FDA Grants Priority Review to Selinexor for Relapsed/Refractory DLBCL

Sharon Shacham, PhD, MBA

The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for selinexor (Xpovio) as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, who have received ≥2 prior therapies.¹

UPDATE 6/22/20: FDA Approves Selinexor for Relapsed/Refractory DLBCL

The application includes updated results from the phase IIb SADAL trial, in which the agent demonstrated a 28.3% overall response rate (ORR), including an 11.8% complete response (CR) rate and a median duration of response (DOR) of over 9 months.²

“We look forward to supporting the FDA through the review process for our second NDA for Xpovio as there remains significant unmet medical need for patients whose DLBCL has relapsed or is refractory to multiple drug therapies,” Sharon Shacham, PhD, MBA, founder, president and chief scientific officer of Karyopharm, the developer of selinexor, stated in a press release. “This regulatory milestone for Xpovio represents another important step towards bringing a novel, oral treatment option with a unique mechanism of action to patients and families in need.”

Under the Prescription Drug User Fee Act, the FDA will make a decision on the sNDA by June 23, 2020. If the agent becomes available for this indication, Karyopharm stated that it plans to commercialize it by mid-2020. Additionally, the company stated that it expects to submit a Marketing Authorization Application to the European Medicines Agency in 2020 for selinexor in the same indication.

Selinexor is an oral selective inhibitor of exportin 1 (XPO1), which is the major nuclear export protein for tumor suppressor proteins and eIF4E-bound oncoprotein RNAs. XPO1 inhibition via selinexor promotes nuclear localization of eIF4E and activation of tumor suppressor proteins relevant to non-Hodgkin lymphoma including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes.

In the open-label, randomized phase IIb SADAL study, investigators are comparing a 60-mg versus 100-mg dose of twice-weekly selinexor monotherapy administered in 28-day cycles in this patient population. Eligible patients received 2 to 5 prior treatment regimens, and those who achieved a CR or a partial response (PR) to prior therapy required an 8-week washout before enrolling into SADAL.

A total of 129 patients were enrolled as of November 15, 2018. Their median age was 67 years (range, 35-87) and the median time from their DLBCL diagnosis was 2.1 years (range, <1-16.2). Patients received a median of 2 prior lines of treatment (range, 1-6), and 31% had prior transplant. Sixty patients had the germinal center B-cell (GCB)&#8239;histology subtype, 63 had non-GCB, and 5 were unclassified.

Patients were evenly split between good prognosis (45%) and poor prognosis (46%) by the Revised-International Prognostic Index (2% were very good and 7% were unknown). One hundred fifteen patients have been evaluated for response.

Initial data were previously presented at the 2018 ASH Annual Meeting, which showed an ORR of 29.6%, along with a CR rate of 9.6%.3 The response rates were 34.0% in patients with the GCB subtype and 21.1% in those with the non-GCB subtype. Median overall survival (OS) was 9.1 months in the modified intent-to-treat (mITT) group, improving to 29.7 months in patients who achieved a CR or PR.

The mITT group included patients who discontinued selinexor due to toxicity or disease progression, or who had died. The mITT population formed the primary analysis population and was used for exploratory analyses of efficacy.

In addition to the 11 patients who achieved CR, 23 (20.0%) achieved PR and 8 (7.0%) had stable disease. Among the 34 responders, the median DOR was 9.2 months (95% CI, 4.9-23.0). The median DOR was 23.0 months (95% CI, 4.9-23.0) among those who achieved CR and 7.8 months in those with PR (95% CI, 2.8-NE).

Seven of the 11 patients who achieved a CR are still on treatment. Forty-six patients with a post-baseline response reading had reductions in tumor burden.

Among patients with the GCB subtype, 5 (9.4%) had a CR, 13 (24.5%) had PR, and 5 (9.4%) had stable disease. Among those with the non-GCB subtype, the corresponding rates were 10.5%, 10.5%, and 5.3%, respectively.

The updated SADAL findings were presented at the 2019 International Conference on Malignant Lymphoma. The analysis included 127 evaluable patients who had received a median of 2 (range, 1-6) prior treatment regimens. Results showed that the 28.3% ORR comprised 36 responses, including 13 CRs and 23 PRs; the data submitted in the NDA included an additional 2 CRs. The disease control rate was 37%, which included 11 patients with stable disease.

Deep and durable responses occurred in patients, regardless of DLBCL subtype. Among the 59 patients with GCB&#8239;histology, the ORR was 33.9%, and in the 63 patients with the non-GCB subtype, the ORR was 20.6%. In the remaining 5 patients, in whom the disease subtype was unclassified, there was 1 CR and 2 PRs. Responses were often rapid, and the median DOR was 9.2 months. Across the overall population, the median OS was 9 months. Among responders, the median OS had not yet been reached.

Regarding safety, cytopenias and gastrointestinal and constitutional symptoms, were the most frequently reported treatment-related adverse events (AEs). For the most part, the AEs were reversible and alleviated with standard supportive care and dose modifications. Common nonhematologic AEs were mostly grade 1/2 and included nausea (52.8%), fatigue (37.8%), and anorexia (34.6%). Grade 3/4 AEs included thrombocytopenia (39.4%), neutropenia (20.5%), and anemia (13.4%).

The most common nonhematologic treatment-related AEs were gastrointestinal and constitutional, and included nausea (50%), fatigue (35.9%), anorexia (32.0%), vomiting (22.7%), diarrhea (21.9%), and weight loss (21.1%). The vast majority of these were grade 1/2. Hematologic treatment-related AEs observed were thrombocytopenia (49.2% total; 35.2% grade 3/4), anemia (28.1% total; 11.0% grade 3/4), and neutropenia (25.8% total; 20.3% grade 3/4).

References

1. U.S. Food and Drug Administration accepts Karyopharm’s supplemental new drug application for Xpovio (selinexor) as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma [news release]: Newton, MA. Karyopharm Therapeutics, Inc. Published February 19, 2020. https://bit.ly/39R5MMW. Accessed February 19, 2020.
2. Karyopharm reports updated data from the phase 2b SADAL study at the 2019 International Conference on Malignant Lymphoma [news release]: Newton, MA. Karyopharm Therapeutics, Inc. Published June 19, 2019. https://bit.ly/2PO7qrc. Accessed December 23, 2019.
3. Maerevoet M, Vermaat J, Canales MA, et al. Single agent oral selinexor demonstrates deep and durable responses in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in both GCB and non-GCB subtypes: the phase 2b SADAL study. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 1677.