Patients with acute myeloid leukemia (AML) harboring IDH1 mutations who were not suitable for intensive chemotherapy had improved event-free survival (EFS) and overall survival (OS) with the combination of ivosidenib plus azacitidine versus azacitidine plus placebo, according to results of the phase 3 AGILE clinical trial1 presented at the 2021 American Society of Hematology annual meeting.
Ivosidenib plus azacitidine led to a 67% reduction in the risk for treatment failure, relapse, or death, and a 56% OS improvement in older, unfit patients with IDH1 mutation.
The median OS was 24 months with the combination and 7.9 months with azacitidine plus placebo, translating into a significant 56% (P = .0005) reduction in death with the addition of ivosidenib.
“The ivosidenib plus azacitidine combination was safe and tolerable, with fewer infections reported relative to placebo plus azacitidine. In addition, the clinical benefit of the combination was supported by favorable health-related quality of life,” stated lead investigator Hartmut Döhner, MD, Ulm University Hospital, Germany.
“I’m really excited by the results from the AGILE trial,” said Mikkael A. Sekeres, MD, Chief, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, FL, moderator of a press briefing at the meeting. “The results show survival that’s 3 times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” Dr Sekeres said.
The standard treatment for older patients (with or without IDH1 mutations) is fast becoming azacitidine plus venetoclax, which is less difficult to tolerate than standard induction chemotherapy, but nevertheless, it can have tolerability issues.
Dr Sekeres noted that the combination of ivosidenib plus azacitidine may be a better choice for treatment of older patients with AML and IDH1 mutation—particularly those with comorbidities—who may not be able to tolerate venetoclax plus azacitidine.
The analysis of the AGILE study was based on a data cutoff in March 2021, when 146 patients out of a planned 200 total had been randomized to oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2 (subcutaneously or intravenously) or to the same dose of azacitidine plus placebo.
In May 2021, the independent data-monitoring committee recommended to halt the study because an interim analysis showed significant improvements in outcomes among patients who received ivosidenib plus azacitidine.
At baseline, demographic and disease characteristics of patients in both treatment arms were similar (median age, approximately 76 years and approximately 75% of patients had de novo AML). The majority of patients in each group had intermediate cytogenetic risk.
The intent-to-treat analysis included patients without complete remission by week 24 as judged to have had an “event” on day 1 of randomization.
The longest follow-up of the data was 29 months, and at that time significantly fewer study events were found in the azacitidine plus ivosidenib group versus azacitidine (P = .0011). Events were defined as treatment failure by week 24, relapse from remission, or death from any cause.
The EFS and the OS benefits were consistent across all prespecified subgroups. The complete response rate was 34% with the combination versus 11% with azacitidine alone (P <.0001), and the overall response rates were 45% versus 14%, respectively (P <.0001).
Quality-of-life measures were numerically higher for ivosidenib plus azacitidine across all measures, and were significantly better for the combination at day 1 of cycle 5 for diarrhea and appetite loss versus azacitidine plus placebo.
Treatment-emergent adverse events included grade ≥2 differentiation syndrome (14.1% with ivosidenib plus azacitidine vs 8.2% with azacitidine plus placebo). The grade ≥3 QT interval prolongation was 9.9% versus 4.1%, respectively.
Infections of any grade were less frequent with ivosidenib plus azacitidine than with azacitidine alone (28.2% vs 49.3%).
1. Montesinos P, Recher C, 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. Blood. 2021;138(suppl 1):Abstract 697.