Abstract CT132: A Phase 2b randomized study of selinexor in patients with relapsed/refractory Diffuse Large B-Cell Lymphoma (DLBCL) demonstrates durable responses in both GCB & Non-GCB subtypes
Authors: Maerevoet Marie , Westin Jason , Thieblemont Catherine , Zijlstra Josee , Hill Brian T. , Vicente Fatima De La Cruz , Choquet Sylvain , Caimi Paolo , Kaplan Jason , Canales Miguel Albendea , Kuruvilla John , Follows George , Neste Eric Van den , Meade Julie , Wrigley Brendan , Devlin Marissa , Nippgen Conny , Gardner Humphrey , Shacham Sharon , Kauffman Michael G. , Casasnovas Rene-Olivier 
Published: July 2017

Intro: Patients with DLBCL after at least two lines of therapy have limited effective treatments options. The nuclear export protein exportin 1 (XPO1) is upregulated in hematologic malignancies including DLBCL with pleiotropic effects on tumorigenesis such as functional downregulation of tumor suppressor proteins (TSPs) as well as increased export and translation of mRNAs for oncoproteins c-Myc and key survival proteins such as Bcl-2. Selinexor (SEL), an oral XPO1 inhibitor, causes sequestration of TSPs including p53, p21, and IκBα, the latter of which serves to suppress NF-κB driven transcription, along with reductions in c-Myc and Bcl family proteins. SEL has shown activity in canine and rodent models of non-Hodgkin’s lymphoma (NHL), as well as in phase 1 clinical studies including DLBCL. Pts with relapsed/refractory (R/R) DLBCL treated with SEL, had an overall response rate (ORR) of 32% including 4 CRs. Interestingly, 2 of these pts remain in CR for &gt;1 yr. In this clinical study we assess the utility of single agent SEL in pts with R/R DLBCL after ≥2 prior regimens.

Methods: Pts with R/R DLBCL were randomized to 60 or 100 mg of SEL twice weekly (8 doses) per 28-day cycle. Pts were also grouped by DLBCL subtype (GCB or non-GCB). The primary objectives are to determine the ORR, and safety of 60 v 100 mg doses. Disease response was assessed using the Lugano Classification (Cheson, 2014). Pt tissue samples were also collected to evaluate cytogenetics.

Results: In 67 pts (33 pts 60 mg, 34 pts 100 mg) enrolled; the most common related adverse effects (AEs) across both dosing groups (Grade 1/2) were: nausea (46%), anorexia (43%), vomiting (36%), and fatigue (34%). Common Grade 3/4 AEs were: thrombocytopenia (39%), fatigue (18%), neutropenia (16%), and anemia (10%). These were managed with dose interruption/reduction, platelet stimulators, and/or standard supportive care. Grade 3/4 fatigue (13% v 4%) and thrombocytopenia (22% v 16%) were higher in 100 mg arm as compared to the 60 mg arm. Among 65 evaluable pts, the ORR was 21.5%. Responders had a median of 3 prior treatment regimens. 8 pts (12.3%) had a complete response (CR) and 6 pts (9.2%) achieved a partial response. 9 responders, including 7 CR, remain on treatment. Median time on study for CR is 8.8+ mos. ORR by subtype: GCB 23.5%, non-GCB 19.3%. The ORR (26.4%) in the 60 mg arm was higher than 100 mg arm (16.1%), possibly due to better tolerability and less time without drug exposure.

Conclusion: SEL monotherapy shows anti-cancer activity in pts with R/R DLBCL including in pts with GCB subtype. 60 mg SEL twice weekly was more tolerable than 100 mg twice weekly, with less dosing interruptions due to toxicity and a trend towards higher response rates. Objective responses to SEL were durable, suggesting these responses were associated with clinical benefit. Molecular predictors of response are being evaluated.

Citation Format: Marie Maerevoet, Jason Westin, Catherine Thieblemont, Josee Zijlstra, Brian T. Hill, Fatima De La Cruz Vicente, Sylvain Choquet, Paolo Caimi, Jason Kaplan, Miguel Albendea Canales, John Kuruvilla, George Follows, Eric Van den Neste, Julie Meade, Brendan Wrigley, Marissa Devlin, Conny Nippgen, Humphrey Gardner, Sharon Shacham, Michael G. Kauffman, Rene-Olivier Casasnovas. A Phase 2b randomized study of selinexor in patients with relapsed/refractory Diffuse Large B-Cell Lymphoma (DLBCL) demonstrates durable responses in both GCB & Non-GCB subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT132. doi:10.1158/1538-7445.AM2017-CT132