Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome

Abstract Background PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) novel, orally available, selective pan-AKT inhibitor with proven vitro efficacy. Following recent results the use AKT inhibitors Proteus syndrome (PS) AKT-mutant cancers, we investigated its therapeutic two patients severe PROS who had exhausted conventional treatment methods. Results Two patients, one CLOVES variant (P1) facial infiltrating lipomatosis hemimegalencephaly (P2), were commenced on miransertib compassionate basis. In patient one, intra-abdominal paraspinal resulted respiratory compromise, obstructive uropathy, dysfunctional seating lying postures, chronic pain. two, hemifacial difficulties articulation oral function, refractory epilepsy. was continued for median duration 22 months (range 22–28). alleviation compromise observed functionally, postures improved. Serial volumetric MRI analysis revealed 15% reduction calculated volumes fatty between commencement end. seizure burden improved parent-reported quality life measures reported. Treatment discontinued both due lack sustained response, poor compliance year (P2). No significant toxicities Conclusion We report first paediatric case series children PROS. Objective clinical response improvement key qualitative outcomes reported two. well tolerated no This highlights potential utility selected PROS, further demonstrates re-purposing targeted therapies diseases. An open label, Phase 1/2 study PS underway more accurately assess efficacy disorder (NCT03094832).