Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Gounder Mrinal M. , Razak Albiruni Abdul , Somaiah Neeta , Chawla Sant , Martin-Broto Javier , Grignani Giovanni , Schuetze Scott M. , Vincenzi Bruno , Wagner Andrew J. , Chmielowski Bartosz , Jones Robin L. , Riedel Richard F. , Stacchiotti Silvia , Loggers Elizabeth T. , Ganjoo Kristen N. , Le Cesne Axel , Italiano Antoine , Garcia del Muro Xavier , Burgess Melissa , Piperno-Neumann Sophie , Ryan Christopher , Mulcahy Mary F. , Forscher Charles , Penel Nicolas , Okuno Scott , Elias Anthony , Hartner Lee , Philip Tony , Alcindor Thierry , Kasper Bernd , Reichardt Peter , Lapeire Lore , Blay Jean-Yves , Chevreau Christine , Valverde Morales Claudia Maria , Schwartz Gary K. , Chen James L. , Deshpande Hari , Davis Elizabeth J. , Nicholas Garth , Gröschel Stefan , Hatcher Helen , Duffaud Florence , Herráez Antonio Casado , Beveridge Roberto Diaz , Badalamenti Giuseppe , Eriksson Mikael , Meyer Christian , von Mehren Margaret , Van Tine Brian A. , Götze Katharina , Mazzeo Filomena , Yakobson Alexander , Zick Aviad , Lee Alexander , Gonzalez Anna Estival , Napolitano Andrea , Dickson Mark A. , Michel Dayana , Meng Changting , Li Lingling , Liu Jianjun , Ben-Shahar Osnat , Van Domelen Dane R. , Walker Christopher J. , Chang Hua , Landesman Yosef , Shah Jatin J. , Shacham Sharon , Kauffman Michael G. , Attia Steven 
Published: April 2022

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.