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

Abstract

Purpose: 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.

Methods: 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).

Results: 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 P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 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%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 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 CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001).

Conclusion: 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 CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

FIG 1.

CONSORT diagram. AE, adverse event.

FIG 2.

Efficacy by treatment arm. (A) Median progression-free survival. Kaplan-Meier curves by treatment arm. (B) Median OS. Kaplan-Meier curves by treatment arm. (C) Best overall response waterfall plots during blinded treatment: selinexor (upper panel) and placebo (lower panel). HR, hazard ratio; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

FIG 3.

CALB1 expression is associated with selinexor resistance. (A) Flow diagram of patient samples that were sequenced. (B) Volcano plot showing the significance (y-axis) and fold-change (x-axis) of all genes compared between sensitive and resistant tumors in the set 1 comparison using RECIST tumor size change. (C) Expression of CALB1 in the set 1 tumor samples. (D) Significance and fold-change of all genes in the set 2 comparison of patients with favorable and poor PFS. (E) Expression of CALB1 in set 2. (F) CT scans from a patient who had a mesentery lesion that steadily reduced in size over 4 months after starting selinexor treatment on SEAL and then remained stable. A scan on day 251 revealed a small nodule that rapidly grew while the patient continued selinexor treatment, until both tumors were resected on day 349. (G) PFS of phase III selinexor and placebo arm patients restricted to those patients without detectable CALB1. (H and I) PFS of phase III (H) selinexor or (I) placebo arm patients stratified by CALB1 expression. Shaded areas represent 95% CIs. HR, hazard ratio; PFS, progression-free survival; PR, partial response.