Alpelisib in PIK3CA-Related Overgrowth Spectrum (PROS): A Systematic Review of Real-World Evidence in over 100 Patients

Background: PIK3CA-related overgrowth spectrum (PROS) comprises a heterogeneous group of mosaic disorders caused by activating variants in the PIK3CA gene, resulting in dysregulation of the PI3K/AKT/mTOR signaling pathway and abnormal tissue overgrowth. Targeted inhibition of this pathway has recently emerged as a promising therapeutic strategy. Methods: We conducted a literature review to identify published reports describing patients with PROS treated with alpelisib, a selective inhibitor of the p110α catalytic subunit of PI3K. Data regarding patient characteristics, genetic variants, treatment regimens, clinical outcomes, radiological response, and adverse events were extracted and analyzed. Results: Seventeen publications met the inclusion criteria, comprising a total of 114 patients treated with alpelisib. The majority of patients were pediatric (68.4%), with a median age at treatment initiation of 12 years. Clinical manifestations were heterogeneous and included segmental overgrowth, vascular malformations, and soft-tissue hypertrophy. Clinical improvement in at least one disease manifestation was reported in 111 patients (97.3%). Radiological response, defined as reduction ≥20% in lesion volume, was documented in 26 of 60 evaluable cases (47.3%). Adverse events were reported in 64 patients (56.1%) and were generally mild and manageable, with hyperglycemia and diarrhea being the most common. Conclusions: Available real-world evidence suggests that alpelisib provides meaningful clinical benefit across multiple PROS phenotypes, with an acceptable safety profile. However, current data remain limited by small cohort sizes, heterogeneous outcome reporting, and variable follow-up duration. Prospective studies with standardized outcome measures are needed to better define long-term efficacy and safety of PI3K inhibition in PROS.