Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases

Abstract

Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. 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.

Trial registration: ClinicalTrials.gov NCT01292655.

Keywords: AL102; BMS-906024; BMS-986115; Notch pathway; aggressive fibromatosis; rare disease.

Conflict of interest statement

D.C. received honoraria, travel support and research grants from Ipsen and Novartis and research grants from EMD Serono, unrelated to the current research. J.D. received consulting fees from Roche/Genentech, Eisai, BeiGene, GlaxoSmithKline, Amgen, Pierre Fabre, Bayer and research support from Roche/Genentech, Bristol Myers Squibb, GlaxoSmithKline, AstraZeneca, BeiGene, Novartis, Eli Lilly. J.K. and G.G. are employees of Ayala Pharmaceuticals and own stock and/or hold stock options in the company.

Figures

Figure 1

Change in desmoid tumor size from baseline in both patients by RECIST v1.1. Notes: Dotted line denotes change from baseline of 30%. Abbreviations: C, cycle; QW, once weekly; Q2W, once every 2 weeks; Q3W, once every3 weeks; Q4W, once every 4 weeks; W, week; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2

CT scans of target lesions at baseline and after achieving PR in both patients. Abbreviations: C, cycle; CT, computed tomography; D, day; PR, partial response.

Figure 3

HES1 relative expression level at week 1 and week 4 of cycle 1 in Case 1. Abbreviations: C, cycle; D, day; h, hour.