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    Selinexor in advanced, metastatic dedifferentiated liposarcoma: a multinational, randomized, double-blind, placebo-controlled trial

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    Authors
    Gounder, M. M.
    Razak, A. A.
    Somaiah, N.
    Chawla, S.
    Martin-Broto, J.
    Grignani, G.
    Schuetze, S. M.
    Vincenzi, B.
    Wagner, A. J.
    Chmielowski, B.
    Jones, R. L.
    Riedel, R. F.
    Stacchiotti, S.
    Loggers, E. T.
    Ganjoo, K. N.
    Le Cesne, A.
    Italiano, A.
    Garcia Del Muro, X.
    Burgess, M.
    Piperno-Neumann, S.
    Ryan, C.
    Mulcahy, M. F.
    Forscher, C.
    Penel, N.
    Okuno, S.
    Elias, A.
    Hartner, L.
    Philip, T.
    Alcindor, T.
    Kasper, B.
    Reichardt, P.
    Lapeire, L.
    Blay, J. Y.
    Chevreau, C.
    Valverde Morales, C. M.
    Schwartz, G. K.
    Chen, J. L.
    Deshpande, H.
    Davis, E. J.
    Nicholas, G.
    Gröschel, S.
    Hatcher, H.
    Duffaud, F.
    Herráez, A. C.
    Beveridge, R. D.
    Badalamenti, G.
    Eriksson, M.
    Meyer, C.
    von Mehren, M.
    Van Tine, B. A.
    Götze, K.
    Mazzeo, F.
    Yakobson, A.
    Zick, A.
    Lee, Alexander J
    Gonzalez, A. E.
    Napolitano, A.
    Dickson, M. A.
    Michel, D.
    Meng, C.
    Li, L.
    Liu, J.
    Ben-Shahar, O.
    Van Domelen, D. R.
    Walker, C. J.
    Chang, H.
    Landesman, Y.
    Shah, J. J.
    Shacham, S.
    Kauffman, M. G.
    Attia, S.
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    Affiliation
    Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY
    Issue Date
    2022
    
    Metadata
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    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. (Registration: 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.
    Citation
    Gounder MM, Razak AA, Somaiah N, Chawla S, Martin-Broto J, Grignani G, et al. Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2022.
    Journal
    Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/625273
    DOI
    10.1200/jco.21.01829
    PubMed ID
    35394800
    Additional Links
    https://dx.doi.org/10.1200/jco.21.01829
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1200/jco.21.01829
    Scopus Count
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