Gamma-secretase inhibitor-associated hypophosphatemia in patients with desmoid tumor

Nirogacestat, an oral γ-secretase inhibitor (GSI), is the first therapy approved by the Food and Drug Administration to treat desmoid tumors in 2023. Another oral GSI, AL102, is currently being tested in the RINGSIDE phase 2/3 clinical trial in patients with desmoid tumors. Data from recent trials indicate that hypophosphatemia is a class effect of these drugs. The mechanism of GSI-associated hypophosphatemia (GSI-HP) is unknown. We conducted a single-center retrospective cohort analysis of the participants enrolled in the multicenter DeFi trial, compassionate use of nirogacestat, and RINGSIDE trial at our center. Clinical and laboratory data on all patients on a GSI were collected through the electronic medical record system and analyzed. We identified seventeen patients who received nirogacestat or AL102 and had at least one episode of hypophosphatemia between 2020 and 2023. Twelve out of seventeen patients had GSI-HP; nine of them had diarrhea. Among patients with GSI-HP, urine fractional phosphate excretion (FePO4) was available in four patients with diarrhea and two patients without diarrhea. All six patients had high urine FePO4 (⩾5%), normal serum fibroblast growth factor 23 (FGF23), and two of the six patients had elevated parathyroid hormone (PTH) levels. GSI-HP was not severe (median serum phosphate 2.2 mg/dL, IQR: 1.9-2.2), and treatment with phosphate supplements and anti-diarrheal medications allowed the continuation of GSI therapy. The primary mechanism of GSI-HP is likely gastrointestinal phosphate loss due to diarrhea. However, the high urinary FePO4 suggests that urinary phosphate loss may also contribute to GSI-HP. While FGF-23 levels were not elevated, elevated PTH appears to have caused phosphaturia in some, but not all, patients with GSI-HP. This is the first study to elucidate the mechanism of GSI-HP. Future prospective studies are needed to further clarify the pathophysiology of GSI-HP and to develop strategies for the prevention and treatment of hypophosphatemia.