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The combination of ivosidenib plus azacitidine significantly improved event-free survival compared with azacitidine plus placebo in previously untreated patients with IDH1-mutated acute myeloid leukemia, meeting the primary end point of the phase 3 AGILE trial.
The combination of ivosidenib (Tibsovo) plus azacitidine significantly improved event-free survival (EFS) compared with azacitidine plus placebo in previously untreated patients with IDH1-mutated acute myeloid leukemia (AML), meeting the primary end point of the phase 3 AGILE trial (NCT03173248).1
Notably, the trial also met all its important secondary end points, such as complete remission (CR) rate, overall survival (OS), CR and CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR).
The toxicity profile of ivosidenib plus azacitidine proved to be consistent with what has previously been published.
Because a difference of clinical importance was noted between the 2 treatment arms, the Independent Data Monitoring Committee recommended that the study halt further enrollment. Full data from the trial will be shared in a presentation at a future medical meeting, according to Servier Pharmaceuticals.
“The results of AGILE represent a major breakthrough and will be welcome news for patients dealing with previously untreated IDH1-mutated AML,” Claude Bertrand, executive vice president of Research & Development at Servier Group, stated in a press release. “We look forward to sharing the findings from this study with the medical community and with regulatory authorities around the world.”
The multicenter, double-blind, randomized phase 3 trial examined the safety and efficacy of ivosidenib plus azacitidine vs azacitidine plus placebo in newly diagnosed patients with AML who were not candidates for intensive chemotherapy.
To be eligible for enrollment, patients needed to be at least 18 years of age, have previously untreated AML, a tumor that harbors an IDH1 mutation, an ECOG performance status of 0 to 2, and acceptable hepatic and renal function.2 If patients were candidates for, and willing to receive, intensive induction chemotherapy for their disease, had previously received treatment for their disease with the exception of hydroxyurea, received a hypomethylating agent for myelodysplastic syndrome, had a prior IDH1 inhibitor, or had a known hypersensitivity to any of the components of the drugs used on the trial, they were excluded.
The primary end point of the trial is EFS, which was defined as the time from randomization to treatment failure, relapse from remission, or death from any cause. Important secondary end points included CR rate, OS, CRh rate, and ORR.
Previously, a phase 1/2 trial (NCT02677922) examined the safety and tolerability of ivosidenib and azacitidine in newly diagnosed patients with IDH1-mutated AML who were not candidates for intensive chemotherapy.3
Seven patients were enrolled to the dose-finding phase of the trial and 16 were included in the expansion phase. Participants received ivosidenib at a once-daily dose of 500 mg continuously for 28-day cycles plus azacitidine at a daily dose of 75 mg/m2 subcutaneously on days 1 through 7 in each 28-day cycle.
The primary end points of the trial were to identify the recommended combination dose and to establish the safety and tolerability of the regimen. Key secondary and exploratory end points comprised ORR, CR rate, CR + CRh rate, and mIDH1 variant allele frequency (VAF).
At a data cutoff of February 19, 2019, a total of 23 patients had received treatment with the doublet and 10 patients were still on study treatment. The median number of treatment cycles in these patients was 15 (range, 1-30).
The median age of the study participants was 76 years (range, 61-88), with 52% of patients aged 75 years or older. Moreover, 52% of patients were female, the median mIDH1 VAF in bone marrow–derived mast cells was 35%, 61% had an ECOG performance status of 1, and 65% of patients had intermediate cytogenetic risk status. Additionally, 65% of patients had de novo AML and 35% had secondary AML.
Among the 23 patients, the doublet elicited an ORR of 78.3% (95% CI, 56.3%-92.5%), with a median time to response of 1.8 months (range, 0.7-3.8). The median duration of response was not evaluable (95% CI, 10.3–not evaluable). The CR rate in these patients was 60.9% (95% CI, 38.5%-80.3%) and the CR + CRh rate was 69.6% (95% CI, 47.1%-86.8%). The 12-month OS rate in these patients was 82.0% (95% CI, 58.8%-92.8%).
All-grade toxicities that were reported in 30% or more patients included thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (44%), pyrexia (44%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), neutropenia (35%), insomnia (35%), and back pain (30%).
Serious adverse effects reported in 2 or more participants included febrile neutropenia (n = 9), IDH differentiation syndrome (n = 3), sepsis (n = 3), pyrexia (n = 3), lung infection (n = 2), pneumonia (n = 2), and syncope (n = 2).
Six deaths occurred, but none were determined to be related to the treatment. Three on-treatment deaths were due to sepsis, enterococcal infection, and Enterobacter bacteremia; 3 deaths occurred in follow-up and were due to disease complication, disease progression, and an unknown cause. The 30-day mortality rate with the doublet was 0%, and the 60-day mortality rate was 4%.