A PHASE 2B RANDOMIZED STUDY OF SINGLE AGENT S ELINEXOR IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B ‐CELL LYMPHOMA ( DLBCL )

Abstract

Introduction: Patients (pts) with persistent DLBCL after two lines of therapy have limited effective treatment options. The nuclear export protein exportin 1 (XPO1) is upregulated in hematologic malignancies, including DLBCL. Selinexor (SEL), an oral XPO1 inhibitor, causes sequestration of tumor suppressor proteins including p53, p21, and IkBa, the latter of which serves to suppress NF‐kB‐driven transcription, along with reductions in c‐Myc and Bcl family proteins. In a phase I clinical study pts with relapsed/refractory (R/R) DLBCL treated with SEL, an overall response rate (ORR) of 32% including 4 CRs was shown. 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 stratified 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 by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014). Pt tissue samples were also collected to evaluate cytogenetics. Results: 72 pts were enrolled: 37 pts on 60 mg and 35 pts on 100 mg. Both groups had a median of 3 prior treatment regimens. The most common related Grade 1/2 adverse effects (AEs) were fatigue (47%), nausea (46%), anorexia (42%), and vomiting (33%). Common Grade 3/4 AEs were thrombocytopenia (39%), fatigue (18%), neutropenia (18%), and anemia (13%). They were managed with dose interruption/ reduction, platelet stimulators, and/or standard supportive care. Grade 3/4 fatigue (26% v 11%) and thrombocytopenia (46% v 32%) were higher in 100 mg arm as compared to the 60 mg arm. Among the 63 evaluable pts, the ICRR determined ORR was 28.5% (Table ). Nine responders, including 6 CR, remain on treatment. Responders on the 60 mg arm have a median time on treatment of 8.9 months as compared to 3.8 months on the 100 mg arm. Evaluation of molecular predictors of response is currently ongoing including investigation of translocations in c‐Myc and Bcl proteins as well as targeted sequencing for alterations in genes commonly mutated in B‐cell malignancies. Conclusion: SEL monotherapy shows 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 fewer dosing interruptions due to toxicity. Objective responses to SEL were durable at 60 mg BIW, suggesting these responses were associated with clinical benefit. Molecular predictors of response are being evaluated.