Selinexor in advanced, metastatic dedifferentiated liposarcoma: A multinational, randomized, double-blind, placebo-controlled trial Journal Article
| 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, A.; 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. |
| Article Title: | Selinexor in advanced, metastatic dedifferentiated liposarcoma: A multinational, randomized, double-blind, placebo-controlled trial |
| 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 (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. © American Society of Clinical Oncology. |
| Keywords: | adult; child; controlled study; aged; major clinical study; overall survival; clinical trial; constipation; fatigue; neutropenia; doxorubicin; placebo; advanced cancer; diarrhea; drug efficacy; drug withdrawal; side effect; systemic therapy; gemcitabine; cancer patient; antineoplastic agent; dacarbazine; progression free survival; multiple cycle treatment; phase 2 clinical trial; gene expression; anemia; nausea; randomized controlled trial; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; alkylating agent; creatinine; creatinine blood level; protein tyrosine kinase inhibitor; abdominal pain; asthenia; dizziness; dyspnea; hyponatremia; heart failure; multicenter study; lipopolysaccharide; phase 3 clinical trial; phase 1 clinical trial; taxane derivative; trabectedin; anthracycline; crossover procedure; double blind procedure; double-blind method; cyclin dependent kinase inhibitor; triazoles; triazole derivative; liposarcoma; cyclin dependent kinase 4; blurred vision; eribulin; dysgeusia; hydrazines; decreased appetite; hydrazine derivative; lipopolysaccharides; dedifferentiated liposarcoma; body weight loss; immune checkpoint inhibitor; humans; human; male; female; article; rna sequencing; patient history of therapy; selinexor; mouse double minute 2 homolog; calbindin 1 |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 40 |
| Issue: | 22 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2022-08-01 |
| Start Page: | 2479 |
| End Page: | 2490 |
| Language: | English |
| DOI: | 10.1200/jco.21.01829 |
| PUBMED: | 35394800 |
| PROVIDER: | scopus |
| PMCID: | PMC9467680 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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