Enasidenib/Azacitidine Combo Yields Promising Overall Response Rate In IDH2+ AML

Overall response rates were improved with the use of enasidenib (Idhifa) plus azacitidine (Vidaza) compared with azacytidine monotherapy for patients with newly diagnosed IDH2­-mutant acute myeloid leukemia (AML), according to results from an ongoing phase 1b/2 study (NCT02677922) that was published in The Lancet Oncology.

In the phase 2 portion of the study, 74% of patients in the enasidenib group achieved an overall response (95% CI, 61%-84%), compared with 36% (95% CI, 20%-55%) of patients in the azacytidine monotherapy group (OR, 4.9; 95% CI, 2.0-11.9; P = .0003). The complete remission (CR) rate was higher in the combination group then the single agent group (OR, 8.7; 95% CI, 2.7-27.3; P <.0001). The CR rate plus CR rate with incomplete blood count or platelet recovery was 63% in the combination arm compared with 30% in the single agent arm (OR, 4.0; 95% CI, 1.6-9.6; P = .0019).

In the first phase, 130 patients were enrolled, 107 of whom had IDH2-mutant AML and 23 had IDH1­­­-mutant AML. At data cutoff, 24 patients were still receiving their assigned treatment, and 6 patients were enrolled into phase 1b. In the phase 2 portion, 101 patients were randomly assigned to receive either enasidenib plus azacytidine (n = 68) or azacytidine monotherapy (n = 33).

Of those who were in phase 1b dose finding portion of the study, 3 patients received the 100 mg dose of enasidenib and 3 patients 200 mg dose plus azacitadine. Patients in the 100 mg group discontinued treatment due to disease progression and to undergo hematopoietic stem cell transplant (HSCT), while 1 patient in the 200 mg group had disease progression, and another transferred to a commercially available enasidenib group.

One patient discontinued treatment with azacitidine due to toxicity and 1 received enasidenib monotherapy. Additionally, 1 patient in the 100 mg group received monotherapy for 269 days and had a complete remission with platelet recovery and then proceeded to HSCT. One patient in the 200 mg group received enasidenib for 82 days and discontinued because of disease progression. Patients in the 1b group had a treatment duration of 37 months and 35 months as of the data cutoff.

The median follow-up was 14.9 months in the combination group and 13.7 months in the azacytidine only group. At data cutoff, 69% of patients in the combination group and 97% of patients in the single agent azacytidine group discontinued treatment.

At the primary data cutoff, 24% of responding patients in the combination group, and 58% of patients in the azacytidine only group had relapsed or progressed. A total of 58% of patients in the combination group and 40% in the azacytidine only group had sustained responses that lasted for a minimum of 12 months. At the updated data cutoff, the estimated duration of response decreased to 13.9 months (95% CI, 10.0–not reached [NR]) in the combination group and 9.9 months (95% CI, 5.5-13.6) in the single agent azacytidine group.

The median to time to CR and CR with partial hematologic recovery was 4.6 months in the combination group and 3.8 months in the azacytidine monotherapy group. In the combination group, the estimated median duration of CR and CR with partial hematological response was not reached (95% CI, 10.2-NR), and was 14.6 months in the azacytidine only group (95% CI, 3.7-NR). The 1-year overall survival in the combination group was 72% (95% CI, 60%-82%) and 70% (95% CI, 50%-83%) in the azacytidine only group.

The most common grade 3/4 adverse effects (AEs) in the combination and single agent arms, respectively, were thrombocytopenia (37% vs 19%) and neutropenia (37% vs 25). Serious treatment-related AEs (TRAEs) occurred in 43% of patients in the combination group and 44% of patients in the azacytidine group. Serious TRAEs in both groups included febrile neutropenia (13% vs 16%), differentiation syndrome (10% vs 0%), and pneumonia (4% vs 6%).

At data cutoff, 43% of patients in the combination group had died, 22% of which occurred during treatment and 21% during survival follow-up. AEs leading to death in the combination group included respiratory failure, sepsis, and lung infection. At 60 days, 7% of patients in the combination group, as well as 3% of those in the azacytidine group.

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