Alpelisib is an oral phosphatidylinositol 3-kinase (PI3K) inhibitor that primarily inhibits the PI3Kα isoform. It is the world's first approved PI3Kα-selective inhibitor, first approved in the United States in 2019.

Indications for Alpelisib

Alpelisib 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.

Pre-treatment Testing

Tumor tissue specimens are preferred for PIK3CA mutation testing. If a mutation is not detected in a plasma specimen (liquid biopsy), the tumor tissue should be tested. In the SOLAR-1 trial, among 336 patients with tissue-confirmed PIK3CA mutations, only 177 (56%) had detectable mutations in plasma specimens. In other words, ruling out eligibility for treatment based solely on a single negative blood test result is not rigorous.

Mechanism of Action of Alpelisib

Alpelisib inhibits the activity of PI3Kα and blocks the PI3K/Akt signaling pathway. In breast cancer cell lines, it inhibits the phosphorylation of PI3K downstream targets (including Akt) and demonstrates activity in cell lines harboring PIK3CA mutations. In animal xenograft models, it inhibits the PI3K/Akt pathway and reduces tumor growth.

Why Combine with Fulvestrant?

After Alpelisib inhibits PI3K, the transcription of estrogen receptors (ER) in breast cancer cells increases—similar to blocking one pathway, which causes tumor cells to attempt a detour through another. The role of fulvestrant is precisely to degrade estrogen receptors. By blocking both pathways simultaneously, the anti-tumor activity is significantly stronger than that of either single agent alone.

Side Effects of Alpelisib

The incidence of serious adverse reactions is 35%. Dose reductions due to adverse reactions occurred in 55% of patients, and 21% permanently discontinued Alpelisib due to adverse reactions.

1. Common Adverse Reactions

Hyperglycemia occurs at a rate of 65%, with Grade 3 at 33%, Grade 4 at 3.9%, and ketoacidosis at 0.7%.

Diarrhea 58%, rash 52%, nausea 45%, fatigue 42%, decreased appetite 36%, and stomatitis 30%.

2. Severe Adverse Reactions

Severe hypersensitivity reactions (including anaphylactic shock), severe cutaneous adverse reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, etc.), interstitial lung disease and pneumonitis, and dehydration and acute kidney injury resulting from diarrhea or colitis.