Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Current oncology (Toronto, Ont.)	28	5	2021 09 21	3659-3667	Curr Oncol

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
AL102	AL102	0	1

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