Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial
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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/190172 |
| Acceso en línea: | https://hdl.handle.net/2445/190172 |
| Access Level: | acceso abierto |
| Palabra clave: | Sarcoma Placebos Placebos (Medicine) |
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Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled TrialGounder, Mrinal M.Razak, Albiruni AbdulSomaiah, NeetaChawla, SantMarti Broto, JavierGrignani, GiovanniSchuetze, Scott M.Vincenzi, BrunoWagner, Andrew J.Chmielowski, BartoszJones, Robin L.Riedel, Richard F.Stacchiotti, SilviaLoggers, Elizabeth T.Ganjoo, Kristen N.Le Cesne, AxelItaliano, AntoineGarcia Del Muro, XavierBurgess, MelissaPiperno-Neumann, SophieRyan, ChristopherMulcahy, Mary F.Forscher, CharlesPenel, NicolasOkuno, ScottElias, AnthonyHartner, LeePhilip, TonyAlcindor, ThierryKasper, BerndReichardt, PeterLapeire, LoreBlay, Jean YvesChevreau, ChristineValverde Morales, Claudia MariaSchwartz, Gary K.Chen, James L.Deshpande, HariDavis, Elizabeth J.Nicholas, GarthGröschel, StefanHatcher, HelenDuffaud, FlorenceHerráez, Antonio CasadoBeveridge, Roberto DiazBadalamenti, GiuseppeEriksson, MikaelMeyer, ChristianVon Mehren, MargaretVan Tine, Brian A.Götze, KatharinaMazzeo, FilomenaYakobson, AlexanderZick, AviadLee, AlexanderGonzalez, Anna EstivalNapolitano, AndreaDickson, Mark A.Michel, DayanaMeng, ChangtingLi, LinglingLiu, JianjunBen Shahar, OsnatVan Domelen, Dane R.Walker, Christopher J.Chang, HuaLandesman, YosefShah, Jatin J.Shacham, SharonKauffman, Michael G.Attia, StevenSarcomaPlacebosSarcomaPlacebos (Medicine)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: ). 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. (C) 2022 by American Society of Clinical OncologyAmerican Society of Clinical Oncology (ASCO)2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/190172Articles publicats en revistes (Ciències Clíniques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1200/JCO.21.01829Journal of Clinical Oncology, 2022, vol. 40, num. 22, p. 2479-2490https://doi.org/10.1200/JCO.21.01829cc by-nc-nd (c) Gounder, Mrinal M. 2022http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1901722026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| title |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| spellingShingle |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial Gounder, Mrinal M. Sarcoma Placebos Sarcoma Placebos (Medicine) |
| title_short |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| title_full |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| title_fullStr |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| title_full_unstemmed |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| title_sort |
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial |
| dc.creator.none.fl_str_mv |
Gounder, Mrinal M. Razak, Albiruni Abdul Somaiah, Neeta Chawla, Sant Marti 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 |
| author |
Gounder, Mrinal M. |
| author_facet |
Gounder, Mrinal M. Razak, Albiruni Abdul Somaiah, Neeta Chawla, Sant Marti 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 |
| author_role |
author |
| author2 |
Razak, Albiruni Abdul Somaiah, Neeta Chawla, Sant Marti 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 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Sarcoma Placebos Sarcoma Placebos (Medicine) |
| topic |
Sarcoma Placebos Sarcoma Placebos (Medicine) |
| description |
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: ). 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. (C) 2022 by American Society of Clinical Oncology |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/190172 |
| url |
https://hdl.handle.net/2445/190172 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1200/JCO.21.01829 Journal of Clinical Oncology, 2022, vol. 40, num. 22, p. 2479-2490 https://doi.org/10.1200/JCO.21.01829 |
| dc.rights.none.fl_str_mv |
cc by-nc-nd (c) Gounder, Mrinal M. 2022 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc by-nc-nd (c) Gounder, Mrinal M. 2022 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
American Society of Clinical Oncology (ASCO) |
| publisher.none.fl_str_mv |
American Society of Clinical Oncology (ASCO) |
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Articles publicats en revistes (Ciències Clíniques) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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