Selinexor Improves PFS, Time to Next Treatment in Advanced, Metastatic Dedifferentiated Liposarcoma

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Partner | Cancer Centers | <b>Memorial Sloan Kettering Cancer Center </b>

Selinexor monotherapy prolonged progression-free survival, time to next treatment, and reduced pain in patients with advanced, refractory dedifferentiated liposarcoma.

Selinexor (Xpovio) monotherapy prolonged progression-free survival (PFS), time to next treatment, and reduced pain in patients with advanced, refractory dedifferentiated liposarcoma, according to data from the phase 2/3 SEAL trial (NCT02606461) published in the Journal of Clinical Oncology.1

The median PFS with selinexor (n = 188) was 2.8 months vs 2.1 months with placebo (n = 97), translating to a 30% reduction in the risk of disease progression or death vs placebo in this patient population (HR, 0.70; 95% CI, 0.52-0.95; 1-sided P = .01; 2-sided P = .02).

Moreover, the PFS was significantly longer in the investigative arm vs the control arm at 12 weeks or longer, at 46.8% (95% CI, 39.6%-55.1%) vs 34.0% (95% CI, 29.1%-50.7%), respectively (1-sided P = .02; 2-sided P = .04). The 6- and 12-month PFS rates with selinexor were 23.9% (95% CI, 17.7%-32.4%) and 8.4% (95% CI, 4.3%-16.2%), respectively; these rates were 13.9% (95% CI, 29.1%-50.7%) and 2.0% (95% CI, 0.3%-13.4%), respectively, with placebo.

The time to next treatment was also significantly longer with selinexor vs placebo, at 5.8 months vs 3.2 months, respectively (HR, 0.49; 95% CI, 0.37-0.66; 1-sided P < .0001; 2-sided P = .0002). Notably, the number of those who received subsequent therapies proved to be comparable between the arms.

“To our knowledge, the SEAL trial was the first and largest study conducted exclusively on patients with heavily pretreated dedifferentiated liposarcoma,” lead study author Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, wrote in the paper. “The results…showed that the novel mechanism of action provided by single-agent oral selinexor conferred a 30% improvement in PFS with an important minority of patients deriving long-term benefits as demonstrated by clinical improvements in 3-, 6-, and 12-month PFS.”

Selinexor has been shown to have activity in preclinical models of dedifferentiated liposarcoma, including apoptosis in several liposarcoma cell lines with MDM2 and CDK4 amplification. The agent has also been found to hinder tumor growth, reduce XPO1 levels, increase nuclear retention of p53, and inhibit NF-kB in murine xenograft models of human liposarcoma.

Previously, patients with dedifferentiated liposarcoma who were enrolled to a phase 1 trial (NCT01896505) experienced prolonged stable disease with selinexor.2

The multicenter, randomized, double-blind, phase 2/3 SEAL trial enrolled patients with histologically confirmed dedifferentiated liposarcoma who were at least 12 years of age, had measurable disease per RECIST v1.1 criteria, and had previously received 2 to 5 systemic therapies.

To be eligible for enrollment, patients were required to have an ECOG performance status of 0 or 1, creatinine clearance of over 30 mL/min, and acceptable laboratory hematopoietic and hepatic function. If patients had other subtypes of liposarcoma or known central nervous system metastases, they were excluded.

A total of 285 patients were enrolled to the phase 3 portion of the trial; 188 patients comprised the selinexor arm and 97 patients comprised the placebo arm. Those in the investigation arm received selinexor at 60 mg twice weekly in 6-week treatment cycles. Treatment was given until progressive disease, discontinuation, or intolerable toxicity.

Stratification factors included prior eribulin (Halaven) use (yes vs no), prior trabectedin (Yondelis) use (yes vs no), and the number of previous systemic therapies received, excluding eribulin or trabectedin (2 or fewer vs 3 or more).

The primary end point of the trial was PFS, and secondary end points included overall survival (OS), OS among those who did not crossover, time to progression on study treatment, objective response rate (ORR), duration of response (DOR), time to next treatment, and health-related quality of life. Exploratory end points comprised tumor biomarker analysis. Safety was also evaluated.

Patient characteristics were balanced between the treatment arms. The median age of study participants was 65 years (range, 56.0-71.0) and retroperitoneal was the most common primary disease site. Moreover, 71.3% of patients who received selinexor had metastatic disease at study entry vs 68.0% of those who received placebo. Additionally, 35.1% and 36.1% of those in the investigative and control arms, respectively, received prior eribulin; 36.7% and 37.1% of patients, respectively, previously received trabectedin.

Additional findings indicated that selinexor elicited an ORR of 2.7% (95% CI, 0.9%-6.1%) vs 0% with placebo. Among those who responded to selinexor, 2.7% experienced a partial response and 59.0% achieved stable disease. The rate of progressive disease was 26.6%. The median DOR with selinexor was 7.4 months (95% CI, not reached [NR]–NR).

Moreover, 58.8% of those on the placebo arm crossed over to receive open-label selinexor after disease progression was confirmed per independent radiographic assessment.

At a median follow-up of 14.6 months (range, 8.2-23.5), the median OS with selinexor was 10.0 months vs 9.1 months with placebo; this difference was not determined to be statistically significant (HR, 1.02; 95% CI, 0.73-1.42; 1-sided P = .54; 2-sided P = .12).

Investigators also conducted an exploratory analysis of 30 patients whose tumors did not have detectable CALB1 expression. Data showed that among the 16 patients who were randomly assigned to receive selinexor, the median PFS was 6.9 months vs 2.2 months with placebo (HR, 0.19; 95% CI, 0.07-0.56; P = .001).

Additionally, those with no tumor CALB1 expression who received selinexor (n = 13) experienced improved PFS vs those whose tumors did have CALB1 expression (n = 29), with a median PFS of 6.9 months vs 1.7 months, respectively (HR, 0.45; 95% CI, 0.21-0.95; P = .03). No link between PFS and CALB1 expression was observed in the control arm (P = .44).

The most common treatment-emergent adverse effects (TEAEs) experienced in the investigative and control arms, respectively, included nausea (80.7% vs 39.2%), decreased appetite (60.4% vs 22.7%), fatigue (51.3% vs 32.0%), and weight loss (42.2% vs 9.3%).

Grade 3 or 4 TEAEs included anemia (18.7% vs 8.2%), hyponatremia (10.7% vs 0%), asthenia (10.2% vs 0%), and thrombocytopenia (10.2% vs 0%).

Thirty-eight patients on the selinexor arm experienced serious TEAEs vs 18.6% of those on the placebo arm, with gastrointestinal disorders most frequently experienced in both arms, at 11.8% and 6.2%, respectively.

Dose reductions were required by 35.8% of those in the investigative arm vs 3.1% of those in the control arm; 63.1% and 16.5% of patients, respectively, needed dose interruptions.

TEAEs resulted in treatment discontinuation in 9.1% of those who received selinexor and 4.1% of those who were given placebo. In the investigative arm, these toxicities included fatigue (2.7%) and cardiac failure (1.1%). Moreover, 2.1% of those who received selinexor experienced TEAEs that resulted in death vs 3.1% of those who were given placebo.

“Further investigation is warranted for selinexor as a treatment for patients with dedifferentiated liposarcoma with low or high CALB1 expression,” the study authors concluded. “Oral selinexor may represent a therapeutic option for patients with dedifferentiated liposarcoma who have exhausted treatments of known clinical benefit.”


  1. Gounder MM, Razak AA, Somaiah N, et al. Selinexor in advanced, metastatic dedifferentiated liposarcoma: a multinational, randomized, double-blind, placebo-controlled trial. J Clin Oncol. Published online April 8, 2022. doi:10.1200/JCO.21.01829
  2. Gounder MM, Zer A, Tap WD, et al. Phase Ib study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma. J Clin Oncol. 2016;34(26):3166-3174. doi:10.1200/JCO.2016.67.6346