Enasidenib/Azacitidine Combination Significantly Improves ORR in AML

The addition of enasidenib (Idhifa) to azacitidine was both well tolerated and improved overall response rate (ORR) in patients with newly-diagnosed IDH2-mutant acute myeloid leukemia (AML) compared with azacitidine monotherapy, according to a new study published in The Lancet Oncology.

Enasidenib is an oral mutant isocitrate dehydrogenase-2 inhibitor. The current standard of care in AML is induction with myeloablative intensive chemotherapy. For patients who are not chemotherapy eligible, either for age or poor performance status, lower-intensity strategies are used. These include low doses of chemotherapy and the use of targeted agents with FLT3 or IDH2 mutations.

A phase 1/2 study compared azacitidine monotherapy to the experimental combination of azacitidine and enasidenib (NCT02677922). The primary end points are dose-limiting toxicities, adverse events (AEs), pharmacokinetics, and objective response rate. Secondary end points include event-free survival, complete remission, hematologic improvement rate, duration of response, OS, one-year survival, and time to response.

Phase 1b evaluated the efficacy, tolerability, and clinical activity of the combination. During phase 2, the combination was compared head to head with azacitidine monotherapy.

Of the 322 patients accessed for eligibility, 101 were randomly assigned into the 2 arms. Sixty-eight were assigned to the experimental combination arm while 33 received the monotherapy only. In the experimental arm, 47 discontinued treatment. Reasons included disease progression (21), death (12), patient or physician decision (6), stem cell transplant (3), and transition to another treatment (1). Sixty-eight were ultimately analyzed for efficacy.

In the control arm, 31 discontinued treatment. Reasons for discontinuation included disease progression (17), patient or physician decision (7), transition to other treatment (3), adverse events (2), stem cell transplant (1), and death (1).

During phase 1b study, the average age in the enasidenib 100mg plus azacitidine arm (n=3) was 76 (range, 69-79) and 33% were male. Sixty-seven percent had an Arg140 mutation and 33% had an Arg172 mutation. All patients had an ECOG score of 1 and an intermediate cytogenetic risk status. One hundred percent of patients were ineligible for intensive therapy due to age and 67% were ineligible due to comorbidities. Bone marrow blasts were seen in 30% of patients. The average absolute neutrophil count was 5 (range, 0.1-9.8), the average hemoglobin count was 98, the average platelets was 142 (range, 87-196), and the average white blood cell count was 10.2 (range, 0.8-19.6).

In the phase 1b 200 mg cohort (n=3), the average age was 65 (range, 64-67) and 33% were male. An Arg140 mutation was seen in 67% of patients and an Arg172 mutation was seen in 33% of patients. Sixty-seven percent of patients have an ECOG score of 67% and 100% had an intermediate cytogenetic risk status. Age was the reason for intensive therapy ineligibility in 100% of patients and comorbidities was the reason in 67% of patients. Bone marrow blasts were observed in 74% of patients (range, 72-87), the absolute neutrophil count was 0.1 (range, 0.1-3.8), the average hemoglobin count was 97 (range, 93-107), the average platelet count was 42 (range, 19-96), and the average white blood cell count was 6.7 (range, 1.4-19.2)

During phase 2, the average age of the experimental arm (n = 68) was 75 (range, 70-79) and 67% were male. Mutations observed included Arg140 (75%) and Arg172 (245). ECOG status included O (22%), 1 (62%), and 2 (16%). Eighty-three percent of patients had an intermediate cytogenetic risk status, 16% had a poor risk status, and 2% had a good risk status. Reasons for intensive therapy ineligibility included age (50%), comorbidities (34%), patient decision (21%), performance status (9%), unfavorable cytogenetics (4%), and other (4%). Bone marrow blasts were seen in 49% of patients (range, 28-73). The average absolute neutrophil group was 0.6 (range, 0.2-1.1), the average hemoglobin count was 92 (range, 85-102), the average platelet count was 62 (range, 23-109), and the average white blood cell count was 3 (range, 1.7-7.5).

The average age of the control arm (n = 33) was also 75 (range, 71-78), with 47% of patients being male. An Arg140 mutation was seen in 73% of patients, Arg172 was seen in 21% of patients, and both were seen in 3% of patients. ECOG performance statuses represented included 0 (21%), 1 (48%), and 2 (30%). Eighty-eight percent of patients had an intermediate cytogenetic risk status and 12% had a poor cytogenetic risk status. Reasons for intensive therapy ineligibility included age (67%), comorbidities (39%), patient decision (12%), performance status (9%), unfavorable cytogenetics (6%), and other (3%). Bone marrow blasts were seen in 50% of patients (range, 29%-68%). The average absolute neutrophil count was 0.4 (range, 0.2-1.1), the average hemoglobin count was 90 (range, 80-109), the average platelets was 76 (range, 27-130), and the average white blood cell count was 3.5 (range, 2-5.9).

The overall response in the experimental cohort, was 74% (95% CI, 61-84; P =.0003) compared with 36% in the control cohort (95% CI, 20-55; P =.0003). In the experimental arm, the complete remission rate was 54% (95% CI, 42-67; P <0.0001) and the partial remission rate was (9%). A morphological leukemia-free state was seen in 4% of patients, and stable disease was seen in 19% of patients. Disease progression was seen in 1% of patients.

In the control cohort, the complete remission rate was 12% (95% CI, 3-38; P <.0001), and the partial remission rate was 6%. Stable disease was seen in 48% of patients and disease progression in 3% of patients.

In the experimental arm, the time to first response was 1.9 months (range, 1.1-3.9) compared with 3.6 months in the control arm (range, 1.9-4.4). The average time to complete remission in the experimental arm was 5.4 month (range, 3.8-7.6) and the duration of response was 24.1 months (95% CI, 10.0 to not reached [NR]). In the control arm, the average time to first response was 3.6 months (range, 1.9-4.4) and the time to complete remission was 4.4 months (range, 3.8-5.6). The average duration of response was 9.9 months (95% CI, 5.5-13.6). The median duration of complete response was not reached in the experimental arm (95% CI, 7.7-NR) and 12.7 months in the control arm (95% CI, 11.7-NR).

In terms of safety, 91% of patients in the combination group and 81% of patients in the monotherapy group experienced an AE. Common AEs included nausea, neutropenia, thrombocytopenia, vomiting, and anemia.

_REFERENCE:

_{DiNardo C, Schuh A, Stein E, 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. 2021; published online. doi: 10.1016/ S1470-2045(21)00494-0}