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.
Highlights
Desmoid tumors (DT), called aggressive fibromatosis, are benign tumors without metastatic potential that have a variable and unpredictable course, ranging from indolent to locally invasive [1]
Because of the lack of Food and Drug Administration (FDA)-approved treatment options and the complexity of treating the disease, patients with DT should be followed by an experienced multidisciplinary team of soft tissue sarcoma experts to ensure that these patients receive appropriate care [2]
After being treated with AL101, these patients had improvements in quality of life and long-lasting clinical responses, which were maintained more than 8.6 years in Case 1 and 2.6 years in Case 2
Summary
Desmoid tumors (DT), called aggressive fibromatosis, are benign tumors without metastatic potential that have a variable and unpredictable course, ranging from indolent to locally invasive [1]. In the phase 1 dose-escalation study of AL101 (CA216001; NCT01292655), 94 heavily pretreated patients with advanced solid tumors received intravenous doses of AL101; 3 patients with DT were enrolled, of whom 2 had confirmed partial responses (PRs) and 1 had stable disease [17]. In a phase 1 dose-escalation study (NCT00878189) of the GSI nirogacestat (PF-03084014), in which Notch-related target inhibition was observed, 9 patients with DT were enrolled (7 were evaluable for response): 5 had a PR and 2 had stable disease [19]. AL101 monotherapy is being investigated in an ongoing phase 2 study (TENACITY; NCT04461600) in patients with Notch-activated metastatic triple-negative breast cancer who have received ≤3 lines of prior therapy for metastatic disease [25].
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