Nirogacestat and Hypophosphatemia

To the Editor:

Desmoid tumors are locally aggressive rare tumors that arise from fibrous tissue.¹ Nirogacestat is a small-molecule inhibitor targeting the γ-secretase enzyme complex, which is responsible for the proteolytic cleavage of multiple transmembrane proteins, including NOTCH (Neurogenic locus notch homolog protein receptor). Inhibition of NOTCH signaling leads to the disruption of cell growth, possibly slowing tumor growth.¹ A recent study by Gounder et al.¹ reported results of a phase 3 trial; patients receiving nirogacestat had a 71% lower risk of disease progression or death than those on a placebo. The study concluded that after 2 years, the chances of disease-free progression or death was 76% with nirogacestat compared to 44% with placebo.¹

As nephrologists, it was interesting to note that nirogacestat was associated with a 42% incidence of hypophosphatemia, among other adverse events. However, the study does not provide insights into the possible mechanism of hypophosphatemia, and the etiology of the increased incidence of hypophosphatemia in the treatment group remains unclear. A summary of studies on γ-secretase inhibitor use in different cancers with the incidence of hypophosphatemia (%) is presented in Table 1.1, 2, 3, 4, 5 On the basis of these results, we postulate that hypophosphatemia is likely a class effect.

Table 1.

Summary of NOTCH inhibitor trials and associated risk of hypophosphatemia

Cancer	Pt no:/study type	Dose	Incidence of Hypophosphatemia
Desmoid tumor1	70, Phase 3 double-blind, placebo, RCT	Nirogacestat 150 mg BID	42% in Rx arm
Advanced sarcoma2	67, Investigator-initiated trial, phase 1b/2 RCT	RO4929097 (monoRx): 34 RO4929097 + Vismodegib: 33	MonoRx arm: 38% Combination arm: 3%
Desmoid tumor3	17, Open-label, single-arm, Phase 2	150 mg BID	76% Grade 2: 38% Grade 3: 62%
Metastatic breast4	15, Phase 1b dose-escalation trial	The dose escalated over 5 doses (20, 30, 45, 90, and 140 mg)	46.7% Grade 3 AE 13.4%
Solid organ cancer5	36, open-label phase 1 dose-escalation study	Once daily dosing 0.3, 0.6, 1.2, 1.5, 2.0 mg Twice weekly 2, 4, 8 mg	67% in once daily, 58% in weekly schedule

AE, adverse events; monoRx, monotherapy; RCT, randomized control trial; Rx, treatment.

It is uncertain whether this is causally linked to the augmented frequency of diarrhea observed in this cohort (hypophosphatemia mediated by downregulation of sodium phosphate transporter-2b). The potential of nirogacestat to induce renal phosphorus wasting mediated via sodium phosphate transporter-2a necessitates further investigation. Further investigations are required to examine potential concurrent electrolyte abnormalities, particularly involving serum calcium, in association with fractional excretion of phosphorus, as well as the levels of phosphaturic hormones such as parathyroid hormone and fibroblast growth factor-23. These studies will provide valuable insights into the intricate mechanisms that affect phosphate homeostasis in the context of nirogacestat treatment. Mechanistic studies will also aid in preventing strategies to mitigate a common side effect of this class of drugs.