Small PFS Bump With XPO1 Inhibitor for Dedifferentiated Liposarcoma

Treatment with the XPO1 inhibitor selinexor (Xpovio) demonstrated a progression-free survival (PFS) benefit in advanced dedifferentiated liposarcoma, though no overall survival improvement, a randomized study showed.

In the phase II/III SEAL trial, median PFS among nearly 300 heavily pretreated patients was superior with selinexor, at 2.83 months versus 2.07 months with placebo (HR 0.70, 95% CI 0.52-0.95, P=0.0228), meeting the study’s primary endpoint, reported Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York City.

Landmark analyses showed improved PFS rates with selinexor at all time points:

• 3 months: 46.7% vs 38.4%
• 6 months: 23.9% vs 13.9%
• 9 months: 13.1% vs 4.0%
• 12 months: 8.4% vs 2.0%

“Selinexor may be a convenient, novel, oral therapy in patients with dedifferentiated liposarcoma,” said Gounder at the Connective Tissue Oncology Society virtual meeting.

Median overall survival, however, was numerically worse in the selinexor arm, at 10.0 months versus 12.9 months in the placebo arm (HR 1.00, 95% CI 0.72-1.40, P=0.9836), though 58% of placebo patients crossed over to receive the study drug.

A prespecified analysis that excluded crossovers closed that gap, but still showed no significant difference between arms, at 10.0 months compared with 9.1 months, respectively (HR 0.69, 95% CI 0.43-1.11, P=0.12).

“Although there appears to be a trend [with selinexor], these are not statistically significant,” said Gounder. “In addition, these arms may not be carefully balanced.”

Liposarcomas are one of the most common soft-tissue sarcomas, accounting for 15-20% of all sarcomas, Gounder said, and the dedifferentiated subtype represents about one in five liposarcoma cases.

Complete surgical resection is standard of care for localized disease, while for metastatic and unresectable cases, standard treatment consists of palliative chemotherapy with doxorubicin alone or in combination with ifosfamide. Second- and subsequent-line options include eribulin (Halaven) and trabectedin (Yondelis).

Selinexor is an oral, first-in-class, selective inhibitor of nuclear export that inhibits the function of XPO1. The drug is FDA approved as a later-line option in multiple myeloma and diffuse large B-cell lymphoma.

Overall response rates (30% tumor reduction) in the current study were 2.7% in the selinexor arm versus 0% in the placebo arm. Smaller tumor reductions (15% or more) occurred in 7.5% versus 0%, respectively.

Among the 57 placebo patients that crossed over to selinexor, two (3.5%) had a response of 30% or more while three (5.3%) had tumor shrinkage of 15% or more.

“[It’s] very encouraging to see some promising results for dedifferentiated liposarcoma patients,” said discussant Carol Swallow, MD, PhD, of the University of Toronto. “The progression-free survival time for selinexor described here — 2.8 months — may be hinting at greater activity than seen with trabectedin [Yondelis] or eribulin [Halaven] in the second-line setting in dedifferentiated liposarcoma.”

While Swallow highlighted that the objective response rate was comparable to that of single-agent doxorubicin in the first-line setting, she cautioned that adverse events (AEs) in SEAL led to treatment discontinuation in 12.3% of patients on selinexor (vs 4.1% with placebo) and dose modifications in 68% (vs 19% with placebo).

“Side effects were well tolerated with supportive care and dose modifications,” said Gounder.

Treatment-emergent AEs of any grade were reported in 100% of patients on selinexor and 97% of those on placebo. Grade 3/4 AEs occurred in 70% versus 34%, respectively, and serious AEs occurred in 38% versus 19%.

Common treatment-emergent AEs with selinexor included nausea (80.7%), decreased appetite (60.4%), fatigue (51.3%), vomiting (49.2%), anemia (46.5%), decreased weight (41.7%), diarrhea (40.1%), thrombocytopenia (38.0%), constipation (37.4%), and asthenia (31.0%). Gounder also highlighted the incidence of dizziness (22%) and blurred vision (22%) with selinexor, as compared to 6.2% and 3.1% with placebo, respectively.

Grade 3/4 treatment-related AEs included anemia (18.7%), hyponatremia (10.7%), and thrombocytopenia (10.2%).

SEAL was an international, phase II/III trial that randomized 285 patients with relapsed dedifferentiated liposarcoma 2:1 to 60 mg selinexor twice a week or placebo. Patients enrolled had already received two to five prior lines of therapy, had radiographic progression within 6 months of enrollment, and were stratified by prior use of eribulin, trabectedin, and number of prior therapies (2 vs ≥3).

Arms were well balanced, said Gounder. Patients had a median age of 65 (about 10% were over 75), two-thirds were women, and 60% had an Eastern Cooperative Oncology Group performance status score of 1. The retroperitoneum was the primary tumor site in three-fourths of patients, and 70% had distant metastases at study entry.

Patients had a median of two prior surgeries, nearly 90% had received doxorubicin, 35-36% had received eribulin, and 37% had received trabectedin.