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Ref Type Journal Article
PMID (34590610)
Authors Chan D, Kaplan J, Gordon G, Desai J
Title Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases.
Journal Current oncology (Toronto, Ont.)
Vol 28
Issue 5
Date 2021 09 21
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
AL102 AL 102|AL-102|BMS-986115 Gamma secretase inhibitor 13 AL102 inhibits gamma secretase, resulting in inhibition of NOTCH1-4 signaling and potentially leading to inhibition of tumor growth (PMID: 29637471, PMID: 34590610).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut desmoid tumor predicted - sensitive BMS-906024 Case Reports/Case Series Actionable In a clinical case study, BMS-906024 treatment resulted in a partial response that lasted for at least 2.6 years in a patient with a desmoid tumor harboring an inactivating APC mutation (PMID: 34590610). 34590610
CTNNB1 T41A desmoid tumor predicted - sensitive BMS-906024 Case Reports/Case Series Actionable In a Phase I trial, BMS-906024 treatment resulted in a partial response that lasted for 3.6 years on treatment and at least another 4 years after the end of treatment in a patient with a desmoid tumor harboring CTNNB1 T41A (PMID: 34590610; NCT01292655). 34590610