Karyopharm Therapeutics, a partner of Antengene, recently announced that the U.S. Food and Drug Administration (FDA) has approved Xpovio (selinexor) for a second oncology indication: the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including DLCBL caused by follicular lymphoma (FL), who have received at least two prior lines of systemic therapy.
This approval was granted through the FDA's accelerated approval process based on response rate data. Continued approval for this indication may depend on the validation and description of clinical benefit in confirmatory trials. Karyopharm also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in 2021 for Xpovio in the treatment of relapsed or refractory DLBCL.
This DBLCL indication is based on positive results from the multicenter, single-arm phase IIb SADAL study. This study was conducted in 134 patients with relapsed or refractory DLBCL who had previously received a median of two systemic therapies (range: 1–5). Patients received a fixed dose of Xpovio 60 mg twice daily for four weeks per cycle. Patients with germinal center B-cell (GCB) or non-GCB subtypes of DLBCL were also included.
Data showed that Xpovio treatment achieved an overall response rate (ORR) of 29%, a complete response rate (CR) of 13%, and a partial response rate (PR) of 16%. Among patients who achieved remission, the median duration of response (DOR) was longer than 9 months, with 56% of patients achieving a DOR ≥ 3 months, 38% ≥ 6 months, and 15% ≥ 12 months. These data highlight the potential of Xpovio as a novel, first-in-class oral therapy in a population of relapsed or refractory DLBCL patients who have previously received at least two multi-drug regimens, are ineligible for stem cell transplantation, and have extremely limited treatment options.
Xpovio is the only first-in-class selective nuclear export inhibitor (SINE) approved by the FDA. It works by binding to and inhibiting the nuclear export protein XPO1 (also known as CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This restarts and amplifies their tumor-suppressive functions, causing selective apoptosis of cancer cells without significantly affecting normal cells. In August 2018, Antengene and Karyopharm Therapeutics entered into a strategic collaboration to jointly develop four oral innovative drugs, including three SINE XPO1 antagonists: Xpovio (selinexor), eltanexor, and verdinexor, and one PAK4 and NAMPT dual-target inhibitor, KPT-9274. In January 2019, ATG-010 (Xpovio) received clinical trial approval in China for the treatment of refractory and relapsed multiple myeloma. This drug is also the first selective nuclear export inhibitor (SINE) developed for multiple myeloma in the Chinese market. Furthermore, Xpovio is the first approved drug targeting a novel myeloma target (XPO1) since 2015. In July 2019, Xpovio received accelerated approval from the U.S. FDA for use in combination with dexamethasone for patients with relapsed/refractory multiple myeloma (RRMM) who have received at least four prior lines of therapy and are refractory to at least two proteasome inhibitors (PIs), at least two immunosuppressants (IMiDs), and one anti-CD38 monoclonal antibody.
In May of this year, Karyopharm submitted a supplemental New Drug Application (sNDA) to the U.S. FDA for Xpovio, seeking approval as a novel therapy for patients with multiple myeloma (MM) who have received at least one prior line of therapy.
This sNDA is based on positive topline results from the Phase III BOSTON study. This study evaluated the efficacy and safety of once-weekly Xpovio combined with once-weekly Velcade (bortezomib) and low-dose dexamethasone (SVd) and twice-weekly Velcade combined with low-dose dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (MM) who had previously received 1-3 lines of therapy. Vd is a standard treatment for MM.
Results showed that the study met its primary endpoint: compared with the Vd group, the SVd group had a 47% increase in progression-free survival (PFS) of 4.47 months (median PFS: 13.93 months vs 9.46 months), and a significant 30% reduction in the risk of disease progression or death (HR=0.70, p=0.0066). Previously, the SVd group had also shown a significant improvement in overall response rate (ORR) compared to the Vd group. No new safety signals were observed in the SVd group in this study, and there was no imbalance in mortality between the two groups.
If approved, Xpovio will provide an important addition to the treatment modality for patients with relapsed or refractory MM. Currently, Karyopharm is evaluating the potential of selinexor in multiple mid-to-late stage clinical trials for a range of hematologic malignancies and solid tumors, including multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), liposarcoma (SEAL study), endometrial cancer, and relapsed glioblastoma.
Further Reading:
Xpovio is currently the only approved single-agent oral therapy for the treatment of relapsed or refractory DLBCL. Previously, the FDA granted Xpovio Orphan Drug Designation and Fast Track Designation for this indication. Furthermore, Xpovio is the first and only FDA-approved drug for the simultaneous use of myeloma and DLBCL.
