Luspatercept in Metastatic Adult Granulosa Cell Tumor (AGCT) of the Ovary

This patient has AGCT driven by a somatic oncogenic FOXL2 mutation identified through a molecular profiling study. One of the ways in which this mutation drives tumorigenesis is via increased activity of SMAD3, which results in decreased expression of follistatin and allows increased signalling of activin, a TGFB ligand that activates the TGFB pathway. Anti-TGFB approaches have shown promise in preclinical studies of AGCTs and several early phase trials are investigating different levels of TGFB pathway inhibition1.

As an activin receptor ligand trap, luspatercept has been shown to reduce SMAD2/3 signaling and improve anemia in disorders characterized by ineffective erythropoiesis, such as B-thalassemia and myelodysplastic syndromes (MDSs). This study aims to determine if we can apply this rationale to a patient with recurrent AGCT with oncogenic FOXL2 mutation known to drive TGFB/SMAD pathway overactivity.

Luspatercept has not been investigated in AGCT and therefore the efficacy of this specific agent as a cancer therapeutic is not yet known. Other TFGB ligand-trapping agents are in development and early phase clinical trials. One such example is AVID200, a TGFB ligand trap and selective inhibitor of TGFB1 and advanced solid tumors. There were 19 patients included in a phase I study of AVID200 monotherapy in patients with advanced solid tumors. A best response of stable disease for over 12 weeks seen in two patients (adenoid cystic carcinoma and breast carcinoma). The maximum tolerated dose was not reached; no Grade 3 adverse events were seen and only three adverse events were reported overall including diarrhea and lipase elevation.