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Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma
Ingo K Mellinghoff1, Martin J van den Bent1, Deborah T Blumenthal1
1From Memorial Sloan Kettering Cancer Center, New York (I.K.M.); the Brain Tumor Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands (M.J.B.); Tel Aviv Medical Center, Tel Aviv University, Tel Aviv (D.T.B., S.Y.-K.), and the Davidoff Cancer Center, Rabin Medical Center, Petah Tikva (S.Y.-K.) - both in Israel; Sorbonne Université, Institut du Cerveau, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires la Pitié Salpêtrière-Charles Foix, Paris (M.T.), and Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon (F.D.) - both in France; Duke University Medical Center, Durham, NC (K.B.P.); the University of California, San Francisco, San Francisco (J.C.); Huntsman Cancer Institute, University of Utah, Salt Lake City (J.M.); the Royal Marsden Hospital, London (L.W.); Princess Margaret Cancer Centre (W.P.M.), and Sunnybrook Health Sciences Centre (J.R.P.), University of Toronto (W.P.M.) - both in Toronto; the University of Michigan Comprehensive Cancer Center, Ann Arbor (Y.U.); the University of Alabama at Birmingham, Birmingham (B.N.); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore (M.H.); Lundin Family Brain Tumor Research Center, University Hospital of Lausanne, and the University of Lausanne - both in Lausanne, Switzerland (A.F.H.); Kyoto University Graduate School of Medicine, Kyoto, Japan (Y.A.); Hospital Universitario 12 de Octubre, Madrid (J.M.S.); Universitätsklinikum Heidelberg and the German Cancer Research Center - both in Heidelberg, Germany (W.W.); the University of Turin, Turin, Italy (R.S.); Ohio State University Wexner Medical Center, Columbus (P.G.); Sylvester Comprehensive Cancer Center and the Department of Neurology, University of Miami, Miami (M.F.); University of Texas Southwestern Medical Center, Dallas (E.A.M.); Servier Pharmaceuticals (S.S., D.Z., S.S.P., L.S., I.H.) and Dana-Farber Cancer Institute (P.Y.W.) - both in Boston; and the University of California, Los Angeles, Los Angeles (T.F.C.).
Background:
Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.
Methods:
In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.
Results:
A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.
Conclusions:
In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).
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