Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial-Reference-Cited by-同舟云学术

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

Published:2022-08-01 Issue:22 Volume:40 Page:2479-2490
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Gounder Mrinal M.¹^ORCID,Razak Albiruni Abdul²^ORCID,Somaiah Neeta³^ORCID,Chawla Sant⁴,Martin-Broto Javier⁵^ORCID,Grignani Giovanni⁶,Schuetze Scott M.⁷^ORCID,Vincenzi Bruno⁸^ORCID,Wagner Andrew J.⁹^ORCID,Chmielowski Bartosz¹⁰^ORCID,Jones Robin L.¹¹^ORCID,Riedel Richard F.¹²^ORCID,Stacchiotti Silvia¹³,Loggers Elizabeth T.¹⁴^ORCID,Ganjoo Kristen N.¹⁵,Le Cesne Axel¹⁶^ORCID,Italiano Antoine¹⁷^ORCID,Garcia del Muro Xavier¹⁸^ORCID,Burgess Melissa¹⁹,Piperno-Neumann Sophie²⁰,Ryan Christopher²¹,Mulcahy Mary F.²²^ORCID,Forscher Charles²³,Penel Nicolas²⁴^ORCID,Okuno Scott²⁵^ORCID,Elias Anthony²⁶^ORCID,Hartner Lee²⁷^ORCID,Philip Tony²⁸^ORCID,Alcindor Thierry²⁹^ORCID,Kasper Bernd³⁰,Reichardt Peter³¹,Lapeire Lore³²^ORCID,Blay Jean-Yves³³^ORCID,Chevreau Christine³⁴,Valverde Morales Claudia Maria³⁵,Schwartz Gary K.³⁶,Chen James L.³⁷^ORCID,Deshpande Hari³⁸,Davis Elizabeth J.³⁹^ORCID,Nicholas Garth⁴⁰,Gröschel Stefan⁴¹,Hatcher Helen⁴²^ORCID,Duffaud Florence⁴³,Herráez Antonio Casado⁴⁴,Beveridge Roberto Diaz⁴⁵,Badalamenti Giuseppe⁴⁶,Eriksson Mikael⁴⁷,Meyer Christian⁴⁸^ORCID,von Mehren Margaret⁴⁹^ORCID,Van Tine Brian A.⁵⁰^ORCID,Götze Katharina⁵¹^ORCID,Mazzeo Filomena⁵²^ORCID,Yakobson Alexander⁵³,Zick Aviad⁵⁴^ORCID,Lee Alexander⁵⁵^ORCID,Gonzalez Anna Estival⁵⁶^ORCID,Napolitano Andrea⁸^ORCID,Dickson Mark A.¹,Michel Dayana⁵⁷^ORCID,Meng Changting⁵⁷^ORCID,Li Lingling⁵⁷,Liu Jianjun⁵⁷,Ben-Shahar Osnat⁵⁷^ORCID,Van Domelen Dane R.⁵⁷^ORCID,Walker Christopher J.⁵⁷,Chang Hua⁵⁷,Landesman Yosef⁵⁷,Shah Jatin J.⁵⁷,Shacham Sharon⁵⁷,Kauffman Michael G.⁵⁷,Attia Steven⁵⁸

Affiliation:

1. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY

2. Princess Margaret Cancer Center, Toronto, Ontario, Canada

3. The University of Texas MD Anderson Cancer Center, Houston, TX

4. Sarcoma Oncology Center, Santa Monica, CA

5. Fundacion Jimenez Diaz University Hospital, Madrid, Madrid, Spain

6. Division of Medical Oncology, Candiolo Cancer Institute, FPO—IRCCS, Candiolo, Torino, Italy

7. University of Michigan, Ann Arbor, MI

8. Policlinico Universitario Campus Bio-Medico, Roma, Italy

9. Dana-Farber Cancer Institute, Boston, MA

10. Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA

11. The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, United Kingdom

12. Duke Cancer Institute, Durham, NC

13. Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

14. Fred Hutchinson Cancer Research Center, Seattle, WA

15. Stanford Cancer Institute, Stanford, CA

16. Institut Gustave Roussy, Villejuif, France

17. Institut Bergonié, Bordeaux, France

18. Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain

19. University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA

20. Institut Curie, Paris, France

21. Oregon Health & Science University, Portland, OR

22. The Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

23. Cedars-Sinai Medical Center, West Hollywood, CA

24. Centre Oscar Lambret and Lille University, Lille, France

25. Mayo Clinic Rochester, Rochester, MN

26. University of Colorado-Denver, Aurora, CO

27. University of Pennsylvania, Philadelphia, PA

28. Northwell Health Physician Partners, New Hyde Park, NY

29. McGill University Health Centre, Montreal, Quebec, Canada

30. Mannheim University Medical Center, Mannheim, Germany

31. Helios Hospital Berlin-Buch, Berlin, Germany

32. University Hospital Gent, Gent, Belgium

33. Centre Leon Berard, Lyon, France

34. Institut Claudius Regaud–IUCT-O, Toulouse, France

35. Vall d'Hebron University Hospital, Barcelona, Spain

36. Columbia University Irving Medical Center, New York, NY

37. The Ohio State James Cancer Center, Columbus, OH

38. Yale Cancer Center, New Haven, CT

39. The Vanderbilt Clinic, Nashville, TN

40. Ottawa Hospital Cancer Center, Ottawa, Ontario, Canada

41. National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Heidelberg, Germany

42. Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom

43. La Timone University Hospital Center and Aix-Marseille University, Marseille, France

44. Hospital Universitario Clínico San Carlos, Madrid, Spain

45. Hospital La Fe Valencia, Valencia, Spain

46. Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy

47. Skane University Hospital, Lund, Sweden

48. Johns Hopkins, Baltimore, MD

49. Fox Chase Cancer Center, Philadelphia, PA

50. Washington University School of Medicine, St Louis, MO

51. Klinik und Poliklinik für Innere Medizin III, Hämatologie und Onkologie Klinikum rechts der Isar der TU Muenchen, Marburg, Germany

52. UCL Saint-Luc, Brussels, Belgium

53. Soroka University Medical Center, Be'er Sheva, Israel

54. Faculty of Medicine, Hebrew University of Jerusalem, Israel; The Oncology Department, Hadassah Medical Center, Jerusalem, Israel

55. The Christie NHS Foundation, Manchester, United Kingdom

56. Catalan Institute of Oncology (ICO) Germans Trias I Pujol University Hospital, B-ARGO, Barcelona, Spain

57. Karyopharm Therapeutics Inc, Newton, MA

58. Mayo Clinic, Jacksonville, FL

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 (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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.21.01829

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