Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma

Abstract

• Selective inhibitor of nuclear export compounds are a novel class of XPO1 inhibitors.• Selinexor is safe and efficacious in patients with R/R NHL.Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m 2 of selinexor in 3-or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m 2 . The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m 2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m 2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892. (Blood. 2017;129(24):3175-3183)

Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer

“…14–16 In one study, 31% of evaluable patients had an objective response with use of selinexor across a spectrum of non-Hodgkin’s lymphoma subtypes, with a median duration of response exceeding 10 months. 16 In another study, among 157 evaluable patients with advanced or metastatic solid tumors, single-agent selinexor resulted in an objective response rate of 4%, and a stable disease rate of 43%. 17 …”

Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement

“…Moreover, objective responses were correlated with improved PFS and OS. 8 In addition, selinexor has demonstrated excellent brain penetration and promising results in both pre-clinical and clinical models of glioblastoma. 9,10 Recently, a phase 2 study in patients with recurrent glioblastoma showed 17% of PR and 33% of stable disease in 12 patients, which confirms its activity in brain tumors.…”

“…6 Anti-tumor activity of selinexor in DLBCL has recently been demonstrated in phase I trials. 7,8 Moreover, selinexor has shown excellent brain penetration and encouraging efficacy in patients with recurrent glioblastoma. 9,10 Promising results in pre-clinical models of primary CNS lymphoma (PCNSL) have been reported as well.…”

“…The most common adverse events of selinexor reported in phase I/II trials were nausea, fatigue and anorexia. [7][8][9] Our patient presented grade 3 fatigue and grade 2 anorexia which were not controlled with corticosteroids and appetite stimulants resulting in two dose reductions and eventually in treatment discontinuation. Based on our experience, prophylactic appetite stimulants and nutritional counseling should be recommended before starting selinexor to prevent treatment discontinuation.…”

Novel acquisitions on biology and management of transformed follicular lymphoma

“…The nucleocytoplasmic transport is a highly regulated and coordinated function and involves different nuclear transport factors or receptors, namely, importins and exportins. The inhibition of nucleocytoplasmic transport is an innovative strategy in the treatment of neoplastic diseases, including those with multiple genomic alterations and resistance mechanisms such as tFL . The role of BCL‐2 gene lesions in tFL also suggests that drugs interfering with the overexpression of the gene may represent a therapeutic option in this setting of patients …”