Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial

• DOI: 10.1182/blood.2021014901
• Publication Date: 2022-06-17T19:53:53Z
• Authors: Stéphane de Botton; Pau Montesinos; Andre C. Schuh; Cristina Papayann...; Paresh Vyas; Andrew H. Wei; Hans Ommen; Sergey Semochkin; Hee-Je Kim; Richard A. Larson; Jaime Koprivnikar; Olga Frankfurt; Felicitas Thol; Jörg Chromik; Jenny Byrne; Arnaud Pigneux; Xavier Thomas; Olga Salamero; Maria Belen Vidri...; Vadim Doronin; Hartmut Döhner; Amir T. Fathi; Eric Laille; Xin Yu; Maroof Hasan; Patricia Martin-R...; Courtney D. DiNardo
• Keywords: Myeloid; Medical Sciences; Bioinformatics; Clinical Trials and Observations; :Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES]; 610; Medicaments antineoplàstics - Ús terapèutic; :Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores]; Acute; :Other subheadings::Other subheadings::/drug therapy [Other subheadings]; Biomedical Informatics; :neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mieloide aguda [ENFERMEDADES]; 03 medical and health sciences; enasidenib, IDH2, Acute Myeloid Leukemia, target therapy; Medical Specialties; Medicine and Health Sciences; Humans; :Other subheadings::/therapeutic use [Other subheadings]; :fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS]; Aged; 0303 health sciences; Leukemia; :Otros calificadores::/uso terapéutico [Otros calificadores]; Cytarabine; :Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myeloid, Acute [DISEASES]; :acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS]; Isocitrate Dehydrogenase; 3. Good health; Leukemia, Myeloid, Acute; Anomalies cromosòmiques; Oncology; Leucèmia mieloide aguda - Aspectes genètics; Mutation; Leucèmia mieloide aguda - Tractament; :Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS]

Abstract This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.