|Metabolism and nutrition|
|Skin and subcutaneous tissue|
Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular.
|Hair color changes||21||0.5|
|Respiratory, thoracic and mediastinal|
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 4 summarizes the laboratory abnormalities observed in NAVIGATOR.
Table 4. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients Receiving AYVAKIT in NAVIGATOR
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.
|Grade ≥ 3|
|Increased activated partial thromboplastin time||13||0|
|Increased aspartate aminotransferase||51||1.5|
|Increased alanine aminotransferase||19||0.5|
|Increased alkaline phosphatase||14||1|
Strong and Moderate CYP3A Inhibitors
Coadministration of AYVAKIT with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.4)].
Strong and Moderate CYP3A Inducers
Coadministration of AYVAKIT with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease efficacy of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers.
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], 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 animals during the period of organogenesis was teratogenic and embryotoxic in rats at exposure levels approximately 2.7 times the human exposure based on AUC at the 300 mg dose (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.
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 2.7 times the human exposure based on AUC at the 300 mg dose).
There are no data on the presence of avapritinib or its metabolites in human milk or the effects of avapritinib on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose.
Verify the pregnancy status of females of reproductive potential prior to initiating AYVAKIT [see Use in Specific Populations (8.1)].
AYVAKIT can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose.
Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose.
Based on findings from animal studies, AYVAKIT may impair both male and female fertility [see Nonclinical Toxicology (13.1)].
Based on the data from NAVIGATOR, exposure-response relationships for any Grade 3 or 4 adverse reaction were observed at higher exposures with a faster time to onset for adverse reactions with increasing avapritinib exposure.
The effect of AYVAKIT on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered dose of 300 mg or 400 mg (1.3 times the approved recommended dose) once daily. No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (Cmax) of 899 ng/mL.
The median time to peak concentration (Tmax) ranged from 2.0 to 4.1 hours following single doses of avapritinib 30 mg to 400 mg (0.1 to 1.33 times the approved recommended dose).
Effect of Food
The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state.
The mean apparent volume of distribution of avapritinib is 1200 L (43%). In vitro protein binding of avapritinib is 98.8% and is independent of concentration. The blood-to-plasma ratio is 0.95.
The mean plasma elimination half-life of avapritinib was 32 hours to 57 hours following single doses of avapritinib 30 mg to 400 mg (0.1 to 1.33 times the approved recommended dose). The steady state mean apparent oral clearance of avapritinib is 19.5 L/h (48%).
Avapritinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 in vitro. Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds. Following oral administration of AYVAKIT 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.
Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged).
No clinically significant differences in the pharmacokinetics of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on the pharmacokinetics of avapritinib is unknown.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong and Moderate CYP3A Inhibitors on Avapritinib: Coadministration of AYVAKIT 300 mg once daily with itraconazole 200 mg once daily (a strong CYP3A inhibitor) is predicted to increase avapritinib AUC by 600% at steady state.
Coadministration of AYVAKIT 300 mg once daily with fluconazole 200 mg once daily (a moderate CYP3A inhibitor) is predicted to increase avapritinib AUC by 210% at steady state [see Drug Interactions (7.1)].
Effect of Strong and Moderate CYP3A Inducers on Avapritinib: Coadministration of AYVAKIT 400 mg as a single dose with rifampin 600 mg once daily (a strong CYP3A inducer) decreased avapritinib Cmax by 74% and AUC0-INF by 92%.
Coadministration of AYVAKIT 300 mg once daily with efavirenz 600 mg once daily (a moderate CYP3A inducer) is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady-state [see Drug Interactions (7.1)].
Effect of Acid-Reducing Agents on Avapritinib: No clinically significant differences in the pharmacokinetics of avapritinib were identified when coadministered with gastric acid reducing agents in patients with GIST.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: In vitro studies indicate that avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A at clinically relevant concentrations.
Avapritinib is an inhibitor of CYP2C9 at clinically relevant concentrations. Avapritinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6 at clinically relevant concentrations.
Avapritinib is not an inducer of CYP1A2 or CYP2B6. Avapritinib is a substrate of CYP3A.
M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9 at clinically relevant concentrations. M499 is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, or CYP2D6 at clinically relevant concentrations.
Transporter Systems: Avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal BCRP, MATE1, MATE2-K, and BSEP, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2. Avapritinib is not a substrate of P-gp or BCRP. The effect of M499 on transporter systems is unknown.
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 5.
Table 5. 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
N = 38
|Abbreviations: CI=confidence interval; NR=not reached; NE=not estimable|
|+ Denotes ongoing response|
|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+, 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%)|
Advise patients to contact their healthcare provider immediately if experiencing neurological signs and symptoms that may be associated with intracranial hemorrhage [see Warnings and Precautions (5.1)].
Central Nervous System Effects
Advise patients and caretakers to notify their healthcare provider if they experience new or worsening CNS symptoms. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.2)].
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose [see Use in Specific Populations (8.2)].
Advise females and males of reproductive potential that AYVAKIT may impair fertility [see Use in Specific Populations (8.3)].
Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7.1)].
Advise patients to take AYVAKIT on an empty stomach, at least 1 hour before and at least 2 hours after a meal [see Dosage and Administration (2.2)].
Blueprint Medicines Corporation, Cambridge, MA 02139, USA
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