The mTORC1 inhibitor everolimus has anti-tumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma
Mené in vitro puis sur 16 patients atteints d'un lymphome T réfractaire/récidivant, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité de l'évérolimus
The mTOR pathway is constitutively activated in the T cell lymphoma (TCL) cells and is responsible for TCL proliferation.This is first trial to demonstrate that mTORC1 inhibitors (everolimus) have substantial anti-tumor activity (44% ORR) in patients with relapsed TCL. Everolimus is an oral agent that targets the mTOR pathway. This study investigated mTOR pathway activation in T cell lymphoma (TCL) cell lines and assessed anti-tumor activity in patients with relapsed/refractory TCL in a Phase II trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T cell proliferation with minimal cytotoxic effects. Everolimus completely inhibited phosphorylation of ribosomal S6, a raptor/mTORC1 target, without a compensatory activation of the rictor/mTORC2 target Akt (S475). In the clinical trial, 16 patients with relapsed TCL were enrolled and received everolimus 10 mg PO daily. Seven (44%) patients had cutaneous (all mycosis fungoides); 4 (25%) peripheral T-cell NOS; 2 (13%) anaplastic large cell; and 1 each of extranodal NK/T-cell, angioimmunoblastic, and precursor T lymphoblastic leukemia/lymphoma types. The overall response rate was 44% (7/16; 95% CI: 20-70%). The median PFS was 4.1 months (95% CI: 1.5-6.5); and, the median OS 10.2 months (95% CI: 2.6-44.3). The median duration of response for the 7 responders was 8.5 months (95% CI: 1.0-not reached). These studies indicate that everolimus has anti-tumor activity and provide proof-of-concept that targeting the mTORC1 pathway in TCL is clinically relevant. The trial is registered to www.clinicaltrials.gov as NCT00436618.