varegacestat (AL102)

P1, N=22, Recruiting, Immunome, Inc. | Not yet recruiting --> Recruiting

P1, N=22, Not yet recruiting, Immunome, Inc.

P2/3, N=192, Active, not recruiting, Immunome, Inc. | Trial completion date: Feb 2025 --> Oct 2026 | Trial primary completion date: Jan 2025 --> Oct 2025

P2/3, N=192, Active, not recruiting, Ayala Pharmaceuticals, Inc, | Recruiting --> Active, not recruiting

Two GSIs, nirogacestat (PF-03084014) and AL102 are in later-stage clinical development; nirogacestat is being evaluated in a phase 3, randomized, placebo-controlled trial while AL102 is being evaluated in a phase 2/3, dose-finding (part A) and placebo-controlled (part B) trial. This review summarizes current understanding of the molecular pathogenesis of DT focusing on dysregulation of the Wnt signaling pathway, crosstalk with the Notch pathway, and the potential therapeutic role for GSIs in DT.

Tyrosine kinase inhibitors are well studied, and sorafenib is now one of the most utilized therapies, though limited by its side effect profile. In addition to nirogacestat, the gamma-secretase inhibitor AL102 is being investigated for the treatment of patients with progressing desmoid tumors in the phase II/III RINGSIDE trial. Finally, the beta-catenin inhibitor Tegavivint (BC2059) is being investigated in a phase 1 open-label trial in patients with a proven primary or recurrent desmoid tumor that is unresectable and symptomatic or progressive.

Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.