Oral selinexor proves to be safe and effective in patients with primary refractory diffuse large B-cell lymphoma

In a post-hoc analysis of the SADAL study, monotherapy with oral selinexor was found to be associated with an objective response rate (ORR) of 25.4% in heavily pretreated patients with primary refractory diffuse large B-cell lymphoma (DLBCL). Interestingly, 10% of patients even obtained a complete response (CR) to this treatment. In addition to this, safety data in the subgroup of patients with primary refractory disease revealed a comparable toxicity profile as what was observed in the overall SADAL trial population. As patients with primary refractory disease who progress after two or more prior lines of treatment face an extremely poor outcome, treatment with selinexor could provide benefit to this subgroup of patients.

Background

Patients with primary refractory DLBCL who progress after two or more prior lines of therapy face an extremely poor outcome. As such, a critical unmet need exists for the development of new treatment strategies for these patients. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that can selectively bind and inactive exportin 1 (XPO1). In doing so, selinexor induces nuclear accumulation and activation of tumour suppressor proteins and reductions in Bcl2, Bcl-XL and c-Myc oncoprotein levels.

SADAL is a multicentre, open-label, phase IIb study in relapsed/refractory (R/R) DLBCL patients (N=134) who were previously treated with 2-5 lines of prior therapy. The study cohort included both patients who progressed after high dose chemotherapy and an autologous stem cell transplantation (ASCT) and patients who were not a candidate for ASCT. A 60-day window was required for patients who relapsed after achieving a complete response (CR) or partial response (PR) to their prior treatment line. Selinexor (60 mg) was administered orally on days 1 and 3 of each week until disease progression or unacceptable toxicity. Patients were stratified by subtype (germinal centre B-cell [GCB] or non-GCB).

Results

In previous presentations on the SADAL trial, an ORR of 29.1% was reported with a median duration of response (DoR) of 9.3 months and a median overall survival (OS) of 9 months. During the 2020 EHA meeting, Zijlstra et al. presented the results of post-hoc analysis of this trial specifically looking into the efficacy and safety of selinexor in patients with primary refractory disease (N=71, 52%). For this analysis, primary refractoriness was defined as patients who progressed during or within one year of their first-line systemic treatment for DLBCL. Of these primary refractory patients, 30 were classified to the GCB subtype, 37 to the non-GCB subtype and 4 patients remained unclassified.

Median age of the study participants was 65 years with a third of them being older than 70 years. The median number of prior regimens was two with 39.4% of patients having received two or more prior treatment lines. Overall, 23.9% of patients previously underwent an ASCT. Most patients had de novo disease (80.3%). In total, 18 patients with primary refractory disease (25.4%) obtained an objective response, with 7 of them (10%) experiencing a CR. The median DoR was reported at 4.8 months with a median OS of 7.8 months. The ORR was 30.0% among GCB patients and 16.2% among non-GCB patients. In patients who achieved a CR, the median DoR was 10.4 months, while the median OS was not yet reached in this subgroup of patients.

The most frequently reported grade ≥3 treatment-related adverse events (TRAEs) in primary refractory patients included: thrombocytopenia (39.4%), neutropenia (29.6%) anaemia (15.5%), fatigue (11.3%), hyponatremia (8.5%), leukopenia (8.5%) and nausea (5.6%). Of note, these frequencies are similar to what was reported for the overall SADAL population. Serious adverse events occurred in 18.3% of the primary refractory DLBCL patients, as compared to 20.9% of the patients in the overall population.

Conclusions

In patients with primary refractory DLBCL (i.e. progression on or within one year of initial therapy) who were pre-treated with at least two prior regimens, oral selinexor monotherapy induced an ORR of 25.4% with a complete response rate of 10%. Responses were observed in both GCB and non-GCB DLBCL patients. In addition, the safety of selinexor in the primary refractory group was comparable to that observed in the overall SADAL population. These findings suggest that selinexor could provide benefits beyond standard combination therapies for patients with DLBCL who have a suboptimal response to their frontline regimens.