Enasidenib Plus Best Supportive Care Misses OS End Point in Relapsed/Refractory IDH2+ AML

Enasidenib in combination with best supportive care failed to significantly improve overall survival in patients with relapsed/refractory acute myeloid leukemia whose tumors harbor an IDH2 mutation.

Enasidenib (Idhifa) in combination with best supportive care (BSC) failed to significantly improve overall survival (OS) in patients with relapsed/refractory acute myeloid leukemia (AML) whose tumors harbor an IDH2 mutation, failing to meet the primary end point of the phase 3 IDHENTIFY trial (NCT02577406).1

The toxicity profile of the IDH2 inhibitor proved to be in line with previously reported data. Bristol Myers Squibb (BMS), the drug developer, reported that they will complete a full evaluation of the findings from this trial and they will collaborate with investigators involved on the research to present these data at an upcoming medical meeting.

“While we are disappointed by the outcome of the IDHENTIFY study, we remain confident in [enasidenib’s] established role as a treatment option for patients with relapsed/refractory AML with an IDH2 mutation and are grateful to all those who participated in the study,” Noah Berkowitz, MD, PhD, senior vice president of Global Clinical Development, Hematology at BMS, stated in a press release. “AML is one 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.”

In the international, multicenter, open-label phase 3 trial, investigators set out to compare the safety and efficacy of enasidenib plus BSC versus conventional care regimens, which include continuous 28-day treatment cycles of BSC by itself, azacitidine plus BSC, low-dose cytarabine plus BSC, or intermediate-dose cytarabine plus BSC, in patients with AML who have relapsed on or become refractory to 2-3 prior lines of therapy and harbor a IDH2 mutation.

To be eligible to participate, patients had to be 60 years of age or older, have primary or secondary AML per World Health Organization classification, have received second- or third-line treatment for their disease, and become refractory to or relapsed following treatment.2 Patients also had to be eligible for and willing to be given the pre-selected conventional care regimen per investigator assessment, have an ECOG performance status ranging from 0 to 2, have IDH2 gene mutations that were centrally tested and confirmed in samples of bone marrow and peripheral blood, and have adequate organ function.

Any patient who was suspected or proven to have acute promyelocytic leukemia per morphology, immunophenotype, molecular test, or karyotype were not permitted to participate. If the patient had AML that was secondary to chronic myelogenous leukemia, or they received prior treatment with an IDH2-targeted agent, systemic anticancer therapy or radiotherapy less than 2 weeks before study treatment, non-cytotoxic or investigational agents less than 2 weeks or 5 half-lives before study treatment, or undergone hematologic stem cell transplantation (HSCT) within 60 days before study treatment, they were excluded from the analysis.

The primary end point of the trial was OS, and key secondary end points included overall response rate, event-free survival, duration of response (DOR), time to response, treatment mortality at 30 and 60 days, 1-year survival, overall remission rate, complete remission (CR) rate, hematologic improvement rate, rate of HSCT, time to treatment failure, and safety.

In August 2017, the FDA granted enasidenib a full approval for use in patients with relapsed/refractory IDH2-mutated AML based on data from the phase 1/2 AG221-C-001 study (NCT01915498), which showed that the IDH2 inhibitor elicited a CR rate of 19.3% in this patient population.3

Moreover, the median duration of CR was 8.2 months. Four percent of the 199 patients included in the trial had a CR with partial hematologic recovery (CRh), and this response lasted for 9.6 months. Of 157 patients who had been dependent on transplant, 34% were able to stop receiving blood or platelet transfusions after enasidenib treatment.

The regulatory decision was based on data from a total of 199 patients with IDH2-mutant relapsed/refractory disease who received the oral IDH2 inhibitor at a starting dose of 100 mg daily. The median age of participants in this subgroup was 68 years and the median number of previous therapies received was 2. Notably, more than half, or 52%, of participants were refractory to their prior treatment.

Treatment-naïve patients were also enrolled to the trial. Doses of enasidenib were originally escalated, with the starting dose being 30 mg or 50 mg either daily or twice daily. The maximum-tolerated dose of the agent was not reached at doses up to 650 mg/daily, but the phase 2 dose was identified to be 100 mg once daily. A total of 239 patients were treated in the phase 1/2 trial.

For those with relapsed/refractory disease across all doses of the agent (n = 176), the median age of participants was 67 years and the median number of previous therapies was 2. Eighteen percent of these patients had an ECOG performance status of 2 and 34% had poor-risk cytogenetics.

The objective response rate in the relapsed/refractory group was 40.3% and the median time to first response was 1.9 months; the median DOR with the agent was 5.8 months. Moreover, the time to CR with enasidenib was 3.8 months with an overall CR duration of 8.8 months.

Additionally, the median OS with the IDH2 inhibitor was 9.3 months. In those who achieved a CR, the median OS was even longer, at 19.7 months. Non-CR responders experienced a median OS of 13.8 months with the agent. Patients who did not achieve a response had a median OS of 7 months.

Following treatment with enasidenib, transfusion independence for red blood cells and platelets was achieved in the majority of patients, at 95.5%; 94.1% of those with a CR achieved independence. The overall red blood cell and platelet transfusion independence rates were 36.3% and 36.4%, respectively.

With regard to safety, the most commonly observed adverse effects included nausea (46%), hyperbilirubinemia (45%), diarrhea (40%), fatigue (40%), decreased appetite (38%), vomiting (32%), and dyspnea (31%). Treatment-related toxicities that were grade 3 or higher included hyperbilirubinemia (12%), thrombocytopenia (6%), and anemia (5%).


  1. Bristol Myers 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/2Yz3xuj.
  2. An efficacy and safety study of AG-221 (CC-90007) versus conventional care regimens in older subjects with late stage acute myeloid leukemia harboring an Isocitrate Dehydrogenase 2 mutation (IDHENTIFY). ClinicalTrails.gov. Updated June 23, 2020. Accessed August 25, 2020. https://clinicaltrials.gov/ct2/show/NCT02577406.
  3. FDA granted regular approval to enasidenib for the treatment of relapsed or refractory AML. News release. FDA. August 1, 2017. Accessed August 25, 2020. https://bit.ly/34w9Wdn.