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

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

PURPOSEAntitumor 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.METHODSSEAL 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. (Registration: ClinicalTrials.gov identifier: NCT02606461.)RESULTSTwo 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).CONCLUSIONPatients 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.

Original languageEnglish (US)
Article numberJCO.21.01829
JournalJournal of Clinical Oncology
DOIs
StateAccepted/In press - 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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