Enasidenib Misses Primary End Point, Appears Safe in Phase 3 Study of R/R Acute Myeloid Leukemia

Overall survival was not improvement with the combination of enasidenib and best supportive care compared with conventional care regimens when administered to patients relapsed/refractory IDH2-positive acute myeloid leukemia.

Overall survival (OS) was not improvement with the combination of enasidenib and best supportive care compared with conventional care regimens when administered to patients relapsed/refractory acute myeloid leukemia (AML) who are positive for an IDH2 mutation. This is the result of data from the phase 3 IDHENTIFY study (NCT02577406), which was negative for its primary end point, announced Bristol Myers Squibb in a press release.1

Enasidenib also demonstrated a safety profile in IDEHENTIFY that was consistent with previously reported data. The company plans to complete a full evaluation of the study, which will be presented in detail at an upcoming medical meeting.

“While we are disappointed by the outcome of the IDHENTIFY study, we remain confident in IDHIFA’s established role as a treatment option for patients with relapsed or refractory AML with an IDH2 mutation and are grateful to all those who participated in the study,” said Noah Berkowitz, MD, PhD, senior vice president, Global Clinical Development, Hematology, Bristol Myers Squibb, in a statement. “AML is 1 of the most difficult-to-treat blood cancers, and we’re committed to furthering our research and improving on the standards of care for patients living with this aggressive disease.”

The international, multicenter, open-label, randomized IDHENTIFY study compared the efficacy and safety of enasidenib with conventional care regimens, such as continuous 28-day cycles of best supportive care (BSC) only, subcutaneous azacitidine (Vidaza) plus BSC, low-dose cytarabine plus BSC, or intermediate-dose cytarabine intravenously plus BSC. Patients were 60 years or older with relapsed/refractory AML after second- or third-line AML treatment who harbor the IDH2 mutation. Key secondary end points included overall response rate, event-free survival, duration of response, and time to response.

To be included in this study, patients had to be at least 60 years old with primary or secondary AML. Patients had to be relapsed after or refractory to second- or third-line intensive or low-intensive therapy for AML. They also had to have an ECOG performance status of 0, 1, or 2 and harbor the IDH2 gene mutation. Patients were ineligible if they had a suspected or proven acute promyelocytic leukemia, AML secondary to chronic myelogenous leukemia, or have received a targeted therapy against the IDH2 mutation. Patients were also ineligible for the study if they had received prior systemic therapy or radiotherapy 14 days prior to the start of the study treatment, non-cytotoxic, or investigational agents within 14 days or 5 half-lives (whoever is longer), or a hematopoietic stem cell transplantation.

Patients in the experimental arm received continuous 28-day cycles of enasidenib at 100 mg administered orally in combination with best supportive care, which could have been hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-infectives, analgesics, antiemetics, antipyretics, or transfusions and nutritional support. In the control arm, treatment was administered in a continuous 28-day cycle at the following doses in combination with BSC: azacitidine at 75 mg/m2 per day subcutaneously for 7 days, cytarabine at 20 mg twice daily subcutaneously for 10 days, or cytarabine at 0.5 to 1.5 g/m2 intravenously for 3 to 6 days.

Enasidenib is a selective, oral, potent inhibitor of the mIDH2 enzyme that received approval from the FDA in August 2017 as treatment of patients with relapsed/refractory AML harboring an IDH2 mutation. The agent is the first and only FDA-approved treatment for this patient population, in which about 19% of patients with AML harbor the IDH2 mutation.

The approval was based on findings from the phase 1/2 AG221-C-001 study, which enrolled 199 patients. The complete response (CR) rate was 19.3% (95% CI, 13.8-25.9), and the median duration of a CR was 8.2 months. Four percent of patients had a CR with partial hematologic recovery, which lasted 9.6 months, and 34% of 157 patients who were transplant-dependent were able to stop receiving blood or platelet transfusions following treatment with enasidenib.2

Patients had been treated with a starting dose of enasidenib at 100 mg daily. The median age of patients was 68 years (range, 19-100), and the median number of prior therapies was 2 (range, 1-6). In addition, 52% of patients were refractory to their previous treatment.


1. Bristol Meyers Squibb provides update on phase 3 IDHENTIFY trial in patients with relapsed or refractory acute myeloid leukemia. News Release. Bristol Myers Squibb. August 25, 2020. Accessed August 25, 2020. https://bit.ly/32vx35w

2. Stein EM, Dinardo DC, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. J Clin Oncol35; 2017 (suppl; abstr 7004).