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Abstract: SA-PO199

Gamma-Secretase Inhibitor-Associated Hypophosphatemia in Patients with Desmoid Tumors

Session Information

Category: Onconephrology

  • 1700 Onconephrology

Authors

  • Pak, Wai Lun Will, Memorial Sloan Kettering Cancer Center, New York, United States
  • Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Knezevic, Andrea, Memorial Sloan Kettering Cancer Center Department of Epidemiology & Biostatistics, New York, New York, United States
  • Agins, Jordyn, Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Jhaveri, Kenar D., Northwell Health, New Hyde Park, New York, United States
  • Shaikh, Aisha, Memorial Sloan Kettering Cancer Center, New York, New York, United States
Background

Nirogacestat, a γ-secretase inhibitor (GSI), improved progression-free survival in adults with desmoid tumors (DeFi trial, Gounder et al., NEJM, 2023). Hypophosphatemia (HP), a class effect of GSI therapy, occurred in 42% of trial subjects. The mechanism of GSI-associated hypophosphatemia (GSI-HP) is unknown. The objective of the study was to elucidate the mechanism of GSI-HP.

Methods

We used our institute’s electronic medical record system to conduct a retrospective cohort analysis of the subjects in the DeFi trial, the RINGSIDE trial (an ongoing trial of AL102, another GSI), and those on compassionate use of nirogacestat at a single large cancer center. Clinical and laboratory data on all patients on a GSI were collected and analyzed.

Results

We identified seventeen patients who received nirogacestat or AL102 and had at least one episode of HP between 2020 and 2023 (Figure 1). Twelve patients had GSI-HP; nine of them had diarrhea. Urine fractional phosphate excretion (FePO4) was available in four patients with diarrhea and two without diarrhea. All six patients had a high urine FePO4 and a normal serum fibroblast growth factor 23 (FGF23), and two patients had high serum parathyroid hormone (PTH). 25-OH vitamin D level was low in one patient with a high PTH. In most patients, the hypophosphatemia was not severe (median serum phosphate 2.2, IQR: 1.9-2.2), and treatment with phosphate supplements and anti-diarrheal medications allowed the continuation of GSI therapy.

Conclusion

We conclude that the primary mechanism of GSI-HP is gastrointestinal loss due to diarrhea. High urine FePO4 may also contribute to GSI-HP in some patients, but FGF23 does not mediate it. This is the first study to describe the mechanism of GSI-HP. These findings will equip clinicians with the knowledge to assess the cause of GSI-HP and implement effective therapies to manage GSI-HP, ensuring better patient outcomes.

Funding

  • NIDDK Support