Alpelisib, a PI3Kα inhibitor, is indicated for severe PIK3CA-Related Overgrowth Spectrum (PROS) in patients ≥2 years, under accelerated approval. It targets gain-of-function PIK3CA mutations, reducing aberrant PI3K-Akt signaling.

PI3Kα Inhibition in PIK3CA-Related Overgrowth Spectrum

In the EPIK-P1 trial, 27% of patients achieved ≥20% radiological lesion reduction at 24 weeks, with 70% maintaining response ≥6 months. Efficacy is attributed to preventing or reversing PI3K-driven overgrowth in preclinical models. The drug’s clinical benefit is contingent on confirmatory trials. Response optimization in pediatrics may involve dose escalation (50 mg→125 mg) or gradual increases to adult dosing at age 18.