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

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 phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Alpelisib, a phosphoinositide 3-kinase-α (PI3Kα) inhibitor, is a key therapy for VAs; however, it is only approved for <i>PIK3CA</i>-related overgrowth spectrum (PROS), a VA diagnosis with multifaceted genotypic and phenotypic criteria, including a required <i>PIK3CA</i> mutation. Although 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 the patients, 80% of whom did not meet PROS diagnostic criteria. There was no genetic testing in ∼50% of the responders, and ∼25% had mutations in non-<i>PIK3CA</i> genes in the PI3K/AKT/mTOR pathway (<i>TEK</i>, <i>PIK3R1</i>, and <i>PTEN</i>). Among patients with pre- and post-therapy imaging, 100% showed clinical improvement, but only 50% showed 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 end points based on clinical, not radiological, outcomes.