FDA Approval Sought for Selinexor in DLBCL

Article

An application has been submitted to the FDA for selinexor for the treatment of patients with relapsed/refractory diffuse large B-Cell lymphoma who have received at least 2 prior multiagent therapies and who are ineligible for stem cell transplantation, including CAR T-cell therapy.

Karyopharm Therapeutics Inc., has submitted a new drug application (NDA) to the FDA for selinexor (Xpovio) for the treatment of patients with relapsed/refractory diffuse large B-Cell lymphoma (DLBCL) who have received at least 2 prior multiagent therapies and who are ineligible for stem cell transplantation, including CAR T-cell therapy.1

“Earlier this year we reported compelling results from the phase IIb SADAL study investigating Xpovio in patients with relapsed or refractory DLBCL. The updated results submitted in the NDA demonstrate a 28.3% overall response rate [ORR], including an 11.8% [n = 15] complete response [CR] rate, and a median duration of response of over 9 months,” Sharon Shacham, PhD, MBA, founder, president and chief scientific officer of Karyopharm, said in a press release.

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

Deep and durable responses occurred in patients, regardless of DLBCL subtype. Among the 59 patients with germinal center B-cell (GCB) 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 overall survival (OS) was 9 months. The median OS had not yet been reached among responders.

Cytopenias, as well as gastrointestinal and constitutional symptoms, were the most frequently reported treatment-related adverse events (AEs). The AEs were, for the most part, 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%).

Topline data from the SADAL study were previously presented at the 2018 ASH Annual Meeting. The data presented at ASH showed an ORR of 29.6%, 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 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.

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 GCB 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.

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 duration of response (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 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).

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.

References

  1. Karyopharm Submits New Drug Application to U.S. FDA for XPOVIO® (selinexor) as a Treatment for Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Published December 23, 2019. https://bit.ly/374c4ap. Accessed December 23, 2019.
  2. Karyopharm Reports Updated Data from the Phase 2b SADAL Study at the 2019 International Conference on Malignant Lymphoma. 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.

The updated SADAL data were presented in June at the 2019 &#8239;International Conference on Malignant Lymphoma (ICML).2 The analysis included 127 evaluable patients who had received a median of 2 (range, 1-6) prior treatment regimens. The 28.3% ORR comprised 36 responses, including 13 CRs and 23 PRs (the data submitted in the NDA included an addition 2 CRs). The disease control rate was 37%, including 11 patients with stable disease.

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