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Indolent ISMAdvanced SMPDGFRA GIST
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Indolent ISMAdvanced SMPDGFRA GIST
AYVAKIT® (avapritinib) 25 mg white logo

Efficacy demonstrated in the PIONEER clinical trial1

AYVAKIT demonstrated statistically significant improvements vs placebo for primary and key secondary endpoints in the PIONEER study1

PIONEER Trial Overview

PIONEER (N=212) was a phase 2, multipart, randomized, placebo-controlled, double-blind study evaluating the efficacy and safety of AYVAKIT 25 mg + best supportive care (BSC) (n=141) vs placebo + BSC (n=71) over 24 weeks in adult patients (≥18 years) with a centrally confirmed ISM diagnosis per WHO criteria, and with moderate to severe ISM despite receiving at least 2 symptom-directed therapies. Patients were randomized 2:1 to receive once daily AYVAKIT 25 mg + therapies. Patients were randomized 2:1 to receive once daily AYVAKIT 25 mg + BSC or placebo + BSC. Patients who completed the 24-week double-blind portion of the trial had the option to enter an open-label extension (OLE) treatment period for up to 5 years and receive once daily AYVAKIT 25 mg + BSC.1,9
ISM-SAF Total Symptom Score at 24 Weeks

Primary endpoint

AYVAKIT demonstrated a statistically significant improvement in ISM-SAF TSS at 24 weeks1
Week 24AYVAKIT + BSC (N=141)Placebo + BSC (N=71)2-sided P value
Absolute mean change in the ISM-SAF TSS (95% CI)-15.33
(-18.36, -12.31)		-9.64
(-13.61, -5.68)		0.012
ITT analysis: Markov chain Monte Carlo simulation was used to impute the missing values.
ISM-SAF TSS OVER TIME9
Total Symptom Line Graph

ITT analysis: Markov chain Monte Carlo simulation was used to impute the missing values.

LIMITATIONS: Mean change in TSS at all time points except Week 24 were prespecified, nonranked endpoints and were not adjusted for multiplicity. Therefore, treatment differences at these time points cannot be regarded as statistically significant and results should be interpreted with caution.

ITT=intention to treat.

Click a link below to learn more about PIONEER
ISM-SAF
 Individual Symptom
 Scores at 24 Weeks
ISM-SAF
 Total Symptom
 Score Through 48 Weeks
Mast Cell
 Burden
 at 24 Weeks
ISM-SAF Individual Symptom Scores at 24 Weeks

Exploratory endpoint

Exploratory endpoint: Individual symptom scores at 24 weeks6
Reductions across all individual symptom scores were observed at 24 weeks6
MEAN CHANGE FROM BASELINE AT 24 WEEKS BY ISM-SAF INDIVIDUAL SYMPTOM SCORE6
Individual symptom score bar chart
  • Reductions were observed in patients’ most severe symptom, defined as the symptom with the highest score at baseline9

ITT analysis: In this analysis, if a patient was missing more than 7 days of the score between baseline score and Week 2 score, it was considered as missing for the patient. If a patient missed more than 7 days of the score from the 14-day period for calculating the Week 24 score, then the Week 24 score was considered as missing.

LIMITATIONS: Individual components in a descriptive exploratory analysis were prespecified, nonranked endpoints, not adjusted for multiplicity, and not powered. Therefore, data should be interpreted with caution, conclusions cannot be drawn, and treatment differences cannot be regarded as statistically significant.

ISM-SAF Total Symptom Score Through 48 Weeks9

Exploratory endpoint

MEAN CHANGE IN ISM-SAF TOTAL SYMPTOM SCORE THROUGH 48 WEEKS9
mean change in total symptom score at 48 weeks graph

ITT analysis: Patients with use of high-dose steroids (3 patients treated with AYVAKIT and 1 in the placebo group) were included in this analysis that were not included in the primary analysis.

Missing visit data were excluded from calculations for that visit.

  • In an interim analysis, a decrease in TSS was observed for patients who continued on AYVAKIT in an OLE through 48 weeks9

LIMITATIONS: Mean change in TSS at all time points except Week 24 were prespecified, nonranked endpoints and were not adjusted for multiplicity. Therefore, treatment differences at these time points cannot be regarded as statistically significant, results should be interpreted with caution, and conclusions cannot be drawn. In an open-label extension, there is a potential for enrichment of the long-term data in the remaining patient populations since patients who were unable to tolerate or do not respond to the drug often drop out.

Objective Measures of Mast Cell Burden at 24 Weeks

KEY SECONDARY endpoints

Significantly more patients treated with AYVAKIT had reductions in objective measures of mast cell burden at 24 weeks1
PROPORTION OF PATIENTS ACHIEVING ≥50% REDUCTION IN OBJECTIVE MEASURES OF MAST CELL BURDEN AT 24 WEEKS1
Biomarkers bar chart
52.8% of 106 patients receiving AYVAKIT + BSC achieved ≥50% reduction in BM MCs vs 22.8% of 57 patients receiving placebo + BSC (2-sided P<0.0001)1‡

ITT analysis: For patients with high-dose steroid use within 7 days before Week 24, or greater than 14 consecutive days at any point from baseline to Week 24, the Week 24 score was set to missing.

†Percent of patients with ≥50% reduction in peripheral blood KIT D816V VAF or undetectable.

‡Percent of patients with ≥50% reduction in BM MCs or no aggregates.

BM=bone marrow; BSC= best supportive care; MC=mast cell; VAF= variant allele fraction.

Individual results may vary.
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Safety





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INDICATION

AYVAKIT® (avapritinib) 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 <50 x 109/L.

IMPORTANT SAFETY INFORMATION
INDICATION & IMPORTANT SAFETY INFORMATION

Intracranial Hemorrhage (ICH)—Serious ICH may occur with AYVAKIT treatment; fatal events occurred in <1% of patients. No events of ICH occurred in the 246 patients with ISM who received any dose of AYVAKIT in the PIONEER study.

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

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

Permanently discontinue AYVAKIT if ICH of any grade occurs.

Cognitive Effects—Cognitive adverse reactions can occur in patients receiving AYVAKIT and occurred in 7.8% of patients with ISM who received AYVAKIT + best supportive care (BSC) versus 7.0% of patients who received placebo + BSC; <1% were Grade 3. Depending on the severity, withhold AYVAKIT and then resume at the same dose, or permanently discontinue AYVAKIT.

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—AYVAKIT can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use an effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose. Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose.

Adverse Reactions—The most common adverse reactions (≥10%) in patients with ISM were eye edema, dizziness, peripheral edema, and flushing.

Drug Interactions—Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors or inducers.

To report suspected adverse reactions, contact Blueprint Medicines Corporation at 1-888-258-7768 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here to see the full Prescribing Information for AYVAKIT.

References:

  1. AYVAKIT [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation; May 2023.
  2. Kristensen T et al. Am J Hematol. 2014;89(5):493-498.
  3. Garcia-Montero AC et al. Blood. 2006;108(7):2366-2372.
  4. Ungerstedt J et al. Cancers. 2022;14(16):3942.
  5. Pardanani A. Am J Hematol. 2023;98(7):1097-1116.
  6. Data on file. Blueprint Medicines Corporation, Cambridge, MA. 2023.
  7. Gülen T et al. J Intern Med. 2016;279(3):211-228.
  8. Theoharides TC et al. N Engl J Med. 2015;373(2):163-172.
  9. Gotlib J et al. NEJM Evidence. 2023;2(6). Published online May 23, 2023. doi:10.1056/EVIDoa2200339
  10. Padilla B et al. Orphanet J Rare Dis. 2021;16(1):434.