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

Autor:	Gounder MM; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY., Razak AA; Princess Margaret Cancer Center, Toronto, Ontario, Canada., Somaiah N; The University of Texas MD Anderson Cancer Center, Houston, TX., Chawla S; Sarcoma Oncology Center, Santa Monica, CA., Martin-Broto J; Fundacion Jimenez Diaz University Hospital, Madrid, Madrid, Spain., Grignani G; Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy., Schuetze SM; University of Michigan, Ann Arbor, MI., Vincenzi B; Policlinico Universitario Campus Bio-Medico, Roma, Italy., Wagner AJ; Dana-Farber Cancer Institute, Boston, MA., Chmielowski B; Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA., Jones RL; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, United Kingdom., Riedel RF; Duke Cancer Institute, Durham, NC., Stacchiotti S; Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Loggers ET; Fred Hutchinson Cancer Research Center, Seattle, WA., Ganjoo KN; Stanford Cancer Institute, Stanford, CA., Le Cesne A; Institut Gustave Roussy, Villejuif, France., Italiano A; Institut Bergonié, Bordeaux, France., Garcia Del Muro X; Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain., Burgess M; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA., Piperno-Neumann S; Institut Curie, Paris, France., Ryan C; Oregon Health & Science University, Portland, OR., Mulcahy MF; The Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL., Forscher C; Cedars-Sinai Medical Center, West Hollywood, CA., Penel N; Centre Oscar Lambret and Lille University, Lille, France., Okuno S; Mayo Clinic Rochester, Rochester, MN., Elias A; University of Colorado-Denver, Aurora, CO., Hartner L; University of Pennsylvania, Philadelphia, PA., Philip T; Northwell Health Physician Partners, New Hyde Park, NY., Alcindor T; McGill University Health Centre, Montreal, Quebec, Canada., Kasper B; Mannheim University Medical Center, Mannheim, Germany., Reichardt P; Helios Hospital Berlin-Buch, Berlin, Germany., Lapeire L; University Hospital Gent, Gent, Belgium., Blay JY; Centre Leon Berard, Lyon, France., Chevreau C; Institut Claudius Regaud-IUCT-O, Toulouse, France., Valverde Morales CM; Vall d'Hebron University Hospital, Barcelona, Spain., Schwartz GK; Columbia University Irving Medical Center, New York, NY., Chen JL; The Ohio State James Cancer Center, Columbus, OH., Deshpande H; Yale Cancer Center, New Haven, CT., Davis EJ; The Vanderbilt Clinic, Nashville, TN., Nicholas G; Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada., Gröschel S; National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Heidelberg, Germany., Hatcher H; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom., Duffaud F; La Timone University Hospital Center and Aix-Marseille University, Marseille, France., Herráez AC; Hospital Universitario Clínico San Carlos, Madrid, Spain., Beveridge RD; Hospital La Fe Valencia, Valencia, Spain., Badalamenti G; Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy., Eriksson M; Skane University Hospital, Lund, Sweden., Meyer C; Johns Hopkins, Baltimore, MD., von Mehren M; Fox Chase Cancer Center, Philadelphia, PA., Van Tine BA; Washington University School of Medicine, St Louis, MO., Götze K; Klinik und Poliklinik für Innere Medizin III, Hämatologie und Onkologie Klinikum rechts der Isar der TU Muenchen, Marburg, Germany., Mazzeo F; UCL Saint-Luc, Brussels, Belgium., Yakobson A; Soroka University Medical Center, Be'er Sheva, Israel., Zick A; Faculty of Medicine, Hebrew University of Jerusalem, Israel; The Oncology Department, Hadassah Medical Center, Jerusalem, Israel., Lee A; The Christie NHS Foundation, Manchester, United Kingdom., Gonzalez AE; Catalan Institute of Oncology (ICO) Germans Trias I Pujol University Hospital, B-ARGO, Barcelona, Spain., Napolitano A; Policlinico Universitario Campus Bio-Medico, Roma, Italy., Dickson MA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY., Michel D; Karyopharm Therapeutics Inc, Newton, MA., Meng C; Karyopharm Therapeutics Inc, Newton, MA., Li L; Karyopharm Therapeutics Inc, Newton, MA., Liu J; Karyopharm Therapeutics Inc, Newton, MA., Ben-Shahar O; Karyopharm Therapeutics Inc, Newton, MA., Van Domelen DR; Karyopharm Therapeutics Inc, Newton, MA., Walker CJ; Karyopharm Therapeutics Inc, Newton, MA., Chang H; Karyopharm Therapeutics Inc, Newton, MA., Landesman Y; Karyopharm Therapeutics Inc, Newton, MA., Shah JJ; Karyopharm Therapeutics Inc, Newton, MA., Shacham S; Karyopharm Therapeutics Inc, Newton, MA., Kauffman MG; Karyopharm Therapeutics Inc, Newton, MA., Attia S; Mayo Clinic, Jacksonville, FL.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2022 Aug 01; Vol. 40 (22), pp. 2479-2490. Date of Electronic Publication: 2022 Apr 08.
DOI:	10.1200/JCO.21.01829
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu