Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial.

Abstract

Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461). Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided <i>P</i> = .011; medians 2.8 <i>v</i> 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided <i>P</i> < .0001; medians 5.8 <i>v</i> 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] <i>v</i> 11 [5.9]), decreased appetite (113 [60.4%] <i>v</i> 14 [7.5%]), and fatigue (96 [51.3%] <i>v</i> 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of <i>CALB1</i> expression was associated with longer PFS with selinexor compared with placebo (median 6.9 <i>v</i> 2.2 months; HR, 0.19; <i>P</i> = .001). Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of <i>CALB1</i> expression as a predictive biomarker for selinexor in DD-LPS is warranted.