Effect of Age on the Efficacy and Safety of Single Agent Oral Selinexor in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Pivotal Study

Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population.

Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients <65 versus those ≥65 years old.

Results: Of the 134 patients enrolled in the study, 52 (39%) were <65 and 82 (61%) were ≥65 years old. In the <65 group, 14% patients had baseline creatine clearance (CrCl) of 30-<60 mL/min compared with 33% in ≥65 group. Patients with transformed DLBCL accounted for 17% and 27% of patients in the <65 and ≥65 groups, respectively. Subtype analysis revealed 43% GCB and 55% non-GCB DLBCL in ≥65 year olds, and 54% GCB and 40% non-GCB in the <65 group. The <65 group had baseline ECOG performance status of 2 in 8% compared with 13% in the ≥65 group. Patients < 65 received numerically higher median doses of selinexor (1360 and 770 mg [p=0.079]) and a longer duration of treatment (13.5 vs. 8.0 weeks [p=0.049]). There was no statistical difference in ORR in patients <65 vs. ≥65 years old: 36.5% vs. 24.4% (p=0.189). The complete response (CR) rates were 17.3% and 11% (p=0.431), respectively. Median DORs were similar at 9.7 months in the <65 compared to 9.2 months in the ≥65 year olds. While the median progression-free survival (PFS) (3.6 and 2.3 months) was similar between groups, the OS was higher in the <65 year olds: 13.7 vs. 7.8 months (p=0.037). The incidence of treatment-related AEs was comparable between both groups: The most common grade ≥3 AEs in <65 versus ≥65 year olds were thrombocytopenia (42.3% vs. 39.0%), nausea (3.8% vs. 7.3%), and fatigue (5.8% vs. 13.4%). Treatment-related serious AEs occurred in 11.5% of patients <65 (n=6) and 26.8% ≥65 (n=22), with general disorders and administration site conditions (n=12) and fatigue (n=6) as the largest contributors in the ≥65 group. Treatment discontinuations due to AEs occurred at a lower incidence in the <65 group compared with >65 (3.8% vs. 11.0%).

Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those <65 when treated with selinexor, with comparable ORR, CR, PFS, DOR, and safety profile. As expected, younger patients (<65 years old) had a longer overall survival than those ≥65 years old, most likely due to comorbid medical conditions in the patients ≥65 years. These results indicate that selinexor can induce durable responses in younger and older patients with heavily pretreated DLBCL with similar tolerability.