Selinexor demonstrated a statistically significant improvement in progression-free survival compared with matching placebo in patients with advanced unresectable dedifferentiated liposarcoma, following at least 2 prior treatments.
Selinexor (Xpovio) demonstrated a statistically significant improvement in progression-free survival (PFS) compared with matching placebo in patients with advanced unresectable dedifferentiated liposarcoma, following at least 2 prior treatments, according to results of the phase 3 portion of the SEAL trial (NCT02606461) that were presented at the CTOS 2020 Annual Meeting.
Findings showed that the median PFS was 2.83 months with selinexor compared with 2.07 months in the placebo arm, leading to a 30% reduction in the risk of disease progression or death (HR; 0.70; P = .023). Additionally, the 6- and 12-month PFS rates were 23.9% and 8.4% with selinexor compared with 13.9% and 2% with placebo.
"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 lead study investigator Mrinal M. Gounder, MD, attending physician, Sarcoma Service and Developmental Therapeutics Service, of Memorial Sloan Kettering Cancer Center. "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 2 prior therapies. Extending PFS is an important clinical goal for these patients because the rapid progression of this disease often translates into early mortality."
In the double-blind, placebo controlled, cross-over SEAL study, investigators evaluated oral selinexor versus matching placebo in 342 patients with advanced unresectable dedifferentiated liposarcoma following at least 2 prior therapies.
To be eligible for enrollment, patients must have been at least 12 years old along with a body surface area of at least 1.2/m2, histologic evidence of dedifferentiated liposarcoma at any time prior to randomization and current evidence of disease requiring therapy, measurable disease per RECIST v1.1 response criteria, and radiologic evidence of disease progression within 6 months prior to randomization, and must have had at least 2 prior lines of systemic treatment. Patients on prior systemic therapy must have received their last dose must have been at least 21 days prior to randomization.
Those with well-differentiated liposarcoma, myxoid/round cell, or pleomorphic histology; known active hepatitis B, hepatitis C, or HIV infection; or known central nervous system metastases were excluded from enrollment.
Results also showed that 7.5% of patients on selinexor had a 15% or greater reduction in their disease burden, as measured by target lesion size, compared with 0 patients on placebo arm.
Cross over was also permitted on the trial in patients who experienced disease progression on placebo. The median overall survival for patients who received selinexor was 9.99 months compared with 9.07 months for patients who did not cross over to selinexor (HR, 0.69; P = .122).
Regarding safety, the most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms, all of which were found to be consistent with prior studies of selinexor. Most AEs were manageable with dose modifications and/or standard supportive care measures.
Moreover, the most common non-hematologic treatment-related AEs were nausea (81%), decreased appetite (60%), fatigue (51%), and vomiting (49%) and were mostly grade 1/2 events. The most common grade 3/4 treatment-related AEs were anemia (19%), hyponatremia (11%), thrombocytopenia (10%) and asthenia (10%).
"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, the developer of selinexor. "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.”
Karyopharm also stated that it expects to submit a new drug application to the FDA in the first quarter of 2021 for the SEAL patient population studied. Should the agent be approved for this indication, selinexor would be the first oral, non-chemotherapy agent available for patients with dedifferentiated liposarcoma.
Selinexor is currently indicated by the FDA as a treatment for patients with relapsed or refractory multiple myeloma and relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Karyopharm also previously submitted a supplemental new drug application to the FDA to expand selinexor’s label to include patients with multiple myeloma after at least 1 prior line of therapy. Under the Prescription Drug User Fee Act, the FDA will decide on the application by March 19, 2021.
Gounder M, Razak AA, Somaiah N, et al. A phase 2/3, randomized, double blind, cross-over, study of selinexor versus placebo in advanced unresectable dedifferentiated liposarcoma. Presented at: CTOS 2020 Annual Meeting; November 18-21; 2020; virtual. Abstract 20.