Alpelisib, a selective inhibitor of the α isoform of phosphoinositide 3-kinase (PI3Kα), is an antineoplastic agent.1, 2, 3, 4, 5, 6, 7, 11
Alpelisib is used in combination with fulvestrant for the treatment of adults with hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, phosphatidylinositol-3-kinase catalytic subunit α ( PIK3CA )-mutated, advanced or metastatic breast cancer as detected by an FDA-approved diagnostic test (e.g., therascreen ® PIK3CA RGQ PCR Kit) following progression on or after an endocrine-based regimen.1, 2, 8, 10 The alpelisib preparation labeled as Piqray® is specifically indicated for this use.1 In patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer that has progressed during or following endocrine-based therapy, combined therapy with alpelisib and fulvestrant has been shown to prolong progression-free survival compared with fulvestrant alone.1, 2 Guidelines generally recommend alpelisib in combination with fulvestrant in postmenopausal women and men with hormone receptor-positive, HER-2 negative, PIK3CA -mutated advanced or metastatic breast cancer previously treated with endocrine therapy (e.g., aromatase inhibitor with or without a cyclin-dependent kinase [CDK] 4/6 inhibitor).
This indication for alpelisib is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (SOLAR-1; NCT02437318) in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer that had progressed during or following endocrine-based therapy.1, 2 In this study, a cohort of 341 patients with tumors harboring at least one PIK3CA mutation were randomized (stratified by presence of lung or liver metastases and prior therapy with a cyclin-dependent kinase [CDK] 4 and 6 inhibitor) in a 1:1 ratio to receive either alpelisib (300 mg orally once daily) or placebo, each given in combination with fulvestrant (500 mg by IM injection on days 1 and 15 during cycle 1 and then on day 1 of each 4-week cycle thereafter).1, 2 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 2 The primary measure of efficacy was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary end points included overall response rate and overall survival.1, 2
In the SOLAR-1 study, the median age of patients with PIK3CA-mutated tumors was 63 years (range: 25-92 years); 99.8% were female, 66% were Caucasian, 22% were Asian, 50% had lung or liver metastases, 23% had metastasis to bone only, 6% had received prior therapy with a CDK 4 and 6 inhibitor, and 98% had received hormonal therapy as their most recent treatment (52% in the adjuvant setting and 48% in the setting of metastatic disease).1, 2, 8 In this study, 13% of patients with PIK3CA -mutated tumors had primary resistance and 72% had secondary resistance to endocrine therapy.1, 2 Primary resistance was defined as relapse within 24 months while the patient was receiving adjuvant endocrine therapy or progression within 6 months while the patient was receiving endocrine therapy for advanced or metastatic disease; secondary resistance was defined as relapse after at least 24 months while the patient was receiving adjuvant endocrine therapy, relapse within 12 months following discontinuance of adjuvant endocrine therapy, or progression after at least 6 months while the patient was receiving endocrine therapy for advanced or metastatic disease.1, 2 All patients enrolled in the study had a baseline ECOG performance status of 0 or 1.1, 2
The median duration of combined therapy with alpelisib and fulvestrant was 8.2 months; treatment was continued for at least 6 months in 59% of patients.1 At a median follow-up of 20 months, patients with PIK3CA -mutated tumors receiving alpelisib in combination with fulvestrant had longer median progression-free survival (11 versus 5.7 months) and a higher overall response rate (35.7 versus 16.2%) compared with those receiving fulvestrant and placebo.1, 2 Median overall survival had not been reached at the time of the analysis.1, 2 Subgroup analysis based on stratification criteria and important demographic and prognostic factors suggested that the progression-free survival benefit of alpelisib given in combination with fulvestrant was consistent across these subgroups.2 In a final survival analysis of patients with PIK3CA-mutated tumors from the SOLAR-1 study, median overall survival was 39.3 months among patients receiving alpelisib in combination with fulvestrant and 31.4 months among patients treated with fulvestrant plus placebo; this difference was not statistically significant.10
Guidelines from the American Society of Clinical Oncology (ASCO) provide recommendations for treatment of postmenopausal women and men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.70
ASCO recommends CDK4/6 inhibitor therapy with endocrine therapy as first-line treatment.70 Second and third-line treatment options include targeted therapies (e.g., capivasertib, alpelisib) based on tumor genomics and prior endocrine therapy.70 Alpelisib combined with endocrine therapy is an option for tumors harboring PIK3CA mutations, but not AKT1 mutations or PTEN inactivation.70 No comparative efficacy data are available to guide selection between capivasertib or alpelisib when targeting PIK3CA mutations.70 In this situation, ASCO recommends choosing the targeted agent based on perceived risk-benefit considerations (e.g., hyperglycemia, diarrhea, or treatment discontinuation for adverse events).70
Phosphatidylinositol-3-kinase Catalytic Subunit (PIK3CA)-Related Overgrowth Spectrum
Alpelisib is used to treat adults and pediatric patients 2 years of age or older who require systemic therapy for severe manifestations of PIK3CA-related overgrowth spectrum (PROS).11 The alpelisib preparation labeled as Vijoice® is specifically indicated for this use.11 The accelerated approval of alpelisib for this indication is based on radiological response rate and duration of response.11 Continued approval for this indication may be contingent on verification and description of clinical benefit of alpelisib in confirmatory studies.11 Alpelisib has been designated an orphan drug by FDA for the treatment of PROS.12
This indication for alpelisib is based principally on the results of a single-arm clinical study (EPIK-P1) that enrolled patients 2 years of age or older with severe or life-threatening clinical manifestations of PROS requiring systemic therapy.11 Patients were required to have a confirmed PIK3CA mutation.11 In this study, 37 patients with PROS and at least 1 target lesion (identified on imaging performed within 24 weeks prior to receipt of the first dose of alpelisib) were treated with alpelisib at dosages ranging from 50-250 mg orally once daily.11 The primary measure of efficacy was the proportion of patients with radiological response at week 24, defined as a reduction of 20% or greater from baseline in the sum of measurable target lesion volume (1-3 lesions).11 An additional efficacy outcome was duration of response, which was measured from the time of the first documented response to the time of disease progression or death.11
In EPIK-P1 study, the median age of patients was 14 years (range: 2-38 years); 22%, 22%, and 27% of patients were 2-5 years, 6-11 years, and 12 to <18 years of age, respectively.11 Fifty-seven percent of the patients were female and 92% had congenital overgrowth; manifestations of PROS varied and included Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal Syndrome (CLOVES; 81%), Megalencephaly-Capillary Malformation Polymicrogyria (MCAP; 8%), Klippel-Trenaunay Syndrome (KTS; 2.7%), Facial Infiltrating Lipomatosis (FIL; 8%), and other (5%).11
After 24 weeks of treatment with alpelisib, 10 patients (27%) had a radiological response, confirmed by blinded independent central review.11 Seventy percent and 60% of patients had a duration of response of at least 6 or 12 months, respectively.11
Phosphatidylinositol-3-kinase catalytic subunit α-related overgrowth spectrum (PROS) is an umbrella term that comprises a heterogeneous group of disorders characterized by vascular malformations and abnormal tissue growth.13 Examples of disorders classified as PROS include CLOVES, Klippel-Trenaunay syndrome, and megalencephaly capillary malformation.13, 14 All disorders classified as PROS originate from a mutation in PIK3CA that causes hyperactivation of the gene, which results in abnormal growth of epithelial and other tissues.14 Patients affected by these disorders have a wide array of potential complications, including pain, vascular and neurologic complications (e.g., thromboembolism, seizures), functional impairment, and risk of malignancy.14
Currently, various procedures (e.g., sclerotherapy, laser therapy, debulking surgery) are used to treat the disorder; however, these procedures are often not curative.14 Traditional management of overgrowth syndromes has been conservative and limited to addressing complications as they arise; however, targeted therapies (e.g., alpelisib, sirolimus) have emerged as therapeutic options for various syndromes across the spectrum of PROS.13
Alpelisib is commercially available as oral tablets (Piqray®, Vijoice®) or oral granules (Vijoice®).1, 11 The Vijoice® tablets may also be administered as an oral suspension for patients who have difficulty swallowing the whole tablets.11
The most appropriate dosage form of Vijoice® (tablets or granules) should be prescribed based on patient needs and dosage requirements.11
The oral granules are single use and only for patients prescribed a 50 mg daily dose.11 Clinicians should not use multiple packets to achieve a prescribed dose of 125 mg or 250 mg, and should not use partial quantities of the oral granule packets to prepare a dose.11 The oral granules should not be used if the packet seal is broken.11
The tablets should be swallowed whole; do not chew, crush, or split.1, 11 Do not use tablets that are cracked, broken, or otherwise not intact.1
Administer orally with food.1, 11 Take at approximately the same time each day.1, 11
If a dose of alpelisib is missed and cannot be taken within 9 hours of the regularly scheduled time, skip the missed dose and take the next dose at the regularly scheduled time.1, 11
If a dose of alpelisib is vomited, do not take an extra dose; take the next dose at the regularly scheduled time.1, 11
Store alpelisib at 20-25°C (excursions permitted between 15-30°C).1, 11
Preparation of Oral Suspension from Vijoice® Tablets
In individuals who are unable to swallow the intact tablets, the appropriate dose of alpelisib (Vijoice®) tablets may be placed in a cup containing 2-4 ounces of water and allowed to sit for approximately 5 minutes.11 The manufacturer states that no other liquid should be used.11 After allowing the tablets to sit for 5 minutes, a spoon should be used to crush the tablets in the water and to stir the suspension; the resultant suspension should be administered immediately and should not be stored for later use.11 If immediate administration is not possible, the suspension should be discarded within 60 minutes of preparation.11 Following administration of the dose, add 1-2 ounces of water to the cup, stir the water with the same spoon to resuspend any remaining drug and administer the resultant suspension; repeat these steps as necessary.11
Preparation of Vijoice® Oral Granules
For the administration of a 50 mg daily dose, oral granules can be administered via 1 of 2 methods:11
PIK3CA-related Overgrowth Spectrum (PROS)
For the treatment of PROS in pediatric patients 2-18 years of age, the recommended dosage of alpelisib is 50 mg orally once daily.11
After 24 weeks of therapy at a dosage of 50 mg once daily, consider increasing the dosage to 125 mg once daily in patients ≥6 years of age.11 An increase in dosage has not been established in pediatric patients <6 years of age.11
When a patient turns 18 years of age, consider gradually increasing the dosage to the recommended adult dosage of 250 mg once daily.11
Continue treatment until disease progression or unacceptable toxicity occurs.11
For use in combination with fulvestrant in the treatment of hormone receptor-positive, HER2-negative, PIK3CA -mutated, advanced or metastatic breast cancer in men and postmenopausal women with disease progression following endocrine therapy, the recommended adult dosage of alpelisib is 300 mg (two 150-mg tablets) once daily.1 The recommended adult dosage of fulvestrant is 500 mg administered by IM injection on days 1, 15, and 29 and then once monthly thereafter.1
Continue treatment until disease progression or unacceptable toxicity occurs.1
PIK3CA-related Overgrowth Spectrum (PROS)
For the treatment of PROS, the recommended adult dosage of alpelisib is 250 mg orally once daily.11 Continue treatment until disease progression or unacceptable toxicity occurs.11
Dosage Modification for Toxicity
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of alpelisib may be necessary in patients experiencing certain adverse effects.1, 11
The following tables on dosage modifications for alpelisib toxicity indicate the recommended dosage modifications in adults and pediatric patients receiving alpelisib (see Table 1 and Table 2).1, 11
Dosage Reduction after Recovery from Toxicity | Dosage Reduction after Recovery from Toxicity | |
|---|---|---|
Dose Reduction Level | Breast Cancer (Dosage = 300 mg once daily) | PROS (Dosage = 250 mg once daily) |
First | Reduce dosage to 250 mg (one 200 mg and one 50 mg tablet) once daily | Reduce dosage to 125 mg once daily |
Second | Reduce dosage to 200 mg once daily | Reduce dosage to 50 mg once daily |
Third | Permanently discontinue drug | Permanently discontinue drug |
Dosage Reduction after Recovery from Toxicity | Dosage Reduction after Recovery from Toxicity | |
|---|---|---|
Dose Reduction Level | Dosage = 50 mg once daily | Dosage = 125 mg once daily |
First | Permanently discontinue drug | Reduce dosage to 50 mg once daily |
Second | Permanently discontinue drug |
If grade 1 hyperglycemia (fasting plasma glucose concentration exceeding the upper limit of normal [ULN] but not more than 160 mg/dL) occurs in adults or pediatric patients , continue alpelisib therapy at the same dosage.1, 11 Oral antihyperglycemic therapy (e.g., metformin in adults and pediatric patients ≥10 year of a a sodium-glucose cotransporter 2 [SGLT2] inhibitor, a thiazolidinedione, a dipeptidyl peptidase-4 [DPP-4] inhibitor in adults) should be initiated or intensified.1, 11
If grade 2 hyperglycemia (fasting plasma glucose concentration exceeding 160 mg/dL but not more than 250 mg/dL) occurs in adults , may continue alpelisib therapy at the same dosage.1, 11 Oral antihyperglycemic therapy should be initiated or intensified.1, 11 If grade 2 hyperglycemia persists for longer than 21 days despite oral antihyperglycemic therapy, reduce the dosage of alpelisib by one dose level.1, 11
If grade 2 hyperglycemia (fasting plasma glucose concentration exceeding 160 mg/dL but not more than 250 mg/dL) occurs in pediatric patients , may continue alpelisib therapy at the same dosage.11 Oral antihyperglycemic therapy should be initiated or intensified.11 If grade 2 hyperglycemia persists for longer than 21 days despite oral antihyperglycemic therapy, interrupt alpelisib therapy; when hyperglycemia improves to grade 1 or less, resume alpelisib at a dosage of 50 mg once daily.11
If grade 3 hyperglycemia (fasting plasma glucose concentration exceeding 250 mg/dL but not more than 500 mg/dL) occurs in adults , interrupt alpelisib therapy.1, 11 Oral antihyperglycemic therapy should be initiated or intensified and additional antihyperglycemic therapy with insulin may be considered for 1-2 days until hyperglycemia improves.1, 11 The manufacturer states that most patients experiencing alpelisib-induced hyperglycemia may not require insulin therapy because of the short half-life of alpelisib.1 Administer IV fluids and appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required.1, 11 If hyperglycemia improves to 160 mg/dL or less within 3-5 days with appropriate antihyperglycemic therapy, resume alpelisib therapy at a dosage reduced by one dose level.1, 11 If grade 3 hyperglycemia does not improve to 160 mg/dL or less within 3-5 days despite antihyperglycemic therapy, consultation with a clinician with expertise in the management of hyperglycemia is recommended.1, 11 If improvement to 160 mg/dL or less does not occur within 21 days despite oral antihyperglycemic therapy, permanently discontinue alpelisib.1, 11
cIf grade 3 hyperglycemia (fasting plasma glucose concentration exceeding 250 mg/dL but not more than 500 mg/dL) occurs in pediatric patients , interrupt alpelisib therapy.11 Oral antihyperglycemic therapy should be initiated or intensified and additional antihyperglycemic therapy with insulin may be considered for 1-2 days until hyperglycemia improves.11 The manufacturer states that most patients experiencing alpelisib-induced hyperglycemia may not require insulin therapy because of the short half-life of alpelisib.1 Administer IV fluids and appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required.11 If hyperglycemia improves to 160 mg/dL or less within 3-5 days with appropriate antihyperglycemic therapy, resume alpelisib therapy at 50 mg once daily.11 If grade 3 hyperglycemia does not improve to 160 mg/dL or less within 3-5 days despite antihyperglycemic therapy, consultation with a clinician with expertise in the management of hyperglycemia is recommended to determine if alpelisib may be resumed or permanently discontinued.11 If improvement to 160 mg/dL or less does not occur within 21 days despite oral antihyperglycemic therapy, permanently discontinue alpelisib.11 If grade 3 or greater hyperglycemia recurs, consider permanently discontinuing the drug.11
If grade 4 hyperglycemia (fasting plasma glucose concentration exceeding 500 mg/dL) occurs in adults or pediatric patients , interrupt alpelisib therapy.1, 11 Appropriate antihyperglycemic therapy should be initiated or intensified, IV fluids should be administered, and appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances should be considered, if required.1, 11 Reassess fasting plasma glucose concentration within 24 hours and as clinically indicated.1, 11 If hyperglycemia improves to grade 3 or less, follow recommendations for management of grade 3 hyperglycemia.1, 11 If grade 4 hyperglycemia persists, permanently discontinue alpelisib.1, 11
If grade 1 dermatologic toxicity (active skin toxicity affecting less than 10% of the body surface area [BSA]) occurs in adults or pediatric patients , may continue alpelisib therapy at the same dosage.1, 11 Topical corticosteroid therapy should be administered and an oral antihistamine also should be considered for symptomatic management.1, 11 If an active rash does not improve within 28 days of appropriate treatment, add a low dose systemic corticosteroid.1, 11
If grade 2 dermatologic toxicity (active skin toxicity affecting 10-30% of BSA) occurs in adults or pediatric patients , may continue alpelisib therapy at the same dosage.1, 11 Topical corticosteroid and oral antihistamine therapy should be initiated or intensified, and low-dose systemic corticosteroid therapy also considered.1, 11 If rash improves to grade 1 or less within 10 days, may discontinue systemic corticosteroid therapy.1, 11
If grade 3 dermatologic toxicity (e.g., severe rash not responsive to therapy; active skin toxicity affecting more than 30% of BSA) occurs in adults or pediatric patients , interrupt alpelisib therapy.1, 11 Topical/systemic corticosteroid and oral antihistamine therapy should be initiated or intensified.1, 11 If the etiology is not a severe cutaneous adverse reaction (SCAR) in adults , may resume alpelisib therapy at a dosage reduced by one dose level when the toxicity improves to grade 1 or less.1, 11 If the etiology is not a SCAR in pediatric patients , may resume alpelisib therapy at 50 mg once daily while continuing oral antihistamine therapy when the toxicity improves to grade 1 or less or permanently discontinue alpelisib.11 Permanently discontinue alpelisib in pediatric patients if a grade 3 or greater rash recurs or if the patient was already receiving antihistamines at the time of rash onset and the antihistamine dosage cannot be increased further.11
If the etiology of any dermatologic reaction is confirmed to be a SCAR in adults or pediatric patients , permanently discontinue alpelisib.1, 11 Do not reinitiate therapy with alpelisib in patients who have previously experienced SCAR during alpelisib therapy.1, 11
If grade 4 dermatologic toxicity (e.g., severe bullous, blistering, or exfoliating skin conditions; involvement of any percentage of BSA accompanied by extensive superinfection requiring IV anti-infective therapy; life-threatening consequences) occurs in adults or pediatric patients , permanently discontinue alpelisib.1, 11
If grade 1 diarrhea or colitis occurs in adults or pediatric patients , may continue alpelisib therapy at the same dosa however, initiate appropriate therapy for diarrhea and additional monitoring as clinically indicated.1, 11
If grade 2 diarrhea or colitis occurs in adults , interrupt alpelisib therapy; may resume alpelisib at the same dosage when the toxicity improves to grade 1 or less.1, 11 Appropriate therapy for diarrhea should be initiated or intensified, and patients should receive additional monitoring as clinically indicated.1, 11 If grade 2 diarrhea recurs, interrupt alpelisib therapy.1, 11 Resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less.1, 11
If grade 2 diarrhea or colitis occurs in pediatric patients , interrupt alpelisib therapy; may resume alpelisib at the same dosage when the toxicity improves to grade 1 or less.11 Appropriate therapy for diarrhea should be initiated or intensified, and patients should receive additional monitoring as clinically indicated.11 If grade 2 diarrhea recurs, interrupt alpelisib therapy.11 Resume alpelisib at 50 mg once daily when the toxicity improves to grade 1 or less.11
If grade 3 diarrhea or colitis occurs in adults , interrupt alpelisib therapy; resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less.1, 11 Appropriate therapy for diarrhea should be initiated or intensified, and patients should receive additional monitoring as clinically indicated.1, 11
If grade 3 diarrhea or colitis occurs in pediatric patients , interrupt alpelisib therapy; when the toxicity improves to grade 1 or less, alpelisib may be resumed at 50 mg once daily or permanently discontinued.11 Appropriate therapy for diarrhea should be initiated or intensified, and patients should receive additional monitoring as clinically indicated.11 If grade 3 or greater diarrhea recurs, consider permanently discontinuing alpelisib therapy.11
If grade 4 diarrhea or colitis occurs in adults or pediatric patients , permanently discontinue alpelisib.1, 11
If grade 2 or 3 pancreatitis occurs in adults , interrupt alpelisib therapy; may resume alpelisib at a reduced dosage when the toxicity improves to less than grade 2.1, 11 The manufacturer states that only one dosage reduction for pancreatitis is permitted; if pancreatitis recurs, permanently discontinue alpelisib.1, 11
If grade 2 pancreatitis occurs in pediatric patients , interrupt alpelisib; may resume alpelisib at a dosage of 50 mg once daily when the toxicity improves to less than grade 2.11 If pancreatitis recurs or grade 3 pancreatitis occurs, permanently discontinue alpelisib.11
If grade 4 pancreatitis occurs in adults or pediatric patients , permanently discontinue alpelisib.11
If pneumonitis is suspected in adults or pediatric patients , interrupt alpelisib therapy.11 If pneumonitis of any grade is confirmed, permanently discontinue alpelisib.11
For grade 2 elevations in total bilirubin concentrations in adults , interrupt alpelisib therapy; may resume alpelisib at the same dosage if the toxicity resolves or improves to grade 1 or less within 14 days.1, 11 If toxicity improves to grade 1 or less in more than 14 days, resume alpelisib at a dosage reduced by one level.1, 11
For grade 2 elevations in total bilirubin concentrations in pediatric patients , interrupt alpelisib therapy; may resume alpelisib at the same dosage if the toxicity resolves or improves to grade 1 or less within 14 days.11 If toxicity improves to grade 1 or less in more than 14 days, resume alpelisib at a dosage of 50 mg once daily.11
If other grade 1 or 2 adverse reactions occur in adults or pediatric patients , may continue alpelisib therapy at the same dosa however, patients should receive appropriate therapy and additional monitoring as clinically indicated.1, 11
If other grade 3 adverse reactions occur in adults , interrupt alpelisib therapy; may resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less.1, 11 Appropriate therapy for the toxicity should be initiated or intensified, and patients should receive additional monitoring as clinically indicated.11
If other grade 3 adverse reactions occur in pediatric patients , interrupt alpelisib therapy; when the toxicity improves to grade 1 or less, alpelisib may be resumed at 50 mg once daily or permanently discontinued.11 Appropriate therapy for the toxicity should be initiated or intensified, and patients should receive additional monitoring as clinically indicated.11 If the adverse reaction recurs at grade 3 or greater severity, consider permanent discontinuance of the drug.1, 11 Consultation with a clinician with expertise in a field related to the adverse reaction should be considered in pediatric patients experiencing other grade 3 adverse reactions.11
If other grade 4 adverse reactions occur in adults or pediatric patients , permanently discontinue alpelisib.1, 11
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1, 11
No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute).1, 11 Insufficient data are available to provide dosage recommendations for patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1, 11
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 11
Serious hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema have been reported in patients receiving alpelisib in the oncology setting.1, 11 Manifestations may include dyspnea, flushing, rash, fever, and tachycardia.1 In the SOLAR-1 study, grade 3 or 4 hypersensitivity reactions were reported in 0.7% of patients receiving the drug.1 Alpelisib should be permanently discontinued and supportive treatment instituted in patients who experience a severe hypersensitivity reaction.1, 11
Severe cutaneous adverse reactions (SCARs), including erythema multiforme and Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms may occur in patients receiving alpelisib in the oncology setting.1, 11 In the SOLAR-1 study, erythema multiforme and Stevens-Johnson syndrome were reported in 1.1 and 0.4%, respectively, of patients receiving the drug.1 Drug reaction with eosinophilia and systemic symptoms has been reported in the postmarketing surveillance in alpelisib-treated patients.1
If rash (any grade) occurs, consultation with a dermatologist should be considered.1 If signs and symptoms of SCARs (e.g., progressive rash, mucosal lesions, fever, lymphadenopathy, flu-like symptoms) occur, alpelisib therapy should be interrupted and the etiology should be evaluated; consultation with a dermatologist is recommended.1, 11 Permanently discontinue alpelisib if SCARs are confirmed; do not reinitiate in patients who previously experienced SCARs during treatment with alpelisib.1, 11 If SCARs are not confirmed, dosage modification, administration of corticosteroids and/or oral antihistamines, or treatment discontinuance may be necessary.1, 11
Rash (i.e., generalized, macular, maculopapular, papular, or pruritic rash) was reported in 52% of patients receiving alpelisib in the oncology setting; grade 3 rash was reported in 20% of patients.1 Prophylactic administration of an oral antihistamine prior to onset of rash may decrease the incidence and severity of alpelisib-induced rash.1, 11
Severe hyperglycemia (including cases of hyperglycemic hyperosmolar nonketotic syndrome or ketoacidosis) has been reported in patients receiving alpelisib in the oncology setting; some cases reported in the postmarketing setting have been fatal.1, 11 In the SOLAR-1 study, hyperglycemia occurred in 65% of patients receiving alpelisib; grade 3 or 4 hyperglycemia (based on fasting plasma glucose concentrations) occurred in 33 or 3.9%, respectively, of patients receiving the drug.1 Ketoacidosis occurred in 0.7% of patients receiving the drug.1 In the SOLAR-1 study, 87% of patients receiving alpelisib who experienced hyperglycemia received antihyperglycemic agents; 76% of patients with hyperglycemia received metformin alone or in combination with other antihyperglycemic agents (e.g., insulin, dipeptidyl peptidase-4 [DPP-4] inhibitors, sulfonylureas).1 The median time to occurrence of hyperglycemia (grade 2 or higher) was 15 days (range: 5-517 days), and the median time to at least 1 grade improvement of hyperglycemia was 8 days (range: 2-65 days).1 Hyperglycemia resolved and fasting plasma glucose concentrations returned to baseline in 96% of patients who discontinued alpelisib but continued fulvestrant therapy.1 In the EPIK-P1 study, grade 1 or 2 hyperglycemia occurred in 12% of patients receiving alpelisib for phosphatidylinositol-3-kinase catalytic subunit α-related overgrowth spectrum (PROS).11
Fasting plasma glucose concentrations and glycosylated hemoglobin [hemoglobin A1c; HbA1c] should be assessed and blood glucose concentrations optimized prior to initiation of alpelisib therapy.1, 11 Blood glucose concentrations and/or fasting plasma glucose concentrations should be monitored at least once weekly for the first 2 weeks of alpelisib therapy, at least once monthly thereafter, and as clinically indicated.1, 11 More frequent monitoring may be necessary for the first few weeks in patients with risk factors for hyperglycemia (e.g., obesity [body mass index ≥30 kg/m2], elevated fasting glucose, HbA1c at or above the upper limit of normal, concomitant use of corticosteroids, or ≥75 years of age).1, 11 Monitor HbA1c once every 3 months and as clinically indicated.1, 11
If hyperglycemia occurs, fasting plasma glucose concentrations should be assessed as clinically indicated and at least twice weekly until hyperglycemia resolves.1, 11 antihyperglycemic agents should be initiated or optimized as necessary; fasting plasma glucose concentrations and/or blood glucose concentrations should be monitored at least once weekly for 8 weeks after initiating antihyperglycemic therapy and then at least once every 2 weeks and as clinically indicated.1, 11 Consultation with a clinician with expertise in the management of hyperglycemia should be considered.1, 11 Temporary interruption of therapy, dosage reduction, or permanent discontinuance of alpelisib may be necessary depending on the severity of hyperglycemia.1, 11
Patients with a history of type 2 diabetes mellitus should be monitored closely during alpelisib therapy; such patients may require intensified antihyperglycemic therapy.1, 11 Safety of alpelisib has not been established in patients with type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus.1, 11
Consider premedication with metformin prior to initiation of alpelisib in combination with fulvestrant based on patient risk factors for hyperglycemia, GI tolerability, and clinical situation.1 In a clinical study, metformin administration starting 7 days prior to alpelisib therapy reduced the incidence and severity of hyperglycemia events, but increased the incidence and severity of nausea, vomiting, and diarrhea.1
Severe pneumonitis (e.g, acute interstitial pneumonitis and interstitial lung disease [ILD]) has occurred in patients receiving alpelisib in the oncology setting.1, 11 In the SOLAR-1 study, pneumonitis was reported in 1.8% of patients receiving the drug.1
If new or progressive respiratory manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates) occur, alpelisib therapy should be interrupted and patients should be evaluated for ILD/pneumonitis or other causes of respiratory symptoms (e.g., tumor progression, pneumonia).1, 11 If pneumonitis is confirmed, alpelisib should be permanently discontinued.1, 11
Diarrhea, sometimes severe and resulting in dehydration or in some cases acute kidney injury or colitis, has occurred in patients receiving alpelisib in the oncology setting.1, 11 In the SOLAR-1 study, diarrhea was reported in 58% of patients receiving alpelisib; grade 3 diarrhea occurred in 7% of patients.1 The median time to first occurrence of diarrhea (grade 2 or 3) was 46 days (range: 1-442 days).1 Diarrhea requiring dosage reduction or discontinuance of therapy was reported in 6 or 2.8%, respectively, of patients receiving the drug; 63% of patients who experienced diarrhea required antidiarrhea medications (e.g., loperamide).1 In the EPIK-P1 study, grade 1 diarrhea was reported in 16% of patients receiving alpelisib.11
Monitor patients for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool.1, 11 If diarrhea occurs, appropriate therapy (e.g., antidiarrhea agents, fluid replacement) should be initiated.1 Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids.1, 11 Temporary interruption, dosage reduction, or permanent discontinuance of alpelisib may be necessary depending on the severity of the diarrhea or colitis.1, 11, 1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and animal findings, alpelisib may cause fetal harm if administered to pregnant females.1, 11 Maternal toxicity and postimplantation loss were observed in rats receiving alpelisib at exposure levels of approximately 3 times the human exposure at the recommended dosage, and reduced fetal weight and teratogenicity (i.e., skeletal malformations, fetal variations) were observed at exposure levels of approximately equivalent to the recommended pediatric and adult dosage.1, 11 In rabbits, postimplantation loss was observed at exposure levels of approximately 10 times the human exposure at the recommended dosage, and embryofetal deaths, reduced fetal weight, and malformations were observed at exposure levels of approximately 5 times human exposure.1
Pregnancy should be avoided during alpelisib therapy.1, 11 The manufacturer states that a pregnancy test should be performed prior to initiation of alpelisib therapy in females of reproductive potential and that such females should be advised to use effective contraceptive methods while receiving the drug and for at least one week after discontinuance of therapy.1, 11 Males who are partners of such females should be advised to use condoms and effective contraception during treatment and for at least one week after discontinuance of therapy.1, 11 If alpelisib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1, 11
Alpelisib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1, 11
It is not known whether alpelisib is distributed into milk.1, 11 Because of the potential for serious adverse reactions to alpelisib in breast-fed infants, females should be advised to discontinue breast-feeding during alpelisib therapy and for one week after discontinuance of the drug.1, 11 The effects of the drug on breast-fed infants or on milk production are unknown.1, 11
Females and Males of Reproductive Potential
Females should be advised to use effective contraceptive methods while receiving the drug and for at least one week after discontinuance of therapy.1, 11
Males who are partners of such females should be advised to use condoms and effective contraception during treatment and for at least one week after discontinuance of therapy.1, 11
Results of animal studies suggest that alpelisib may impair male and female fertility.1, 11
Safety and efficacy of alpelisib for the treatment of breast cancer have not been established in pediatric patients.1
Safety and efficacy of alpelisib for the treatment of PROS have not been established in pediatric patients <2 years of age.11
No adults ≥65 years of age were enrolled in the EPIK-P1 study evaluating alpelisib in patients with PROS.11
In the SOLAR-1 study evaluating alpelisib in patients with breast cancer, 41% of patients receiving alpelisib were 65 years of age or older, while 12% were 75 years of age or older.1 No overall differences in efficacy were observed between geriatric patients 65 years of age or older and younger adults; however, grade 3 or 4 hyperglycemia occurred more frequently in geriatric patients (44 versus 32%).1 Experience with alpelisib in patients 75 years of age or older is insufficient to determine whether efficacy and safety of the drug in this age group are similar to those in younger adults.1 However, in the SOLAR-1 study, hyperglycemia (74 versus 66%) and grade 3-4 hyperglycemia (56 versus 36%) occurred more frequently in patients 75 years of age or older compared to patients younger than 75 years of age, respectively.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of alpelisib are not substantially altered in patients with mild to severe hepatic impairment (Child-Pugh class A, B, or C).1, 8, 11
Population pharmacokinetic analysis suggests that the pharmacokinetics of alpelisib are not substantially altered in patients with mild to moderate renal impairment (creatinine clearance of 30-89 mL/minute).1, 8, 11 The effect of severe renal impairment (creatinine clearance less than 30 mL/minute) on the pharmacokinetics of alpelisib has not been established.1, 11
Adverse effects reported in 20% or more of patients receiving alpelisib for the treatment of breast cancer include increased serum glucose, increased serum creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.1
Adverse effects reported in 10% or more of patients receiving alpelisib for the treatment of PROS include diarrhea, stomatitis, and hyperglycemia.11
Alpelisib is metabolized principally by chemical and enzymatic hydrolysis and to a lesser extent by cytochrome P-450 (CYP) isoenzyme 3A4.1, 11
In vitro studies indicate that alpelisib inhibits CYP isoenzyme 3A4 in a time-dependent manner and also induces CYP isoenzymes 2B6, 2C9, and 3A4.1, 11
In vitro studies also indicate that alpelisib inhibits the efflux transporter P-glycoprotein (P-gp), but has a low potential to inhibit breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), bile salt export pump (BSEP), organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) transporter 1, and MATE2-K at clinically relevant concentrations.1, 11 In vitro, alpelisib is a substrate of BCRP.1, 11
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of alpelisib and potent inducers of CYP3A4 may result in decreased systemic exposure to, and decreased therapeutic efficacy of, alpelisib.1, 11 Avoid concomitant use of alpelisib with potent CYP3A4 inducers and consider an alternative concomitant drug with no or minimal potential to induce CYP3A4.1, 11
Drugs Metabolized by Hepatic Microsomal Enzymes
Coadministration of repeated doses of alpelisib 300 mg with a single dose of sensitive substrates of CYP3A4 (midazolam), CYP2C8 (repaglinide), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2B6 (bupropion) did not reveal clinically significant pharmacokinetic interactions.1 No clinically significant differences in the pharmacokinetics of everolimus (CYP3A4 and P-gp substrate) were seen when given concomitantly with alpelisib.1
Inhibitors of Breast Cancer Resistance Protein
Alpelisib is a substrate of BCRP in vitro.1, 11 Concomitant use of alpelisib and BCRP inhibitors may result in increased alpelisib plasma concentrations and a possible increased risk of alpelisib toxicity.1, 11 Avoid concomitant use of alpelisib and BCRP inhibitors.1, 11 If concomitant use cannot be avoided, closely monitor for adverse effects.1, 11
Drugs Affecting Gastric Acidity
Concomitant administration of alpelisib with drugs that increase the pH of the upper GI tract (e.g., histamine H2-receptor antagonists) may decrease the solubility of alpelisib, which may result in decreased plasma alpelisib concentrations.1, 8, 11 Concomitant administration of ranitidine and alpelisib with a low-fat, low-calorie meal or in a fasted state decreased the area under the concentration-time curve (AUC) of alpelisib by 21 or 30%, respectively, and decreased peak plasma concentrations of alpelisib by 36 or 51%, respectively.1, 11 Because alpelisib is administered with food and food has a more pronounced effect on solubility of the drug than does gastric pH, the manufacturer states that alpelisib may be administered concomitantly with drugs that increase the pH of the upper GI tract.1, 8, 11
Use of alpelisib with bone resorption inhibitors (a bisphosphonate [e.g., alendronate, ibandronate, risedronate, zoledronic acid] or human receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitor [e.g., denosumab]) may increase the risk of osteonecrosis of the jaw.1 In the SOLAR-1 study, osteonecrosis of the jaw was reported in 4.2 or 1.4% of patients receiving alpelisib or placebo, respectively, in combination with fulvestrant; all patients who experienced osteonecrosis of the jaw were receiving or had previously received therapy with a bisphosphonate or RANKL inhibitor.1
Alpelisib, a selective inhibitor of the α isoform of phosphatidylinositol-3-kinase (PI3Kα), is an antineoplastic agent.1, 2, 3, 4, 5, 6, 7, 11 Phosphatidylinositol-3-kinases are lipid kinases consisting of a catalytic subunit that exists in 4 different isoforms (α, β, γ, δ).4, 6, 7 Alpelisib is predominantly active against the PI3K-α isoform.1, 2, 3, 4, 5, 6, 7, 11 Mutations in the gene that encodes the PI3Kα isoform (PIK3CA) are expressed in approximately 40% of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancers and result in PI3Kα/Akt signaling, cellular transformation, and generation of tumors.1, 2, 3, 6, 7, 8 In breast cancer cell lines, alpelisib inhibited phosphorylation of PI3K/Akt downstream targets and exhibited activity in cell lines harboring a PIK3CA mutation.1, 6, 7 In xenograft models of PI3Kα-dependent tumors in mice, alpelisib blocked PI3K/Akt signaling and decreased tumor growth.1, 2, 6, 7 PI3K inhibition by alpelisib has been shown to induce estrogen receptor transcription in breast cancer cells.1, 9 The combination of alpelisib and the estrogen antagonist fulvestrant demonstrated increased antitumor activity compared with either drug alone in xenograft models of PIK3CA-mutated, estrogen receptor-positive breast cancer.1, 2, 9
Activating mutations in PIK3CA also induce various overgrowth and malformations that ultimately cause PIK3CA-related overgrowth spectrum (PROS) disorders.11 In an animal model of Congenital Lipomatous Overgrowth, Vascular Malformations, Epiderman Nevi, Scoliosis/Skeletal and Spinal syndrome (CLOVES), a phenotype of PROS, alpelisib therapy was associated with improvements in organ dysfunction via inhibition of the PIK3 pathway.11
Systemic exposure to alpelisib increases in a dose-proportional manner over a dose range of 30-450 mg in a fed state.1, 11 Bioavailability of alpelisib in the fasted state is limited by low solubility.1, 8 Following oral administration of a single dose of alpelisib with a high-fat, high-calorie or low-fat, low-calorie meal, systemic exposure to the drug was increased by 73 or 77%, respectively, and peak plasma concentrations were increased by 84 or 145%, respectively, compared with administration in the fasted state.1, 11 Peak plasma concentrations of the drug are attained 2-4 hours following oral administration.1, 11 With once-daily dosing, the accumulation ratio is 1.3-1.5 and steady-state concentrations are reached within 3 days.1, 11 Alpelisib is 89% bound to plasma proteins.1, 11 Alpelisib is metabolized to its major metabolite, BZG791, principally by chemical and enzymatic hydrolysis; the drug is metabolized to a lesser extent by cytochrome P-450 (CYP) isoenzyme 3A4.1, 11 Following oral administration of a single 400-mg dose of radiolabeled alpelisib in the fasted state, 81% of the dose was recovered in feces (36% as unchanged drug) and 14% was recovered in urine (2% as unchanged drug); approximately 12% of the dose was recovered as metabolites formed by CYP3A4-mediated metabolism.1, 11 The terminal half-life of alpelisib is 8-9 hours.1, 8, 11
Population pharmacokinetic analysis indicated that age (21-87 years), sex, race (Japanese, Caucasian), and body weight (37-181 kg) do not have clinically important effects on the pharmacokinetics of alpelisib.1, 11
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. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Granules | 50 mg | Vijoice® (Single-use packet) | Novartis |
Tablets, film-coated | 50 mg | Novartis | ||
Vijoice® | Novartis | |||
125 mg | Vijoice® | Novartis | ||
150 mg | Piqray® | Novartis | ||
200 mg | Piqray® | Novartis | ||
Vijoice® | Novartis |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions January 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Novartis Pharmaceuticals. Piqray® (alpelisib) tablets prescribing information. East Hanover, NJ; 2024 Jan [Web]
2. André F, Ciruelos E, Rubovszky G et al. Alpelisib for PIK3CA -Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med . 2019; 380:1929-40. [PubMed 31091374]
3. Juric D, Janku F, Rodón J et al. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol . 2019; 5:e184475. [PubMed 30543347]
4. De Buck SS, Jakab AG, Boehm M et al. Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies. Br J Clin Pharmacol . 2014; 78:543-55. [PubMed 24617631]
5. Ando Y, Iwasa S, Takahashi S et al. Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci . 2019; 110:1021-31. [PubMed 30588709]
6. Akinleye A, Avvaru P , Furqan M et al. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol . 2013; 6:1-17. [PubMed 26793003]
7. Fritsch C, Huang A, Chatenay-Rivauday C et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther . 2014; 13:1117-29. [PubMed 24608574]
8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212526Orig1s000: Multi-discipline review. From FDA website. [Web]
9. Bosch A, Li Z, Bergamaschi A et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med . 2015; 7:283ra51. [PubMed 25877889]
10. André F, Ciruelos EM, Juric D et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol . 2021; 32:208-217. [PubMed 33246021]
11. Novartis Pharmaceuticals. Vijoice® (alpelisib) tablets and oral granules prescribing information. East Hanover, NJ; 2024 Apr. [Web]
12. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA web site. [Web]
13. Hughes M, Hao M, Luu M. PIK3CA vascular overgrowth syndromes: an update. Curr Opin Pediatr . 2020; 32:539-546. [PubMed 32692051]
14. Canaud G, Hammill AM, Adams D et al. A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations. Orphanet J Rare Dis . 2021; 16:306. [PubMed 34238334]
70. Burstein HJ, DeMichele A, Fallowfield L, Somerfield MR, Henry NL, for the Biomarker Testing and Endocrine and Targeted Therapy in Metastatic Breast Cancer Expert Panels. Endocrine and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2- negative metastatic breast cancer - capivasertib-fulvestrant: ASCO rapid recommendation update. J Clin Oncol . 2024;42(12):1450-1453.