The combination of enasidenib plus azacitidine was well tolerated and induced significantly improved response rates compared with azacitidine alone in patients with newly diagnosed, IDH2-mutant acute myeloid leukemia.

The combination of enasidenib (Idhifa) plus azacitidine for injection (Vidaza) was well tolerated and induced significantly improved response rates compared with azacitidine alone in patients with newly diagnosed, IDH2-mutant acute myeloid leukemia (AML), according to results from the phase 1b/2 AG221-AML-005 trial (NCT02677922) published in Lancet Oncology.1

Results from the study showed that among patients who received the combination of enasidenib plus azacitidine, the overall response rate (ORR) was 74% (95% CI, 61%-84%) vs 36% (95% CI, 20%-55%) for patients who received azacitidine alone (odds ratio 4.9; 95% CI, 2.0-11.9; P = .0003).

“Combination therapy with enasidenib plus azacitidine was safe, generally well tolerated, and had antileukemic activity in these older patients with IDH2-mutant AML who were ineligible for intensive chemotherapy,” the study authors wrote. “The overall response rate and complete remission rate in the combination group were more than 2 times greater than in the azacitidine-only group, and more than double the rates with enasidenib monotherapy in patients with newly diagnosed AML, suggesting a greater-than-additive effect when combining these drugs.”

For patients with AML, induction with myeloablative intensive chemotherapy is the standard-of-care initial treatment for those who are fit to receive it. For those who are not candidates for this approach, lower-intensity strategies, such as low- dose cytarabine, hypomethylating agents such as venetoclax (Venclexta), glasdegib (Daurismo); and other targeted therapies for patients with FLT3, IDH1, or IDH2 mutations, are available options.

Enasidenib is an oral, small-molecule IDH2 inhibitor that has been shown to suppress 2-hydroxyglutarate concentrations and inhibit the gain-of-function activity of mutant IDH2 proteins. The FDA approved the agent in 2017 for the treatment of patients with relapsed or refractory IDH2-mutated AML, based on results from the phase 1/2 AG221-C-001 trial (NCT01915498). The study enrolled 345 patients with IDH2-mutant hematological malignancies, including 39 with treatment-naive, newly diagnosed AML who were not candidates for intensive chemotherapy. Results showed that enasidenib monotherapy yielded an ORR of 31% (95% CI, 17%-48%), and a median overall survival of 11.3 months (95% CI, 5.7-15.1).

Azacitidine, a hypomethylating agent and DNA methyltransferase inhibitor, has been shown to promote clinical responses and improve survival in patients with newly diagnosed AML. Treatment with the agent has been associated with a modest morphological response rate, as well as a median overall survival (OS) of approximately 10 to 12 months.

Combining enasidenib and azacitidine in vitro has been shown to enhance apoptosis vs azacitidine alone and is associated with greater-than-additive increases in hemoglobin and reduced leukemic stem cell and progenitor cell populations. As such, investigators sought to examine the safety, activity, and recommended dose of the combination alone, as part of the phase 1b portion of the study, and compared with azacitidine monotherapy, as part of the phase 2 portion.

AG221-AML-005 is a multicenter, open-label, phase 1b/2 study that was performed at 43 clinical sites in 12 countries including the United States, Germany, Canada, the United Kingdom, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea. Eligible patients were those 18 years or older with newly diagnosed, IDH2-mutant AML, and an ECOG performance status of 0 to 2. Patients had to be ineligible for treatment with intensive chemotherapy.

In the phase 1b portion of the study, enasidenib was examined at 2 doses, 100 mg or 200 mg daily, in combination with subcutaneous azacitidine at a dose of 75 mg/m2 daily. Enasidenib was administered orally, in continuous 28-day treatment cycles, and subcutaneous azacitidine was administered on days 1 through 7 of each 28-day cycle. Dose escalation for enasidenib followed a standard 3 + 3 study design, and dose-limiting toxicities were assessed during the first treatment cycle for patients receiving one or more doses of enasidenib. The recommended enasidenib dose for phase 2 was 100 mg daily.

In the phase 2 portion, patients were randomized 2:1 to receive with either enasidenib (100 mg daily) plus azacitidine (75 mg/m2) or azacitidine (75 mg/m2) monotherapy.

The primary end points for the phase 1b portion of the study were safety, tolerability, and the recommended phase 2 dose of enasidenib. Secondary end points included ORR and rate of complete remission plus complete remission with partial hematological recovery. The primary end point for the phase 2 portion was ORR.

Secondary end points for the phase 2 portion included complete remission (CR) rate; rate of CR plus CR with partial hematological recovery; rate of hematological improvement in the erythroid, neutrophil, or platelet lineages; time to response TTR; duration of response DOR; time to CR plus CR with partial hematological recovery; duration of CR plus CR with partial hematological recovery; event-free survival; OS; and 1-year OS rate.

From June 2016 to August 2018, 322 patients with newly diagnosed AML were assessed for eligibility and 130 were enrolled on the study. Of those patients, 107 had IDH2-mutant AML. At data cutoff for the interim analysis, 24 patients were still receiving their assigned treatment, 6 had received enasidenib plus azacitidine in the phase 1b dose-finding portion, and 101 patients in phase 2 were randomly assigned either the combination (n = 68) or azacitidine only (n = 33).

Among the 6 patients included on the phase 1b portion of the study, the median age was 68 years old (range, 65-76). A majority of patients were female (67%), had a Arg140 IDH2 mutation (67%), and had an ECOG performance status of 1 (83%). All patients had intermediate cytogenetic risk status (100%), and the most common reasons that patients were ineligible for intensive therapy included age (100%) and comorbidities (67%).

Among the 101 patients included on the phase 2 portion of the study, the median age was 75 years old (range, 71-78). Most patients were male (53%), had a Arg140 IDH2 mutation (74%), and had an ECOG performance status of 1 (57%). Most patients had intermediate cytogenetic risk status (84%), and the most common reasons that patients were ineligible for intensive therapy included age (71%) and comorbidities (36%).

Additional data from the phase 1b portion of the study showed that the combination of enasidenib plus azacitidine was well tolerated at both the 100 mg and 200 mg dose levels of enasidenib, and the overall safety profile was consistent with that of each agent as monotherapy. The median treatment duration in phase 1b portion was 11 cycles (range, 5-30), and the ORR was 67% (n = 4/6), including 3 (50%) complete remissions (CR; 1 in the 100 mg cohort, and 2 in the 200 mg cohort), and 1 in the 100 mg cohort had CR with incomplete blood count. Moreover, 67% of patients in each dosing cohort had a CR or complete remission with partial hematological recovery.

In terms of safety in the phase 1b portion, 6 patients had an adverse effect (AE) that as considered to be potentially related to treatment with enasidenib, azacitidine, or both. The most frequently reported AEs were nausea (n = 4/6), hyperbilirubinemia (n = 2/6), diarrhea (n = 2/6), fatigue (n = 2/6), neutropenia (n = 2/6), thrombocytopenia (n = 2/6), and vomiting (n = 2/6). Treatment-related AEs of grade 3/4 that were reported in more than 1 patient were neutropenia (n = 2/6), thrombocytopenia (n = 2/6), and hyperbilirubinemia (n = 2/6). No dose-limiting toxicities were reported in either dosing cohort.

Additional data from the phase 2 portion of the study showed that median follow-up for those who received the combination was 14.9 months (range, 8.7-20.0), and 13.7 months (range, 9.2-24.6) for those who received azacitidine alone. Moreover, at data cutoff, 69% of patients in the combination group and 97% of patients in the azacitidine-only group had discontinued treatment.

Patients in the combination arm achieved a CR rate of 54% (95% CI, 42%-67%) vs 12% (95% CI, 3%-28%) in the azacitidine arm. Additionally, the rate of CR or CR with partial hematological recovery was 57% in the combination arm vs 18% in the azacitidine arm. The rate of CR with incomplete blood count or platelet recovery was 9% in the combination arm vs 18% in the azacitidine arm.

Six percent of patients in each study arm achieved a partial remission, and 19% in the combination arm had stable disease vs 48% in the azacitidine arm. The median time to first response was 1.9 months (range 1.1-3.9) in the combination arm vs 3.6 months (range 1.9-4.4) in the azacitidine arm. The time to CR was 5.4 months (range, 3.8-7.6) vs 4.4 months (3.8-5.6), respectively.

The median DOR in the combination arm was 24.1 months (95% CI, 10.0–not reached [NR]) vs 9.9 months (95% CI, 5.5-13.6). The median duration of CR was NR (95% CI, 7.7–NR) and 12.7 months (95% CI, 11.7-NR), respectively.

At data cutoff, 24% of patients in the combination group, and 58% of patients in the azacitidine group had relapsed or progressed, and 58% and 40%, respectively, had sustained responses lasting at least 12 months.

The median time to CR plus CR with partial hematological recovery was 4.6 months (range, 2.3-6.7) in the combination group and 3.8 months (range, 3.5-5.4) in the azacitidine-only group. Moreover, the median duration of CR plus CR with partial hematological recovery was NR (95% CI, 10.2–NR) in the combination group vs 14.6 months (95% CI, 3.7–NR) in the azacitidine-only group.

In terms of safety, the combination of enasidenib and azacitidine was generally well tolerated, with 91% of those in the combination group vs 81% in the azacitidine-only group experiencing a treatment-related AE. The most common grade 1/2 AEs in the combination group were nausea (49%), vomiting (29%), and diarrhea (21%). Furthermore, the most common grade 3/4 AEs reported on the combination arm were neutropenia (37%), thrombocytopenia (37%), and anemia (19%).

“AEs led to interruption of enasidenib, azacitidine, or both in 28 (41%) of 68 patients in the combination group, and azacitidine was interrupted in nine (28%) of 32 patients in the azacitidine-only group,” study authors wrote. “Five (7%) patients discontinued combination therapy because of adverse events.”

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