On November 20, 2020 Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported it will present positive results from the Phase 3 portion of the randomized, double blind, placebo controlled, cross-over SEAL study evaluating single agent, oral XPOVIO (selinexor) versus matching placebo in patients with liposarcoma at the Connective Tissue Oncology Society 2020 Annual Meeting (CTOS 2020) (Press release, Karyopharm, NOV 20, 2020, View Source [SID1234571490]). As previously reported, the SEAL study met its primary endpoint of a statistically significant increase in median progression-free survival (PFS) in patients with advanced unresectable dedifferentiated liposarcoma following at least two prior therapies.
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"Dedifferentiated liposarcoma is a particularly aggressive cancer that arises in the body’s fat tissue and is typically associated with high rates of metastatic recurrence and mortality. Unfortunately, there are few effective treatment options available for patients with advanced disease," said Mrinal M. Gounder, MD, Attending Physician, Sarcoma Service and Developmental Therapeutics Service, Memorial Sloan Kettering Cancer Center, and lead investigator of the SEAL study. "The data presented at CTOS 2020 demonstrated that patients treated with XPOVIO experienced a statistically significant improvement in median PFS compared to placebo in patients with at least two prior therapies. Extending PFS is an important clinical goal for these patients because the rapid progression of this disease often translates into early mortality."
"We are delighted to share these significant results from the Phase 3 portion of the SEAL study, the first, late-stage clinical data for XPOVIO in a solid tumor indication," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "We believe these data strongly support our goal of developing twice-weekly XPOVIO as an effective, convenient, novel oral therapy that can extend PFS for patients with advanced unresectable dedifferentiated liposarcoma. We are especially excited by these data because XPOVIO is the first oral therapy to show activity in patients with previously treated liposarcoma. We look forward to submitting a New Drug Application to the U.S. Food and Drug Administration (FDA) during the first quarter of 2021, requesting approval of XPOVIO to treat the patient population studied in SEAL. If approved, XPOVIO would represent the first oral, non-chemotherapy agent available for patients with dedifferentiated liposarcoma."
Results from the Phase 3 Portion of the Phase2/3 SEAL Study
The median PFS in the XPOVIO arm of the Phase 3 portion of the SEAL study was 2.83 months compared to 2.07 months in the placebo arm (hazard ratio (HR)=0.70; p=0.023). These data indicate that treatment with XPOVIO reduced the risk of disease progression or death by approximately 30%, compared to placebo. The estimated 6-month PFS survival probability was 23.9% on the selinexor arm compared to 13.9% on placebo. Additionally, the 12-month PFS survival probability was 8.4% on the selinexor arm compared to 2% on the placebo arm. Finally, 7.5% of patients on the selinexor arm had a 15% or greater reduction in their disease burden as measured by target lesion size while none of the patients on the placebo arm achieved this level of reduction. The trial allowed patients on placebo with objective progression to cross over to the XPOVIO treatment arm. The median overall survival for patients who received XPOVIO was 9.99 months compared to 9.07 months for patients who never crossed over to the XPOVIO treatment arm (HR=0.69; p=0.122).
The most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from other selinexor studies. Most AEs were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (81%), decreased appetite (60%), fatigue (51%), and vomiting (49%) and were mostly Grade 1 and 2 events. The most common Grade 3 and 4 treatment-related AEs were anemia (19%), hyponatremia (11%), thrombocytopenia (10%) and asthenia (10%).
XPOVIO is currently approved by the FDA as a treatment for patients with relapsed or refractory multiple myeloma and relapsed or refractory diffuse large B-cell lymphoma (DLBCL). XPOVIO is currently the only XPO1 inhibitor approved by the FDA and has been extensively tested in clinical trials across numerous cancer indications worldwide since 2012. Karyopharm has also submitted a supplemental New Drug Application (sNDA) for XPOVIO that is currently under review by the FDA for the expansion of XPOVIO’s label to include XPOVIO as a treatment for patients with multiple myeloma after at least one prior line of therapy. The sNDA has been assigned an action date by the FDA of March 19, 2021 under the Prescription Drug User Fee Act. The full Prescribing Information for XPOVIO is available at www.XPOVIO.com.
Details for the oral presentation at CTOS 2020 are as follows:
Title: A Phase 2/3, Randomized, Double-Blind, Cross-Over Study of Selinexor Versus Placebo in Advanced Unresectable Dedifferentiated Liposarcoma (DDLS)
Presenter: Mrinal Gounder, MD, Memorial Sloan Kettering Cancer Center
Paper #: 20
Session: 7. Liposarcoma
Date and Time: Friday, November 20, 2020, 10:30 a.m. to 11:30 a.m. ET
Conference Call Information
Karyopharm will host a conference call today, Friday, November 20, 2020, at 12:00 p.m. Eastern Time, to discuss the results from the SEAL study. The call will feature Dr. Gounder and another recognized sarcoma expert Sant P. Chawla, MD, FRACP, Director of the Sarcoma Oncology Center, Santa Monica, CA, along with members of the Karyopharm executive leadership team. To access the conference call, please dial (877) 870-4263 (local) or (412) 317-0790 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with slides, will be available under "Events & Presentations" in the Investor section of the Company’s website, View Source An archived webcast will be available on the Company’s website approximately two hours after the event.
About the SEAL Study
SEAL (Selinexor in Advanced Liposarcoma) is a Phase 2/3, randomized, double blind, placebo controlled, multicenter study (NCT02606461) designed to evaluate the efficacy and safety of twice-weekly, 60mg fixed dose of XPOVIO (selinexor) in patients with advanced unresectable dedifferentiated liposarcoma following at least two prior therapies. The Phase 2 portion of the study enrolled approximately 57 patients (1:1 randomization) and the Phase 3 portion enrolled approximately 285 patients (2:1 randomization). Patients on the placebo arm with confirmed progressive disease were permitted to cross over to the XPOVIO treatment arm. The primary endpoint of the study is PFS.
About Liposarcoma
Liposarcoma is a rare type of cancer that occurs in the fat cells in the body, most often in the muscles of the limbs or abdomen. Dedifferentiated liposarcoma (DDLS) is a high grade type of liposarcoma that grows more aggressively than a low grade, well differentiated liposarcoma and is associated with poorer prognosis.1 Liposarcoma accounts for approximately 20% of all soft tissue sarcomas2. In liposarcoma, the risk of recurrence and metastasis increases with higher grade disease.3
About XPOVIO (selinexor)
XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor in this same RRMM indication. Karyopharm’s supplemental New Drug Application (sNDA) requesting an expansion of its current indication to include the treatment for patients with multiple myeloma after at least one prior line of therapy has been accepted for filing by the FDA. In June 2020, Karyopharm received accelerated FDA approval of XPOVIO for its second indication in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including as a potential backbone therapy in combination with approved myeloma therapies (STOMP), in liposarcoma (SEAL) and 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.