For patients with newly diagnosed, IDH1-mutated acute myeloid leukemia (AML), ivosidenib (IVO) plus azacytidine (AZA) showed benefits in overall survival (OS), event-free survival (EFS), and clinical responses versus placebo plus AZA, based on findings from the phase 3 AGILE trial.

The treatment combination had a satisfactory safety profile with practicable treatment-emergent adverse events (TEAEs), according to Courtney D. DiNardo, MD, MSCE, and colleagues, who presented these findings at the 10th Annual Meeting of the Society of Hematologic Oncology. “Moreover, patients treated with IVO + AZA reported better HRQOL outcomes in comparison with patients in the placebo + AZA arm,” wrote Dr. DiNardo and team.

In AGILE—a global, randomized, double-blind study—200 adult patients were randomized 1:1 to receive oral IVO 500 mg once daily plus AZA 75 mg/m2 subcutaneously or intravenously (N=72) or matching placebo in combination with AZA (N=72). EFS was the primary endpoint, whereas OS, objective response rate (ORR), complete response (CR) rate, and CR plus CR with hematologic recovery (CRh) were secondary endpoints.

Consistent Event-Free Survival Benefit With IVO/AZA

Participants enrolled in the study had previously untreated AML with IDH1 mutation, adequate liver and kidney function, an ECOG performance status of 0-2, and eligibility for intensive chemotherapy.

Among patients in the experimental arm, 75.0% patients had de novo AML, compared with 71.6% in the comparator arm. Secondary AML was noted in 25% of the IVO/AZA arm and 28.4% of the placebo/AZA arm. In a baseline bone marrow analysis, the median IDH1 mutation variant allele frequency was 36.7% in the experimental arm versus 35.5% in the control arm.

At a median follow-up of 12.4 months, EFS improvement with IVO/AZA was considerable when compared with placebo/AZA (HR, 0.33; 95% CI, 0.16-0.69; two-sided P=0.0023). By week 24, patients who did not achieve a CR were considered to have an EFS event at day 1 of randomization. “The EFS benefit observed with IVO/AZA was consistent across the subgroups in the study,” noted Dr. DiNardo and colleagues.

With IVO/AZA, the median OS observed was 24.0 months, compared with 7.9 months in the placebo arm (HR, 0.44; 95% CI, 0.27-0.73; two-sided P=0.001). The ORR with IVO/AZA was 62.5%, with a CRh rate of 52.8% and a CR rate of 47.2%. In comparison, the placebo/AZA arm showed an ORR of 18.9%, with a 17.6% CRh rate and 14.9% CR rate.

Favorable Safety Profile With IVO Plus AZA & Fewer TEAEs

Nearly all patients (98.6%) in the experimental arm presented with any-grade TEAEs; 93% experienced grade 3 or higher. Hematologic TEAEs of any grade occurred in 77.5% of patients, whereas grade 3 or higher TEAEs occurred in 70.4%. In 100% of patients in the control arm, any-grade TEAEs were observed, with 94.5% having experienced grade 3 or higher. In 65.8% of the control arm, any-grade hematologic TEAEs occurred; in 64.4%, these events were grade 3 or higher.

In the IVO/AZA and placebo/AZA groups, the most common any-grade hematologic TEAEs were thrombocytopenia (28.2% vs 20.5%, respectively), neutropenia (28.2% vs 16.4%), febrile neutropenia (28.2% vs 34.2%), and anemia (31.0% vs 28.8%). In the experimental and control arms, the most common TEAEs were diarrhea (35.3% vs 35.6%, respectively), nausea (42.3% vs 38.4%), constipation (26.8% vs 52.1%), vomiting (40.8% vs 26.0%), pneumonia (23.5% vs 31.5%), and pyrexia (33.8% vs 39.7%).

Compared with the control arm, treatment with the combination of IVO/AZA improved absolute neutrophil count. Moreover, compared with the control arm, a greater percentage of patients in the IVO/AZA arm achieved transfusion independence.

There was a significant improvement in HRQOL with IVO/AZA over time, but there were few clinically relevant improvements observed in the placebo/AZA arm, the study authors observed. “The safety profile of IVO + AZA was favorable, with fewer febrile neutropenia and infection events with IVO + AZA versus placebo + AZA,” Dr. DiNardo and colleagues wrote.