Important Safety Information


PIQRAY® (alpelisib) tablets is contraindicated in patients with severe hypersensitivity to it or any of its components. Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphy...

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Indication
PIQRAY is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

PIK3CA Mutation

 

PIK3CA mutations are a common indicator of poor prognosis1,2

PIK3CA is the most commonly mutated gene in HR+/HER2- aBC1,3-5

~40% of patients with HR+/HER2- breast cancer have a PIK3CA mutation ~40% of patients with HR+/HER2- breast cancer have a PIK3CA mutation

Patients with a PIK3CA mutation face a worse prognosis Patients with a PIK3CA mutation face a worse prognosis

The PI3K Pathway

PIQRAY specifically addresses PIK3CA mutations6

PIQRAY is a potent and selective inhibitor of PI3Kα6,7

    • PIQRAY inhibits the α isoform of PI3K 50 times more potently than other PI3K isoforms (β, γ, δ))7

 

PIQRAY MOA PIQRAY MOA

Based on in vitro/in vivo studies. Preclinical activity does not necessarily correlate with clinical outcomes.

PIK3CA mutations may lead to hyperactivation of PI3Kα, a key upstream component of the PI3K pathway8-10

    • Inhibiting PI3Kα interrupts AKT-dependent and AKT-independent signaling cascades in the PI3K pathway6,11,12
    • PIQRAY and fulvestrant work synergistically to inhibit both the PI3K and ER pathways6

AKT, protein kinase B; ER, estrogen receptor; PI3Kα, α-isoform of phosphatidylinositol-3-kinase.

 

Targeting PIK3CA mutations may overcome resistance to endocrine-based therapies used in HR+/HER2- aBC Targeting PIK3CA mutations may overcome resistance to endocrine-based therapies used in HR+/HER2- aBC

Testing

Knowledge of PIK3CA mutation status can inform an up-front treatment plan

PIK3CA testing is a critical component of aBC management

Why to test

  • Only patients with a PIK3CA mutation are eligible for biomarker-driven therapy with PIQRAY6

When to test

  • Test for PIK3CA mutations when a patient presents with metastases from breast cancer15*
  • PIK3CA mutations are generally stable16

 How to test

  • PIK3CA mutations can be detected in tissue or plasma specimens6†
  • Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at fda.gov/CompanionDiagnostics

Test for PIK3CA mutation Test for PIK3CA mutation

*Following progression on or after an endocrine-based regimen.
Please refer to section 2.1 of the full Prescribing information.

References: 1. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. 2. Sobhani N, Roviello G, Corona SP, et al. The prognostic value of PI3K mutational status in breast cancer: a meta-analysis. J Cell Biochem. 2018;119(6):4287-4292. 3. Tolaney S, Toi M, Neven P, et al. Presented at: 2019 American Association for Cancer Research (AACR) Annual Meeting; March 29 - April 3, 2019; Atlanta, GA. 4. Di Leo A, Johnston S, Seok Lee K, et al. Lancet Oncol. 2018;19(1):87-100. 5. Moynahan ME, Chen D, He W, et al. Br J Cancer. 2017;116(6):726-730. 6. Piqray [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019.7. Data on file. Novartis Pharmaceuticals Corp; 2018.8. Al-Sukhun S, Lataifeh I, Al-Sukhun R. Defining the prognostic and predictive role of PIK3CA mutations: sifting through the conflicting data. Curr Breast Cancer Rep. 2016;8:73-79. 9. Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N Engl J Med. 2018;379(21):2052-2062. 10. Croessmann S, Sheehan JH, Lee KM, et al. PIK3CA C2 domain deletions hyperactivate phosphoinositide 3-kinase (PI3K), generate oncogene dependence, and are exquisitely sensitive to PI3Kα inhibitors. Clin Cancer Res. 2018;24(6):1426-1435. 11. Paplomata E, O’Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014;6(4):154-166. 12. Chalhoub C, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2009;4:127-150. 13. Miller TW, Hennessy BT, González-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer. J Clin Invest. 2010;120(7):2406-2413. 14. Mayer IA, Abramson VG, Formisano L, et al. A phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23(1):26-34. 15. Van Poznak C, Somerfield MR, Bast RC, et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2015;33(24):2695-2704. 16. Arthur LM, Turnbull AK, Renshaw L, et al. Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer. Breast Cancer Res Treat. 2014;147(1):211-219.

Indication

PIQRAY® (alpelisib) tablets is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

Important Safety Information

PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components.

Severe Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, were reported in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia. The incidence of grade 3 and 4 hypersensitivity reactions was 0.7%. Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.

Severe Cutaneous Reactions: Severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in patients treated with PIQRAY. SJS and EM were reported in 0.4% and 1.1% of patients, respectively. Do not initiate PIQRAY treatment in patients with a history of SJS, EM, or toxic epidermal necrolysis (TEN). If signs or symptoms of severe cutaneous reactions occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.

If SJS, TEN, or EM is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous reactions during PIQRAY treatment. If it is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment.

Advise patients of the signs and symptoms of severe cutaneous reactions (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, or progressive skin rash).

Hyperglycemia: Severe hyperglycemia, including ketoacidosis, has been reported in patients treated with PIQRAY. Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG >250-500 mg/dL) and Grade 4 (FPG >500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n=2) treated with PIQRAY.

Before initiating treatment with PIQRAY, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with PIQRAY, monitor blood glucose and/or FPG at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor blood glucose and/or FPG as clinically indicated, and at least twice weekly until blood glucose or FPG decreases to normal levels. During treatment with antidiabetic medication, continue monitoring blood glucose or FPG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a health care practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.

The safety of PIQRAY in patients with type 1 and uncontrolled type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor patients with diabetes.

Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients of the signs and symptoms of hyperglycemia (eg, excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).

Pneumonitis: Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, has been reported in patients treated with PIQRAY. Pneumonitis was reported in 1.8% of patients treated with PIQRAY.

In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.

Permanently discontinue PIQRAY in all patients with confirmed pneumonitis. Advise patients to immediately report new or worsening respiratory symptoms.

Diarrhea: Severe diarrhea, including dehydration and acute kidney injury, occurred in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade 3 diarrhea occurred in 7% (n=19) of patients. Based on the severity of the diarrhea, PIQRAY may require dose interruption, reduction, or discontinuation. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their health care provider if diarrhea occurs while taking PIQRAY.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

The most common adverse reactions (all grades, incidence ≥20%) were diarrhea (58%), rash (52%), nausea (45%), fatigue (42%), decreased appetite (36%), stomatitis (30%), vomiting (27%), weight decreased (27%), and alopecia (20%). The most common grade 3/4 adverse reactions (incidence ≥2%) were rash (20%), diarrhea (7%), fatigue (5%), weight decreased (3.9%), nausea (2.5%), stomatitis (2.5%), and mucosal inflammation (2.1%).

The most common laboratory abnormalities (all grades, incidence ≥20%) were glucose increased (79%), creatinine increased (67%), lymphocyte count decreased (52%), gamma glutamyl transferase (GGT) increased (52%), alanine aminotransferase (ALT) increased (44%), hemoglobin decreased (42%), lipase increased (42%), calcium decreased (27%), glucose decreased (26%), and activated partial thromboplastin time (aPTT) prolonged (21%). The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were glucose increased (39%), GGT increased (11%), lymphocyte count decreased (8%), and lipase increased (7%), and potassium decreased (6%).

Please see full Prescribing Information.