Background: PROS comprises a group of rare overgrowth disorders driven by activating somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), the gene encoding phosphoinositide 3-kinase alpha (PI3Kɑ). Disease onset is typically congenital or during early childhood and may progress and cause early death. Clinical manifestations are very diverse according to the localization of the mutation and the tissues affected and can range from localized to extensive overgrowth, which may be debilitating (particularly in pediatric pts) and life threatening. Treatment (tx) of PROS largely relies on invasive procedures and surgeries, which are rarely curative. The PI3Kα-specific inhibitor ALP was granted FDA Accelerated Approval based on its efficacy in pts receiving tx under a compassionate use program; it is the first and only US-approved pharmacological agent for pts age ≥2 y with severe PROS manifestations. Here, we report results from EPIK-P2 (NCT04589650), the first prospective study of ALP in pts with PROS.

Methods: Adult (age ≥18 y) and pediatric (ages 6-17 y) pts with a diagnosis of PROS with symptomatic and/or progressive overgrowth, ≥1 measurable PROS-related lesion, and documented PIK3CA mutation underwent double-blind 2:1 randomization to receive ALP (125 mg for adults [half of current indicated dosing]; 50 mg for pediatric pts) or placebo (PBO) for 16 weeks; after week 16, all pts received ALP (henceforth “ALP tx period”). The primary objective was to demonstrate efficacy based on the proportion of pts randomized to ALP with confirmed response (≥20% reduction from baseline in sum of target lesion volumes of 1 to 3 lesions, assessed by MRI by a blinded independent review committee) at any time. Statistical significance was prespecified as the lower bound of the 97.5% CI exceeding 15%. Secondary objectives include comparison of the proportion of pts with objective response at week 16 (key objective) in ALP vs PBO, duration of response (DOR), safety, impact on PROS signs and symptoms, and proportion of pts with rescue surgery during the PBO-controlled period and overall while taking ALP.

Results: In total, 165 pts (81 adults, 84 pediatric) were included; the data cutoff date for this analysis was March 20, 2024. The primary objective was not met; confirmed objective response with ALP (any time) was achieved in 16.7% (9/54; 97.5% CI: 7.0%-31.1%) and 23.2% (13/56; 97.5% CI: 11.9%-38.3%) of adult and pediatric pts, respectively. The adjusted p values were 0.42 and 0.14, respectively. Median DOR was not estimable. None of the 9 adult pts with confirmed response had disease progression; 2 of the 13 pediatric pts with confirmed response had disease progression. Objective response at week 16 was 11.1% (6/54) vs 0% (0/27) in the ALP and PBO arms, respectively, in adults; 8.9% (5/56) vs 0% (0/28) in pediatric pts. No new safety signals were observed during the study. During the PBO-controlled period, all-grade (grade ≥3) tx-related adverse events were reported in 57.4% (9.3%) vs 44.4% (3.7%) of pts in the ALP vs PBO arms, respectively, in adults and in 33.9% (5.4%) vs 32.1% (0%) in pediatric pts. Most common (≥40%, any arm) PROS-related signs and symptoms at baseline were hypertrophy, vascular malformation, lymphatic malformation, and pain in the extremity in adults, and hypertrophy, vascular malformation, lymphatic malformation, and nevus flammeus in pediatric pts. By the last assessment of the PBO-controlled period, most of these PROS-related complications were generally stable in both ALP and PBO arms, in adult and pediatric pts. By the last assessment of the ALP tx period, a similar trend was observed, with the exception of pain in the extremity, with improvements reported in 18/35 (51.4%) and 8/20 (40.0%) adult and pediatric pts, respectively. None of the pts required rescue surgery during the study.

Conclusions: EPIK-P2 showed durable radiological responses in a meaningful proportion of pts treated with ALP, and the tx was well tolerated in both adult and pediatric pts, although the prespecified efficacy boundary was not crossed. These data support further prospective investigation of approved dosing of ALP in pts with PROS.

Disclosures

Canaud:Novartis: Consultancy, Honoraria, Patents & Royalties. López-Gutiérrez:Pierre Fabre Pharmaceuticals: Other: Travel support, Speakers Bureau. Hammill:Diagonal Therapeutics Inc.: Consultancy, Other: Consultant/Disease Expert; Ipsen Innovation SAS: Consultancy; Relay Therapeutics: Other: Sponsored Travel, Advisory Board participation; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation on Advisory Boards. Weibel:Novartis: Other: PI in clinical study; Sanofi: Honoraria; Boehringer Ingelheim: Other: PI in clinical study. Niglis:Novartis Pharma AG: Current Employment. Paul:Novartis: Current Employment. Papadimitriou:Novartis: Current Employment, Other: Current holder of stock options in the company. Wroclawska:Novartis: Current Employment. Adams:Novartis: Consultancy.

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2024
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