Alpelisib Receives FDA Approval for PIK3CA Mutation-Related Overgrowth Spectrum

For severe symptoms requiring systemic treatment in PIK3CA-related overgrowth spectrum (PROS), the targeted drug alpelisib (Vijoice, Novartis) received accelerated FDA (US Food and Drug Administration) approval on 5 April 2022 for adults and pediatric patients older than 2 years.

Alpelisib had previously been approved on 24 May 2019 for postmenopausal patients with hormone receptor-positive, HER2-negative advanced or metastatic PIK3CA-mutated breast cancer under the brand name Piqray, in combination with the hormonal therapy drug fulvestrant (see the related approval).

What Is PIK3CA-Related Overgrowth Spectrum?

PIK3CA-related segmental overgrowth also known as PROS (PIK3CA-Related Overgrowth Spectrum), typically arises from PIK3CA gene somatic mutations that cause overgrowth of body parts. It is a group of rare disorders, and is called a "spectrum" because it comprises a group of disorders rather than a single disease. These disorders include;

• Fibroadipose hyperplasia (fibroadipose overgrowth)
• Clove syndrome
• Megalencephaly capillary malformation syndrome (MCAP syndrome)
• Hemihyperplasia multiple lipomatosis syndrome (HHML syndrome)
• Hemimegalencephaly
• Infiltrating lipomatosis of the face (a congenital disorder causing overgrowth of one side of the face)

The symptoms of PROS vary depending on the condition it causes and may include an abnormally large brain (megalencephaly), low muscle tone (hypotonia), seizures, intellectual disabilities, changes in blood vessels and overgrowth of one or more body regions.

Efficacy of Alpelisib for PROS

The efficacy of alpelisib was evaluated using real-world data from EPIK-P1, a single-arm clinical study conducted in patients older than 2 years who received alpelisib under an expanded access program in the hope of helping another patient group.

Patients with clinical manifestations of PROS were classified as severe or life-threatening by their treating physicians. There was also documentation of a mutation in the PIK3CA gene.

The efficacy of alpelisib was evaluated in a total of 37 patients who had at least one target lesion identified on imaging performed for the 24 weeks before the first dose.

Results

The main efficacy outcome measure was the proportion of patients with a radiological response at week 24, as determined by blinded independent central radiology review. This was defined as a ≥20% reduction from baseline in the sum of measurable target lesions, up to 3 lesions, confirmed by at least 1 subsequent imaging assessment. Duration of response was an additional efficacy outcome measure.

• Of the 37 patients included in the efficacy population, 27% had a radiological response at week 24.
• Of the responders, 60% had a long-term response (12 months or longer).

The most common (≥ %10) side effects in patients were;

• Diarrhea
• Stomatitis (inflammation of the mouth)
• Hyperglycemia

The recommended alpesilib dose;

• For pediatric patients aged 2 – 18 years, 50 mg orally once daily with food.
• If clinically indicated, the dose may be increased to 125 mg after week 24 in pediatric patients aged 6 years and older.
• For adult patients older than 18 years, 250 mg orally once daily with food.