Alpelisib Displays Clinical Benefit in Pediatric PIK3CA-Related Overgrowth Spectrum Disease

Guillaume Canaud, MD, PhD

Alpelisib (Piqray) decreased the need for surgery and led to improvements in performance status and disease-related signs and symptoms in pediatric patients with PIK3CA-related overgrowth spectrum (PROS) disease who received treatment with the PI3K inhibitor under compassionate use, according to findings from the prespecified secondary end point of the retrospective EPIK-P1 study (NCT04285723) presented at the 2022 ESMO Congress.

The findings showed that lipomatosis, scoliosis, hypertrophy, inflammation, and developmental delays occurred in at least 20% of pediatric patients at the index date and were improved as early as 12 weeks. Notably, the improvement in performance status score at 24 weeks was seen in 24.2% of pediatric patients, and no patients required surgery because of disease progression during this period vs 84.6% (n = 33/39) of those who underwent at least 1 surgery (range, 1-15) between diagnosis and the pre-index period.

“In the EPIK-P1 study, a clinically meaningful proportion of pediatric patients attained response,” lead study author Guillaume Canaud, MD, PhD, and coauthors wrote in the poster. “The majority of the patients had any reduction in the sum of their target lesion volume and none of the patients had radiologically confirmed disease progression during the study period.”

Alpelisib is an oral, alpha-selective, PI3K inhibitor that received an accelerated approval from the FDA on April 6, 2022, for the treatment of adult and pediatric patients at least 2 years of age with severe manifestations of PROS who require systemic therapy. The agent has shown clinical benefit and an acceptable safety profile in prior studies performed in this population.

In primary findings from EPIK-P1, 37.5% of complete cases (n = 12/32) showed at least a 20% reduction in target lesion volume after 24 weeks.

EPIK-P1 was a retrospective, noninterventional chart review of patients at least 2 years of age with PROS experiencing severe or life-threatening conditions.

To be eligible for inclusion, patients had to receive at least 1 dose of alpelisib on or before September 23, 2019 and have relevant evaluations on or before the cut-off date of March 9, 2020.

The entire study population (n = 57) was used for all efficacy and safety analyses apart from the primary end point, which evaluated only the patients without a missing response assessment (n = 32).

The primary end point was the proportion of patients with at least a 20% reduction from the index date in the sum of measurable target lesion volume at week 24. Secondary end points included treatment effect on performance status, frequency of PROS-related surgeries, changes in signs/symptoms over time, and safety.

Of the total patient population, 39 were pediatric patients who had a median age of 10 years (range, 2-17). The overall median patient age was 14.0 years (range, 2-50). Most patients in both populations had congenital overgrowth as opposed to early childhood-onset overgrowth, mosaic distribution vs sporadic occurrence, and CLOVES subtype compared with MCAP/MCM, KTS, FIL, or other.

Pediatric patients received a median dose of alpelisib of 50.0 mg per day (range, 50.0-250.0).

Regarding safety, 79.5% (n = 31) of pediatric patients experienced at least 1 adverse effect (AE); treatment-related AEs (TRAEs) occurred in 23.1% (n = 9) of pediatric patients.

The most common any-grade AEs were diarrhea (n = 5; 12.8%), vascular malformation (n = 4; 10.3%), stomatitis (n = 3; 7.7%), aphthous ulcers (n = 3; 7.7%), inflammation (n = 3; 7.7%), hypoglycemia (n = 3; 7.7%), hyperglycemia (n = 2; 5.1%), disseminated intravascular coagulation (n = 2; 5.1%), and gait disturbance (n = 2; 5.1%). Grade 3/4 AEs included cellulitis, adrenal insufficiency, dyspnea, and wound infection (n = 1; 2.6% each).

The most frequent TRAEs were aphthous ulcer, stomatitis (n = 3; 7.7% each), and hyperglycemia (n = 2; 5.1%).

The most common serious AEs in pediatric patients were gait disturbances (n = 2; 5.1%) and vascular malformations (n = 2; 5.1%), neither of which was determined to be treatment related.

No AE led to treatment discontinuation, although 2 patients (5.1%) required dose interruptions because of AEs. No deaths occurred during the study.

“Treatment with alpelisib allowed [patients] to avoid PROS-related surgeries and resulted in improvement of performance status [and] PROS-related signs and symptoms,” the study authors wrote. “In addition to the previously reported lesion volume reduction and well tolerated safety profile, these real-world data [show] a meaningful clinical benefit with alpelisib in pediatric patients with PROS.”

The confirmatory EPIK-P2 trial (NCT04589650) is recruiting patients to further assess the efficacy, safety, and pharmacokinetics of alpelisib in pediatric and adult patients with PROS.

Reference

Canaud G, Irvine A, Ankrah N, et al. Clinical benefit of alpelisib in pediatric patients with PIK3CA-related overgrowth spectrum (PROS): an EPIK-P1 analysis. Ann Oncol. 2022;33(suppl 7):S755. doi:10.1016/annonc.2022.07.597