On June 19, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported updated results from the Phase 2b SADAL (Selinexor Against Diffuse Aggressive Lymphoma) study evaluating selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue and CAR-T (chimeric antigen receptor modified T cell) therapy (Press release, Karyopharm, JUN 19, 2019, View Source [SID1234537162]). The data were highlighted in an oral presentation at the 2019 International Conference on Malignant Lymphoma (ICML) being held June 18-22, 2019, in Lugano, Switzerland.
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Top-line results for the SADAL study were previously presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting in December 2018. The results being presented at ICML remain consistent with those reported at ASH (Free ASH Whitepaper) and include efficacy results from the final 12 patients who had not reached their first response assessment in time to be included in the previously released top-line efficacy analyses. For the SADAL study’s primary endpoint, single-agent selinexor achieved an overall response rate (ORR) of 28.3%. Two additional patients achieved a complete response (CR) since the ASH (Free ASH Whitepaper) presentation for a total of 13 CRs and a CR rate of 10.2% in these patients with heavily pretreated relapsed or refractory DLBCL. Key secondary endpoints included a median duration of response (DOR) in the responding patients of 9.2 months and median overall survival (OS) across the entire study population of 9.0 months.
"Single-agent oral selinexor continues to demonstrate encouraging response rates in these heavily pretreated patients with DLBCL who have received two or more prior therapies and are not eligible for transplantation or CAR-T therapy, and have limited therapies available to treat their disease," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "We look forward to sharing these data with the U.S. and European regulatory authorities and plan to seek regulatory approval of selinexor as a potential new therapeutic option for patients battling highly refractory DLBCL."
Karyopharm expects to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in the first half of 2020. These submissions will include requests for accelerated approval and conditional approval, respectively, of selinexor as a treatment for patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for stem cell transplantation, including CAR-T therapies. In addition to Orphan Drug Designation, selinexor was granted Fast Track designation by the FDA in 2018 for the patient population evaluated in the SADAL study.
Updated Phase 2b SADAL Results
Among the 127 patients (median of 2 prior treatment regimens with a range 1-6) who were evaluable for response, as adjudicated by an independent central radiological committee, 36 patients responded (13 CRs and 23 partial responses (PRs)) for an ORR of 28.3%. An additional 11 patients experienced stable disease (SD) for a disease control rate of 37.0%. Selinexor also demonstrated deep and durable responses in patients with either GCB or non-GCB subtypes of DLBCL: the ORR in the 59 patients with the GCB-subtype was 33.9% and the ORR was 20.6% in the 63 patients with the non-GCB subtype. In addition, there were 5 patients enrolled whose subtype was unclassified and 1 of these patients achieved a CR while 2 of these patients achieved a PR.
The median DOR across responding patients was 9.2 months and responses tended to occur rapidly. Median OS for the entire patient population was 9.0 months while median OS has not yet been reached in patients who achieved either a CR or PR. Patients whose disease progressed or had no response to selinexor had a median OS of 4.1 months, which is consistent with the expected poor prognosis for patients who have relapsed or refractory DLBCL and have been previously treated with 2 or more lines of therapy.
All 127 patients were included in the safety analyses. The most common treatment-related adverse events (AEs) were cytopenias along with gastrointestinal and constitutional symptoms and 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 and 2 events. As expected, the most common Grade 3 and 4 AEs were thrombocytopenia (39.4%), neutropenia (20.5%) and anemia (13.4%) and were generally not associated with clinical sequelae.
Details for the ICML 2019 oral presentation are as follows:
Title: A Phase 2b Study of Selinexor in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): SADAL Trial
Lead author:Nagesh Kalakonda, University of Liverpool
Abstract #: 031
Session: Focus On: Results from Single-Agent Trials
Date and Time:Wednesday, June 19, 2019; 17:25 – 17:45 CEST
Location: Auditorium (USI Università)
About Selinexor
Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple class refractory multiple myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm’s New Drug Application (NDA) seeking accelerated approval has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients based on data from the STORM study. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.