Patients with acute myeloid leukemia (AML) harboring IDH1 mutations who were not suitable for intensive chemotherapy had improved event-free survival and overall survival (OS) with the combination of ivosidenib (Tibsovo) plus azacitidine (Onureg) versus azacitidine plus placebo, according to results of the phase 3 AGILE trial presented at the 2021 ASH Annual Meeting and Exposition.
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, Medical Director, Internal Medicine, Ulm University Hospital, Germany.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, MS, Chief, Division of Hematology, Leukemia Section, Sylvester Comprehensive Cancer Center, University of Miami, FL, who was moderator of a press briefing at the meeting. “The results show survival that is 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 (Venclexta), which is easier to tolerate than standard induction chemotherapy, but nevertheless, can have toxicity issues.
Dr Sekeres noted that the combination of ivosidenib plus azacitidine may be a better choice for the treatment of older patients with IDH1-mutated AML—particularly those with comorbidities—who may not be able to tolerate venetoclax plus azacitidine.
The analysis of the AGILE trial was based on a data cutoff in March 2021, when 146 patients out of a planned 200 had been randomly assigned 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 a halt to the trial because an interim analysis showed significant improvements in outcomes among patients randomized to 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 longest follow-up of the data was 29 months, and at that time significantly fewer study events were found in the ivosidenib plus azacitidine group versus azacitidine alone (P = .0011). Events were defined as treatment failure by week 24, relapse from remission, or death from any cause.
The event-free survival and OS benefits were consistent across all prespecified subgroups, including patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
The complete response rate was 34% with the combination and 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%, respectively).
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