Phase I study of IDHIFA (enasidenib) in patients with relapsed/ refractory acute myeloid leukemia and an isocitrate dehydrogenase-2 (IDH2) mutation.- Celgene + Agios Pharma

Celgene Corporation and Agios Pharmaceuticals, Inc. announced new efficacy and safety data from the ongoing Phase 1 dose-escalation and expansion study evaluating investigational oral IDHIFA (enasidenib) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-2 (IDH2) mutation.

IDHIFA is an investigational first-in-class, oral, targeted inhibitor of the mutant IDH2 enzyme, which demonstrated an overall response rate of 40.3 percent, including a complete response rate of 19.3 percent in the study. The data were presented in an oral session at the American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published online in the journal Blood.

As of April 15, 2016, a total of 239 patients with advanced hematologic malignances and an IDH2 mutation were enrolled into the Phase 1 study, of which 176 patients had R/R AML. Data reported include patients receiving enasidenib at total daily doses ranging from 50 mg to 650 mg in the dose-escalation arm and 100 mg once daily in the Phase 1 expansion arms. A maximum tolerated dose was not reached. The median age of the patients enrolled in the study is 70 (ranging from 19-100). Patients with R/R AML received a median of two prior lines of therapy (ranging from one to 14). The overall safety profile observed for enasidenib was consistent with previously reported data. Twenty-four percent of patients had treatment-related serious adverse events (SAEs), notably IDH differentiation syndrome (8%), leukocytosis (4%), tumor lysis syndrome (3%) and hyperbilirubinemia (2%). The most common treatment-emergent AEs were nausea (46%) hyperbilirubinemia (45%), diarrhea (40%) and fatigue (40%). Data from 176 R/R AML patients with an IDH2 mutation demonstrated a 40.3 percent (71 of 176 patients) overall response rate, which was the primary endpoint of the study. Further, the complete response rate was 19.3 percent (34 of 176 patients). Median duration of response was 5.8 months [95% CI 3.9, 7.4] for all patients who responded and 8.8 months [95% CI 6.4, NR] for patients who achieved a CR. Median time to first response was 1.9 months (0.5-9.4) and median time to CR was 3.8 months (0.5-11.2). Median overall survival (OS) for R/R AML patients as observed in the study was 9.3 months [95% CI 8.2, 10.9]. Additional results including qualitative improvement in response over time, improvement in hematological parameters over time, OS for patients achieving a CR and transfusion independence were also reported.

Comment: A New Drug Application (NDA) for IDHIFA is currently under Priority Review with the FDA for the treatment of patients with relapsed or refractory AML with an IDH2 mutation. The NDA has been given a Prescription Drug User Fee Act (PDUFA) action date of 30 August. 2017.

See- "Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia"- Eytan M. Stein, Courtney D. DiNardo, Daniel A. Pollyea, Amir T. Fathi, Gail J. Roboz,et al.,- Blood 2017 :blood-2017-04-779405; doi: https://doi.org/10.1182/blood-2017-04-779405.