Enasidenib plus Azacytidine Improved Response Rates for Newly Diagnosed IDH2-Mutant Acute Myeloid Leukemia

A phase 1b/2 trial found that the combination of enasidenib plus azacytidine improved overall responses and was well tolerated compared with azacytidine monotherapy for patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia.

Enasidenib plus azacytidine was well tolerated and improved responses compared with azacytidine treatment alone among patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia (AML), according to results from the phase 1b/2 AG221-AML-005 trial (NCT02677922) published in Lancet Oncology.

The overall response rate (ORR) was 74% (95% CI, 61%-84%) among patients in the enasidenib plus azacytidine group compared with 36% (95% CI, 20%-55%) among patients in the azacytidine alone group (odds ratio [OR], 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 mutant-IDH2 acute myeloid leukemia who were ineligible for intensive chemotherapy,” the investigators 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 acute myeloid leukemia.”

Eligibility for study enrollment required patients to be aged 18 years or older with newly diagnosed, mutant-IDH2 disease. Additionally, patients were required to have an ECOG performance status of 0 to 2, and be ineligible for intensive chemotherapy.

The dose-escalation portion of the study featured enasidenib doses of 100 mg or 200 mg per day in combination with subcutaneous azacytidine at 75 mg/m2 for 7 days of each cycle. In the phase 2 portion of the study, the 100 mg dose of enasidenib was selected and administered daily with subcutaneous azacytidine on days 1 to 7 of continuous 28-day treatment cycles. Dose escalation of enasidenib followed a 3+3 design.

The primary end points of the phase 1b dose-escalation portion of the trial included safety, tolerability, and the recommended dose of enasidenib. Secondary end points included ORR and complete remission (CR) rate plus CR with partial hematological recovery. For the phase 2 portion, the primary end point was ORR, with similar secondary end points as the phase 1b portion.

A total of 130 patients with newly diagnosed AML were enrolled in the trial between June 3, 2016, and August 2, 2018, 107 of whom had IDH2-mutant disease. Six patients enrolled in the phase 1b portion and received 1 of the 2 doses of enasidenib in combination with azacytidine. The phase 2 portion featured 101 patients who were randomly assigned to receive either enasidenib plus azacytidine (n = 68) or azacytidine only (n = 33). The median patient age was 75 years (IQR, 71-78).

The CR rate in the phase 2 portion was higher in the enasidenib plus azacytidine group compared with the azacytidine alone group (OR, 8.7; 95% CI, 2.7-27.3; P <.0001). Moreover, the CR rate plus CR with incomplete blood count or platelet recovery was also higher in the enasidenib plus azacytidine group (63%) compared with the azacytidine alone group (30%; OR, 4.0; 95% CI, 1.6-9.6; P = .0019).

Overall survival (OS) rates at 1-year were 72% (95% CI, 60%-82%) and 70% (95% CI, 50%-83%) in the enasidenib plus azacytidine and azacytidine alone groups, respectively. The median OS was not reached (95% CI, 22.0 months–not reached) for patients in the enasidenib plus azacytidine group with a morphological CR. At data cutoff, the median treatment exposure was 12.1 months (IQR, 3.7-16.7) and 6.2 months (IQR, 3.2-10.6) in the enasidenib plus azacytidine and azacytidine alone groups, respectively.

Gastrointestinal and hematologic adverse effects (AEs) were observed in 91% of patients in the enasidenib plus azacytidine group and 81% of patients in the azacytidine alone group. Common treatment-related AEs included nausea, neutropenia, thrombocytopenia, vomiting, and anemia.

All but 1 patient in the phase 2 portion of the study experienced a grade 3 or 4 AE. Cytopenias were the most common grade 3 or 4 AEs, including thrombocytopenia, anemia, neutropenia, and febrile neutropenia.

“To our knowledge, this is the first trial to assess the safety and activity of enasidenib in combination with azacytidine in patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia,” the investigators concluded.

Reference

DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. Published online October 18, 2021. doi:10.1016/S1470-2045(21)00494-0