alpelisib

Alpelisib is a selective oral inhibitor of phosphoinositide 3-kinase alpha (PI3Kα), encoded by the PIK3CA gene. By blocking PI3Kα, it dampens downstream signaling in the AKT/mTOR pathway that promotes tumor cell growth and survival. It is used in combination with fulvestrant for the treatment of hormone receptor–positive, HER2-negative advanced breast cancer in patients whose tumors harbor a PIK3CA mutation, and after progression on or following aromatase inhibitor therapy.

Regulatory status and use: In the United States, alpelisib received approval from the FDA in 2019 for use with fulvestrant in PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer after progression on aromatase inhibitors. Regulatory approvals in other regions have followed, reflecting its role in this molecularly defined subset of breast cancer.

Administration and dosing: Alpelisib is administered orally once daily with a meal. The commonly used dose is 300 mg, given in combination with fulvestrant, with dose modifications considered for the management of adverse events.

Adverse effects and monitoring: The most notable adverse events include hyperglycemia, rash, diarrhea, nausea, stomatitis, decreased appetite, and fatigue. Hyperglycemia can be clinically significant, necessitating monitoring of fasting glucose and HbA1c and, if needed, initiation or adjustment of antidiabetic therapy. Other risks include noninfectious pneumonitis, dehydration, and photosensitivity. Management often requires dose interruptions and reductions. Drug interactions are relevant: strong CYP3A4 inhibitors increase alpelisib exposure, while inducers decrease exposure.

Testing and eligibility: PIK3CA mutation status should be determined with a validated diagnostic test before initiating therapy. Alpelisib is generally reserved for patients whose tumors carry the mutation and meet the specified breast cancer criteria.