Guillaume Canaud, MD, PhD, of the Paris Descartes University, describes the clinical studies that led to the approval of alpelisib to treat persons with PiK3CA-related overgrowth syndrome (PROS).

PROS is a group of rare congenital disorders that lead to the overgrowth of parts of the body. PROS is caused by gain of function mutations in the PIK3CA gene. Specific disorders under the umbrella of PROS include:

  • Fibroadipose hyperplasia
  • Hemihyperplasia multiple lipomatosis (HHML)
  • Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome
  • Macrodactyly
  • Fibroadipose infiltrating lipomatosis
  • Megalencephaly-capillary malformation (MCAP)
  • Dysplastic megalencephaly (DMEG) 

As Dr. Canaud explains, he was involved in a study in 2018 showing the efficacy of alpelisib, PI3K inhibitor more commonly used to treat a subset of breast cancer, in both a mouse model of PROS and in patients with PROS. Based on that study, a retrospective chart review study – EPIK-P1 – was undertaken and results from that study led to the accelerated approval of alpelisib by the FDA.

In the EPIK-P1 study, 27% of patients (10/37) achieved a confirmed response to treatment, defined as 20% or greater reduction in the sum of PROS target lesion volume. Also, 74% of patients showed some reduction in target lesion volume and no patients signs of disease progression during the study. Additionally, improvements in pain (90%), fatigue (76%), vascular malformation (79%), limb asymmetry (69%, 20/29), and disseminated intravascular coagulation (55%) were reported.

The most common adverse events (AEs) of any grade were diarrhea (16%), stomatitis (16%), and hyperglycemia (12%). The most common grade 3/4 AE was cellulitis (4%); one adult case was considered treatment-related. 

Continued approval will be contingent upon additional placebo-controlled studies that will confirm the clinical benefit of the orphan drug in PROS patients.

To learn more about PROS and other rare congenital disorders, visit