Alpelisib, a PI3Kα inhibitor, effectively treats vascular anomalies with diverse genotypes and phenotypes Open Access

1. Alpelisib shows benefit across a broad spectrum of vascular anomalies, including those without confirmed PIK3CA mutations or PROS diagnoses

2. Clinical and radiologic response did not correlate in half of patients, stressing need for outcome measures prioritizing symptom improvement

Vascular anomalies (VAs) are complex, highly morbid conditions that are increasingly managed by hematologists with targeted therapies. They are often driven by activating mutations in the PI3K/AKT/mTOR pathway. Alpelisib, a phosphoinositide 3-kinase-α (PI3Kα) inhibitor, is a key therapy for VAs; however, it is only approved for PIK3CA-related overgrowth spectrum (PROS), a VA diagnosis with multi-faceted genotypic and phenotypic criteria, including a required PIK3CA mutation. Though there is a mechanistic rationale for alpelisib use in non-PROS VAs, published data supporting alpelisib use outside of PROS are limited. We conducted a single-center, retrospective study of 41 children and adults with VAs treated with alpelisib. Most patients failed prior therapies, including sirolimus. Alpelisib led to clinical improvement in 92% of patients, 80% of whom did not meet PROS diagnostic criteria. There was no genetic testing in ∼50% of responders, and ∼25% had mutations in non-PIK3CA genes in the PI3K/AKT/mTOR pathway (TEK, PIK3R1, PTEN). Among patients with pre- and post-therapy imaging, 100% had clinical improvement but only 50% had radiological improvement, highlighting discordance between imaging and clinical response. Our findings support expanding alpelisib use to VAs beyond PROS. In addition, they underscore the need for clinical trial endpoints based on clinical, not radiological, outcomes.