1. Butler, Sara PharmD, BCOP, BCPS

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What is alpelisib?

Alpelisib is a kinase inhibitor of phosphatidylinositol-3-kinase (PI3K), specifically PI3K[alpha].


How does alpelisib work?

Alpelisib is an oral agent that inhibits phosphorylation of PI3K downstream targets such as Akt in cells that have a PIK3CA mutation resulting in reduced tumor growth. It also increases estrogen receptor (ER) transcription in breast cancer cells.


What is this approved for?

Alpelisib is indicated in combination with fulvestrant for the treatment of post-menopausal women or men with hormone-receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative, PI3KCA-mutated, advanced or metastatic breast cancer after following progression on or after an endocrine-based treatment.


What is the basis for this approval?

Alpelisib was approved based on the results of the SOLAR-1 trial, a phase III, randomized trial comparing alpelisib plus fulvestrant to placebo plus fulvestrant in HR+, HER-2-advanced breast cancer patients (N Engl J Med 2019;380:1929-1940).


Two cohorts of patients were enrolled based on PIK3CA mutational status, including 341 patients with PIK3CA-mutated disease. The proof of concept criteria was only met in the PIK3CA-mutated patients. The primary endpoint of progression-free survival was 11.0 months in the alpelisib-fulvestrant group versus 5.7 months in the placebo-fulvestrant group for patients with PIK3CA mutations (p < 0.001). The overall response rate was higher in the alpelisib-fulvestrant group than placebo-fulvestrant (26.6% vs. 12.8%) (N Engl J Med 2019;380:1929-1940).


How do you administer this drug?

Alpelisib is given as 300 mg (two 150 mg tablets) orally twice daily with food. This should be given in combination with fulvestrant 500 mg intramuscularly on day 1, 15, and 29, then monthly thereafter.


Are there any premedications needed for alpelisib?

No premedications are needed with alpelisib, but patients may benefit from an anti-nausea medication prior if they experience nausea with the medication.


What are the common side effects associated with alpelisib (> or =10%)?


* General: fever (14%), peripheral edema (15%), fatigue (42%), headache (15%)


* Dermatologic: skin rash (52%), alopecia (20%), pruritis (18%)


* Endocrine: hyperglycemia (65%), increased gamma-glutamyl transferase (52%), decreased serum calcium (27%), weight loss (27%), decreased serum glucose (26%), decreased serum albumin (14%), decreased serum potassium (14%), decreased serum magnesium (11%)


* GI: diarrhea (58%), nausea (45%), increased serum lipase (42%), decreased appetite (36%), stomatitis (19%), vomiting (27%), dysgeusia (18%), dyspepsia (11%)


* Hematologic: lymphocytopenia (52%), prolonged PTT (21%), decreased platelets (14%)


* Hepatic: increased serum alanine aminotransferase (44%)


* Renal: increased serum creatinine (67%)


What are the uncommon side effects associated with alpelisib (less than 10%)?

Additional side effects include urinary tract infection (10%), anemia (2%), osteonecrosis of the jaw (4%), acute renal failure (3%), pneumonitis (2%).


Are there any important drug interactions I should be aware of?

Alpelisib is metabolized to a small degree by CYP3A4. As such, coadministration with strong CYP3A4 inducers may decrease concentrations of alpelisib.


How do I adjust the dose in the setting of renal or hepatic insufficiency?

There are no known renal dose adjustments, but alpelisib has not been studied in patients with CrCl < 30 mL/min. There are no dose adjustments for baseline hepatic impairment, but if hepatotoxicity develops during treatment, doses should be held until grade 1 and then resumed at the same dose level if resolved in <= 14 days or a lower dose level if > 14 days.


Practical tips


* Alpelisib is only indicated in advanced or metastatic breast cancer patients that are PIK3CA-mutated as detected by an FDA-approved test.


* Hyperglycemia was seen in 65 percent of patients receiving alpelisib. Type I and uncontrolled type II diabetic patients were not included in the clinical trial.


* Hemogloblin A1c and fasting plasma glucose should be tested prior to starting alpelisib and periodically throughout treatment. Oral anti-hyperglycemic medications such as metformin or an insulin sensitizer should be utilized if fasting plasma glucose is > 160 mg/dL.


What should my patients know about alpelisib?

Patients should contact their health care provider if they experience any of the following: elevated blood glucose, diarrhea, rash, shortness of breath.


What else should I know about alpelisib?


* Dose reductions may be necessary if blood glucose is not able to be controlled with metformin or an insulin sensitizer.


* Antidiarrheal medications such as loperamide are effective at managing alpelisib induced diarrhea.


* Rashes associated with alpelisib can mostly be managed with topical corticosteroids and oral antihistamine therapy.


What useful links are available regarding alpelisib?


* FDA approval for alpelisib in combination with fulvestrant:,


* Drug Trials Snapshots:


Any ongoing clinical trials related to alpelisib?

Clinical trials with alpelisib are ongoing in combination with chemotherapy or anti-HER-2 directed therapy in breast cancer as well as evaluation in the treatment of oropharyngeal, renal, and pancreatic cancer. More information is available about the clinical trials at


SARA BUTLER, PHARMD, BCOP, BCPS, is Manager of Clinical Pharmacy and Investigational Drug Services at Barnes-Jewish Hospital, St Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is the Manager of Clinical Pharmacy Services and practices as an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

Sara Butler, PharmD,... - Click to enlarge in new windowSara Butler, PharmD, BCOP, BCPS. Sara Butler, PharmD, BCOP, BCPS
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