Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Abstract

Background Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. Methods SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling).

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53

“…2 a). ABC-DLBCL and GCB-DLBCL cells were similarly vulnerable to selinexor (Additional file 1 : Figure S1E), consistent with results in the SADAL clinical trial [ 3 ]. Biomarkers significantly associated with higher sensitivity (lower IC50) to selinexor cytotoxicity included BCL2 -R and HGBCL-DH (Fig.…”

“…Targeting XPO1 is a promising therapeutic approach in cancer [ 1 , 2 ]. The XPO1 inhibitor selinexor has received FDA approval recently to treat refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) after at least 2 lines of systemic therapy, showing an overall response rate of 28% in the SADAL trial [ 3 ]. However, it remains largely unknown whether and how XPO1 interplays with other adverse predictors in DLBCL, how to predict selinexor effectiveness, and what combination therapy is optimal in R/R DLBCL patients.…”

“…Previous studies showed the synergy between selinexor and venetoclax in DLBCL and double-hit lymphoma [ 10 , 11 ]. However, in the SADAL trial [ 3 ], patients with MYC high (but not BCL2 high ) expression had a lower overall response rate than those without. MYC expression can be inhibited by targeting the bromodomain and extra-terminal domain (BET) proteins [ 12 ].…”

New agents and regimens for diffuse large B cell lymphoma

“…The most well-known SINE inhibitor is selinexor (KPT-330, XPOVIO), which is a first-in-class, investigational oral therapeutic that selectively blocks exportin 1 (XPO1) and leads to reductions in MYC and BCL2 oncogenes (Fig. 4 ) [ 126 ]. Selinexor has demonstrated notable efficacy in the open-label SADAL phase IIb study [ 126 ] and received final approval from FDA for the treatment of patients with r/r DLBCL after at least 2 lines of systemic therapy in June 2020.…”

“…4 ) [ 126 ]. Selinexor has demonstrated notable efficacy in the open-label SADAL phase IIb study [ 126 ] and received final approval from FDA for the treatment of patients with r/r DLBCL after at least 2 lines of systemic therapy in June 2020. Among this SADAL population of 127 patients, selinexor produced an ORR of 28% and CR of 12%, with a median DoR of 9.3 months.…”