The heterogeneity of the various subtypes of non-Hodgkin lymphomas (NHLs) necessitates the development of specific therapies that address fundamental mechanisms that are dysregulated in these cancers. One such viable therapeutic target is tumor suppressor proteins, nearly all of which are exported from the nucleus to the cytoplasm by Exportin 1 (XPO1).
A phase I study published in Blood evaluated the safety and efficacy of selinexor, an orally bioavailable, first-in-class XPO1 inhibitor, in patients with relapsed/refractory NHL or chronic lymphocytic leukemia (CLL). Investigators found that selinexor was associated with an “encouraging” objective response rate across various NHL subtypes, but also with a high rate of withdrawal due to adverse events (AEs).
“We are finally starting to see the development of a new generation of therapies in aggressive NHL,” lead author John Kuruvilla, MD, from the Division of Medical Oncology and Hematology at the Princess Margaret Cancer Centre and the University of Toronto in Canada, told ASH Clinical News. “There is more work to be done, but we have an active new agent that will hopefully be integrated into the standard of care for patients with NHL.”
The multicenter, dose-escalation study was conducted at 12 sites in the United States, Canada, and Denmark, and it enrolled 79 heavily pretreated adult patients (median age = 64 years; range = 30-82 years; median number of prior therapies = 4; range = 1-12 therapies) between July 2012 and December 2014. Patients were included if they had relapsed or refractory disease and adequate hematologic and cardiovascular function. “This early-phase study had inclusion criteria that allowed clinicians to recruit sick patients with poor blood counts who typically would be excluded from clinical trials,” Dr. Kuruvilla explained.
Patients who had received any form of anti-cancer therapy within 2 weeks prior to treatment cycle 1 or had active graft-versus-host disease after allogeneic hematopoietic cell transplantation were excluded.
During the dose-escalation phase, 47 patients (40 with NHL and 7 with CLL) received selinexor at 13 dose levels, ranging from 3 to 80 mg/m2 doses in 3- or 4-week cycles. As the maximum tolerated dose was not reached, and based on preclinical toxicology studies, investigators used 35 mg/m2 or 60 mg/m2 doses to assess the safety, tolerability, and efficacy of selinexor in the dose-expansion phase, which included 32 patients (28 with diffuse large B-cell lymphoma [DLBCL], 3 with Richter’s transformation, and 1 with follicular lymphoma grade 3b).
The median treatment duration was 49 days (range = 4-1,071 days), with 18 percent of patients continuing treatment for more than 6 months and 8 percent continuing for more than 1 year. In the dose-expansion cohorts, the median durations of therapy were 66 days for the 35 mg/m2 dose (range = 23-602 days) and 32 days for the 60 mg/m2 dose (range = 11-314 days; p values not provided).
For the 70 patients who were evaluable for response, treatment with selinexor led to an objective response rate (ORR) of 31 percent (n=22), including four complete responses (CRs; 6%) and 18 partial responses (PRs; 26%).
The most common non-hematologic AEs were nausea (66%), fatigue (61%), anorexia (57%), vomiting (37%), and diarrhea (34%), and the most common grade 3/4 hematologic AEs were thrombocytopenia (47%), neutropenia (32%), and anemia (27%). Fifty serious AEs were reported, 11 of which were deemed treatment-related and occurred at selinexor doses of 30-70 mg/m2.
“Grade 3 or 4 AEs were largely hematologic in nature,” the authors wrote, adding, “Given the permissive inclusion criteria of the study, many patients presented at baseline with significant cytopenias, and therefore high incidences of grade 3 or 4 hematologic toxicities are expected in this patient population.”
Twelve patients required dose reductions from a median of 35 mg/m2 (range = 30-70 mg/m2) to 23 mg/m2 (range = 20-60 mg/m2). Twenty-eight patients withdrew from the study, 15 because of incidence or severity of AEs. The 35 mg/m2 dose was further identified as the recommended phase II dose.
Of the 79 enrolled patients, nine were not evaluable for response because of withdrawal from the study (n=6), death unrelated to selinexor (n=2), or inadequate baseline imaging (n=1). Nearly one-third of patients (30%; n=21) had stable disease, which was sustained for more than 4 months in five patients, for a disease control rate (DCR) of 61 percent.
In the 41 evaluable patients with DLBCL (the most common NHL subtype in the study population), the ORR was 32 percent, including four CRs and nine PRs, and the DCR was 51 percent.
“Compared with other targeted therapies studied across a spectrum of relapsed/refractory NHL, selinexor showed comparable or favorable response rates with durable clinical benefit [median duration of response >7 months],” the authors concluded. “Selinexor for the treatment of patients with DLBCL warrants further development, as this is the most common NHL in the Western world and is a high unmet medical need population given the inferior overall survival of patients who fail primary rituximab-based therapy.”
The study is limited by its small patient population and non-comparative design. “Selinexor will undergo further testing to determine the optimal dose as a single agent, to better understand toxicities at this dose and optimized schedule, and to identify biomarkers of response and resistance,” Dr. Kuruvilla added.
Kuruvilla J, Savona M, Baz R, et al. Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin’s lymphoma. Blood. 2017 May 3. [Epub ahead of print]