Nirogacestat and Hypophosphatemia

Desmoid tumors are locally aggressive rare tumors that arise from fibrous tissue.1Gounder M. Ratan R. Alcindor T. et al.Nirogacestat, a gamma-secretase inhibitor for desmoid tumors.N Engl J Med. 2023; 388: 898-912https://doi.org/10.1056/NEJMoa2210140Crossref PubMed Scopus (8) Google Scholar 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.1Gounder M. Ratan R. Alcindor T. et al.Nirogacestat, a gamma-secretase inhibitor for desmoid tumors.N Engl J Med. 2023; 388: 898-912https://doi.org/10.1056/NEJMoa2210140Crossref PubMed Scopus (8) Google Scholar A recent study by Gounder et al.1Gounder M. Ratan R. Alcindor T. et al.Nirogacestat, a gamma-secretase inhibitor for desmoid tumors.N Engl J Med. 2023; 388: 898-912https://doi.org/10.1056/NEJMoa2210140Crossref PubMed Scopus (8) Google Scholar 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.1Gounder M. Ratan R. Alcindor T. et al.Nirogacestat, a gamma-secretase inhibitor for desmoid tumors.N Engl J Med. 2023; 388: 898-912https://doi.org/10.1056/NEJMoa2210140Crossref PubMed Scopus (8) Google Scholar 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 1.1Gounder M. Ratan R. Alcindor T. et al.Nirogacestat, a gamma-secretase inhibitor for desmoid tumors.N Engl J Med. 2023; 388: 898-912https://doi.org/10.1056/NEJMoa2210140Crossref PubMed Scopus (8) Google Scholar, 2Gounder M.M. Rosenbaum E. Wu N. et al.A phase Ib/II randomized study of RO4929097, a gamma-secretase or notch inhibitor with or without vismodegib, a hedgehog inhibitor, in advanced sarcoma.Clin Cancer Res. 2022; 28: 1586-1594https://doi.org/10.1158/1078-0432.CCR-21-3874Crossref PubMed Scopus (8) Google Scholar, 3GHOS C. Kummar S. Steinberg S.M. et al.Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors.J Clin Oncol. 2022; 4011545https://doi.org/10.1200/JCO.2022.40.16_suppl.11545Crossref Google Scholar, 4Means-Powell J.A. Mayer I.A. Ismail-Khan R. et al.A Phase Ib Dose Escalation Trial of RO4929097 (a gamma-secretase inhibitor) in Combination with exemestane in Patients with ER + Metastatic Breast Cancer (MBC).Clin Breast Cancer. 2022; 22: 103-114https://doi.org/10.1016/j.clbc.2021.10.013Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 5Aung K.L. El-Khoueiry A.B. Gelmon K. et al.A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours.Investig New Drugs. 2018; 36: 1026-1036https://doi.org/10.1007/s10637-018-0597-6Crossref PubMed Scopus (21) Google Scholar On the basis of these results, we postulate that hypophosphatemia is likely a class effect.Table 1Summary of NOTCH inhibitor trials and associated risk of hypophosphatemiaCancerPt no:/study typeDoseIncidence of HypophosphatemiaDesmoid tumor1Gounder M. Ratan R. Alcindor T. et al.Nirogacestat, a gamma-secretase inhibitor for desmoid tumors.N Engl J Med. 2023; 388: 898-912https://doi.org/10.1056/NEJMoa2210140Crossref PubMed Scopus (8) Google Scholar70, Phase 3 double-blind, placebo, RCTNirogacestat 150 mg BID42% in Rx armAdvanced sarcoma2Gounder M.M. Rosenbaum E. Wu N. et al.A phase Ib/II randomized study of RO4929097, a gamma-secretase or notch inhibitor with or without vismodegib, a hedgehog inhibitor, in advanced sarcoma.Clin Cancer Res. 2022; 28: 1586-1594https://doi.org/10.1158/1078-0432.CCR-21-3874Crossref PubMed Scopus (8) Google Scholar67, Investigator-initiated trial, phase 1b/2 RCTRO4929097 (monoRx): 34RO4929097 + Vismodegib: 33MonoRx arm: 38%Combination arm: 3%Desmoid tumor3GHOS C. Kummar S. Steinberg S.M. et al.Extended progression-free survival and long-term safety of nirogacestat in patients with desmoid tumors.J Clin Oncol. 2022; 4011545https://doi.org/10.1200/JCO.2022.40.16_suppl.11545Crossref Google Scholar17, Open-label, single-arm, Phase 2150 mg BID76%Grade 2: 38%Grade 3: 62%Metastatic breast4Means-Powell J.A. Mayer I.A. Ismail-Khan R. et al.A Phase Ib Dose Escalation Trial of RO4929097 (a gamma-secretase inhibitor) in Combination with exemestane in Patients with ER + Metastatic Breast Cancer (MBC).Clin Breast Cancer. 2022; 22: 103-114https://doi.org/10.1016/j.clbc.2021.10.013Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar15, Phase 1b dose-escalation trialThe dose escalated over 5 doses (20, 30, 45, 90, and 140 mg)46.7%Grade 3 AE 13.4%Solid organ cancer5Aung K.L. El-Khoueiry A.B. Gelmon K. et al.A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours.Investig New Drugs. 2018; 36: 1026-1036https://doi.org/10.1007/s10637-018-0597-6Crossref PubMed Scopus (21) Google Scholar36, open-label phase 1 dose-escalation studyOnce daily dosing 0.3, 0.6, 1.2, 1.5, 2.0 mgTwice weekly 2, 4, 8 mg67% in once daily, 58% in weekly scheduleAE, adverse events; monoRx, monotherapy; RCT, randomized control trial; Rx, treatment. Open table in a new tab 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.