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RESEARCH PRODUCT
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial
Mrinal M. GounderAlbiruni Abdul RazakNeeta SomaiahSant ChawlaJavier Martin-brotoGiovanni GrignaniScott M. SchuetzeVincenzi BrunoAndrew J. WagnerBartosz ChmielowskiRobin L. JonesRichard F. RiedelSilvia StacchiottiElizabeth T. LoggersKristen N. GanjooAxel Le CesneAntoine ItalianoXavier Garcia Del MuroMelissa BurgessSophie Piperno-neumannChristopher RyanMary F. MulcahyCharles ForscherNicolas PenelScott OkunoAnthony EliasLee HartnerTony PhilipThierry AlcindorBernd KasperPeter ReichardtLore LapeireJean-yves BlayChristine ChevreauClaudia Maria Valverde MoralesGary K. SchwartzJames L. ChenHari DeshpandeElizabeth J. DavisGarth NicholasStefan GröschelHelen HatcherFlorence DuffaudAntonio Casado HerráezRoberto Diaz BeveridgeGiuseppe BadalamentiMikael ErikssonChristian MeyerMargaret Von MehrenBrian A. Van TineKatharina GötzeFilomena MazzeoAlexander YakobsonAviad ZickAlexander LeeAnna Estival GonzalezAndrea NapolitanoMark A. DicksonDayana MichelChangting MengLingling LiJianjun LiuOsnat Ben-shaharDane R. Van DomelenChristopher J. WalkerHua ChangYosef LandesmanJatin J. ShahSharon ShachamMichael G. KauffmanSteven Attiasubject
PlacebosCancer ResearchHydrazinesOncologyDouble-Blind MethodHumansSarcomaLiposarcomaTriazolesChildPlacebos (Medicine)selinexor dedifferentiated liposarcoma (DD-LPS)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: 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2022-08-01 |