Serabelisib, a Selective PI3Kα Inhibitor, for Slow-Flow Vascular Malformations in a Phase 3 Multicenter Single-Arm Study with Natural History Comparison

Background/Objectives: Slow-flow vascular malformations, including venous malformation (VM), lymphatic malformation (LM), and Klippel–Trenaunay syndrome (KTS), are rare, symptomatic disorders with limited treatment options. This study evaluated the efficacy and safety of serabelisib, an orally available selective phosphoinositide 3-kinase α inhibitor, in these patients. Methods: This phase 3, multicenter, single-arm, confirmatory study was conducted in Japan (September 2023–June 2025). Patients aged ≥2 years received oral serabelisib once daily (100 mg for body weight ≥ 40 kg; 60 mg/m2 for <40 kg) for up to 52 weeks. The primary endpoint was the response rate at the final evaluation (≥24 weeks), defined as the proportion of patients achieving a ≥20% reduction from baseline in target lesion volume on blinded, centrally reviewed magnetic resonance imaging. The response rate was compared with a natural history-based null rate of 6.7% (exact binomial test). Trial registration: jRCT2041230064. Results: Thirty-six patients received serabelisib. The response rate was 30.6% (11/36; 95% confidence interval, 16.3–48.1%; p < 0.001) and remained significant in post hoc sensitivity analyses for null rates of up to 16%. Response rates were 19.0% (VM), 33.3% (LM), and 50.0% (KTS). Quality of life did not improve consistently. Adverse drug reactions (ADRs) occurred in 52.8% of patients (grade 3 or 4, 22.2%), most commonly hyperinsulinemia (13.9%), nausea (11.1%), and liver function test abnormal (11.1%); most hepatic ADRs (13 of 15 events) resolved after dose interruption or discontinuation. One death (tubulointerstitial nephritis) was judged unrelated to treatment. Conclusions: Serabelisib produced radiological responses exceeding a natural history benchmark in refractory VM, LM, and KTS, with hepatic toxicity requiring monitoring. Larger controlled studies with longer follow-up are needed to confirm its clinical benefit and long-term safety.