The addition of ivosidenib to azacitidine improved response and prolonged overall survival (OS) compared with placebo plus azacitidine among patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy induction, according to results of the phase 3 AGILE trial presented at the 2021 American Society of Hematology (ASH) Annual Meeting.
Ivosidenib is already approved by the U.S. Food and Drug Administration as a single-agent for the treatment of relapsed/refractory AML and patients age 75 or older with newly diagnosed AML or with comorbidities that make them ineligible for intensive chemotherapy induction, Hartmut Dōhner, MD, of University Hospital Ulm in Germany, and lead author of the study, said.
The double-blind, phase 3 AGILE trial (ClinicalTrials.gov Identifier: NCT02677922) randomly assigned 146 patients to receive ivosidenib or placebo in addition to azacitidine as first-line treatment for newly diagnosed AML not eligible for intensive chemotherapy induction. The primary endpoint was event-free survival (EFS) and secondary endpoints included the objective response rate (ORR), OS, and the complete response (CR) rate.
At baseline, the median age was 76 and the majority of patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Approximately 25% of patients had secondary AML and the remaining had de novo disease. Cytogenetic risk was intermediate or poor among 63.1% and 24.6% of patients, respectively.
The Independent Data Monitoring Committee recommended that the trial stop enrollment due to a substantial difference of clinical importance between the treatment groups.
The combination of ivosidenib plus azacitidine significantly prolonged OS with a median of 24.0 months compared with 7.9 months with placebo plus azacitidine (hazard ratio [HR], 0.44; 95% CI, 0.27-0.73; P =.0005). The OS benefit was consistent across all subgroups. The EFS was also improved in the ivosidenib group compared with the placebo group (HR, 0.33; 95% CI, 0.16-0.69; P =.0011).
The ivosidenib group also demonstrated a higher ORR of 62.5% compared with 18.9% in the placebo group (P <.0001), with a median duration of response of 22.1 and 9.2 months, respectively.
There were 47.2% of patients who achieved CR in the ivosidenib group compared with 14.9% in the placebo group. The CR plus CR with partial hematologic recovery rate was 52.8% and 17.6% among patients treated with ivosidenib or placebo, respectively.
Dr Dōhner noted that, “The clinical benefit of the combination was supported by favorable health-related quality of life.”
Grade 3 to 4 treatment-emergent adverse events (TEAEs) occurred in 70.4% and 64.4% of patients in the ivosidenib or placebo arms, respectively. The most common TEAEs in the ivosidenib group was pneumonia, infections, and hematologic events. Of special interest, grade 2 or higher differentiation syndrome occurred more commonly with ivosidenib at 14.1% compared with 8.2% with placebo and grade 3 or higher QT prolongation at 9.9% and 4.1%, respectively. There were no grade 5 events related to treatment.
Disclosures: This research was supported by Agios Pharmaceuticals, Inc. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
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Dōhner H, Montesinos P, Vives S, et al. AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. Presented at ASH 2021; December 11-14, 2021. Abstract 697.