FDA Approves PIQRAY (Alpelisib) to be used 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

FDA Approves PIQRAY (Alpelisib) to be used 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

On May 24, 2019, the U.S. Food and Drug Administration (FDA) approved PIQRAY (alpelisib) to be used 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. Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at http://www.fda.gov/CompanionDiagnostics.

The approved recommended dose of PIQRAY is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with food. Continue treatment until disease progression or unacceptable toxicity occurs. Patients should take their dose of PIQRAY at approximately the same time each day. If a dose of PIQRAY is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take PIQRAY at the usual time.

When given with PIQRAY, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant.

PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components. Additional information regarding dosage and administration, dose modification for adverse reactions, and important warnings and precautions about severe hypersensitivity reactions, severe cutaneous reactions, hyperglycemia, pneumonitis, diarrhea, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

• MOA: Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα.
• General PK: Steady-state alpelisib maximum plasma concentration (C_max) and AUC increased proportionally over the dose range of 30 mg to 450 mg (0.1 to 1.5 times the approved recommended dosage) under fed conditions. The mean accumulation of alpelisib is 1.3 to 1.5 and steady-state plasma concentrations are reached within 3 days following daily dosage. The mean steady-state alpelisib [coefficient of variation (CV%)] for C_max was 2480 (23%) ng/mL and AUC_0-24hr was 33224 (21%) ng*h/mL.
• Absorption: The median time to reach peak plasma concentration (T_max) ranged between 2.0 to 4.0 hours.
• Effect of Food: A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and C_max by 84%, and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and C_max by 145% following a single dose of PIQRAY. No clinically significant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.
• Distribution: The mean (CV%) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 L (46%). Protein binding of alpelisib is 89% and is independent of concentration.
• Elimination: The half-life of alpelisib is predicted to be 8 to 9 hours. The mean (CV%) clearance of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.
• Metabolism: Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and to a lesser extent by CYP3A4, in vitro.
• Excretion: Following a single oral dose of 400 mg radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged, 32% BZG791) and 14% (2% unchanged, 7.1% BZG791) in urine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.

Drug Interactions

• CYP3A4 Inducers: Coadministration of PIQRAY with a strong CYP3A4 inducer may decrease alpelisib concentration, which may decrease alpelisib activity. Avoid coadministration of PIQRAY with strong CYP3A4 inducers.
• BCRP Inhibitors: Coadministration of PIQRAY with a BCRP inhibitor may increase alpelisib concentration, which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions when PIQRAY is used in combination with BCRP inhibitors.
• CYP2C9 Substrates: Coadministration of PIQRAY with CYP2C9 substrates (e.g., warfarin) may reduce the plasma concentration of these substrates. Closely monitor when PIQRAY is used in combination with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of alpelisib were predicted based on age (21 to 87 years), sex, race/ethnicity (Japanese or Caucasian), body weight (37 to 181 kg), mild to moderate renal impairment (CLcr 30 to < 90 mL/min based on the Cockcroft-Gault formula), or mild to severe hepatic impairment (Child-Pugh Class A, B, and C). The effect of severe renal impairment (CLcr < 30 mL/min) on the pharmacokinetics of alpelisib is unknown.

Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with PIQRAY and for 1 week after the last dose.

Efficacy and Safety

Efficacy of PIQRAY was demonstrated at the approved recommended dosage in a randomized, double-blind, placebo-controlled trial of PIQRAY plus fulvestrant versus placebo plus fulvestrant in patients with HR-positive, HER2-negative, advanced or metastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-based treatment (with or without CDK4/6 combination). Patients were excluded if they had inflammatory breast cancer, diabetes mellitus Type 1 or uncontrolled Type 2, or pneumonitis. The major efficacy outcome was investigator-assessed progression-free survival (PFS) in the cohort with a PIK3CA mutation per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were overall response rate (ORR) and overall survival (OS) in the cohort with a PIK3CA mutation. Additional information regarding efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, GGT increased, nausea, ALT increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, aPTT prolonged, and alopecia.

Full prescribing information is available at https://go.usa.gov/xmAt2.

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A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

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