FDA Approves Selinexor for R/R Diffuse Large B-Cell Lymphoma

The FDA has granted an accelerated approval for selinexor (Xpovio) for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), not otherwise specified, who have received at least 2 prior systemic treatments.¹ The indication includes patients with DLBCL that is arising from follicular lymphoma. 

Selinexor is now the only single-agent, oral therapy approved for the treatment of patients with R/R DLBCL, and the only nuclear export inhibitor approved by the FDA for use in 2 hematologic malignancies, multiple myeloma and DLBCL, according to a press release from Karyopharm.

“We have a drug with a very novel mechanism of action. That is something that we can give to patients who have already been through 2 lines of chemotherapy regimen and have the hope that they can respond to this drug with a novel mechanism of action. And if they do respond, that response has a significant duration, and because it's an oral drug, it's something that they can take at home rather than come into the hospital for intravenous chemotherapy,” Michael W. Schuster, MD, director of the Bone Marrow Transplant Program at Stony Brook Cancer Center, told Targeted Oncology in an interview.

Approval for the first-in-class, oral selective inhibitor of nuclear export for the DLBCL indication was based on findings from the phase 2b SADAL trial.

The overall response rate (ORR) was 29%, which consisted of complete responses in 13% and partial responses in 16%. 

According to findings previously presented at the 2019 International Conference on Malignant Lymphoma (ICML), the ORR by independent central radiological review was 28.3%, consisting of 13 complete responses and 23 partial responses. The total disease control rate was 37.0%.² 

Among patients with germinal center B-cell (GCB) disease, the ORR was 33.9% compared with 20.6% for patients with non-GCB subtypes. The median time to response was 1.8 months (range, 1.5-6.4). The overall median duration of response (DOR) was 9.2 months (95% CI, 4.8-23.0) and was 13.5 months (95% CI, 9.3-23.0) in patients who achieved a complete response. 

After a median follow-up of 11 months, the median overall survival (OS) was 9.0 months (95% CI, 6.2-13.7) for the overall population. Among patients who achieved a partial response or better, the median OS had not yet been reached compared with 4.1 months in patients with disease progression or no response to treatment (P <.0001). In patients who had stable disease, the median OS was 18.3 months (95% CI, 11.1-28.0). 

SADAL is a multicenter, open-label phase 2b study that explored the use of selinexor in patients with R/R DLBCL who have no therapeutic options (NCT02227251). 

The study enrolled 134 patients with pathologically confirmed de novo DLBCL who had received 2 to 5 prior systemic therapies and had an ECOG performance status of 0 to 2. Patients who had achieved a complete or partial response from their last treatment were able to start on the trail sooner than others. Prior stem cell transplant was allowed.

Exclusion criteria for the trial included mucosa-associated lymphoid tissue lymphoma, composite lymphoma, or DLBCL transformed from diseases other than indolent non-Hodgkin lymphoma; ineligibility for high-dose therapy with autologous stem cell transplant; primary mediastinal large B-cell lymphoma; known central nervous system lymphoma; and active Hepatitis B or C infection or HIV.

Patients received a mixed dose of 60 mg of oral selinexor twice weekly on days 1 and 3 each week of the 28-day cycle. The primary end point was ORR and secondary endpoints included DOR and safety.

A total of 129 patients were enrolled in the study and 59% were male. The median age was 67 years and the median number of prior therapies was 2 (range, 1-6), including 31% who had previously undergone stem cell transplant. Fifty-nine patients had the GCB subtype. Two patients were excluded from the analysis as they did not meet the eligibility criteria. 

The most common treatment-related adverse events (AEs) were cytopenias and gastrointestinal/constitutional symptoms; these events were generally reversible and managed with dose modifications and/or standard supportive care. 

The most common non-hematologic AEs were nausea (52.8%), fatigue (37.8%), and anorexia (34.6%) and were mostly grade 1 or 2. Frequent grade 3/4 AEs included thrombocytopenia (39.4%), neutropenia (20.5%), and anemia (13.4%).

No treatment-related grade 5 AEs were reported in the overall study population.

“For most of the patients with relapsed, large cell lymphoma who either have failed an autologous transplant or who are not eligible for autologous stem cell transplant, the options for those patients are limited. Especially patients were older, especially patients were unfit, especially patients who have other comorbidities. This is yet another option that we now have for treating those patients,” Schuster added. 

The FDA has agreed to use the XPORT-DLBCL-030 study as the confirmatory trial for selinexor for the DLBCL indication. The trial, which is expected to open by the end of the year, according to Karyopharm, will assess the use of selinexor versus placebo plus a standard backbone immunochemotherapy of rituximab (Rituxan), gemcitabine, dexamethasone, and platinum in patients with DLBCL who have received 1 to 3 prior treatments.¹

Selinexor previously received a fast track designation from the FDA for the treatment of patients with R/R DLBCL. 

The nuclear export inhibitor is also FDA approved in combination with dexamethasone for the treatment of adult patients with R/R multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody. 

_References:

_{1. Karyopharm Announces FDA Approval of XPOVIO® (selinexor) for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL). News release. Karyopharm. June 22, 2020. Accessed June 22, 2020. https://bit.ly/37PV21r}

_{2. Kalakonda N, Cavallo F, Follows G, et al. A phase 2b study of selinexor in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (dlbcl). Hematol Oncol. 2019;37(S2). doi:10.1002/hon.31_2629}