The combination of the IDH1 inhibitor ivosidenib and azacitidine demonstrated significant clinical benefit in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), according to phase III results published in The New England Journal of Medicine. With a median follow-up of just more than one year, the median event-free survival (EFS) was significantly longer for patients treated with ivosidenib plus azacitidine compared with those treated with azacitidine plus placebo (hazard ratio [HR] for treatment failure, relapse from remission, or death = 0.33; 95% CI 0.16-0.69; p=0.002). See TABLE for an overview of additional study outcomes.
Older patients with IDH1-mutated disease who are considered unfit for intensive curative approaches represent a difficult-to-treat population. Results from a phase Ib trial of ivosidenib plus azacitidine in patients with newly diagnosed disease showed encouraging clinical activity.
In this phase III trial, researchers led by Pau Montesinos, MD, PhD, of University Hospital La Fe in Spain, randomly assigned 146 patients with IDH1-mutated AML who were ineligible for intensive induction chemotherapy to oral ivosidenib plus subcutaneous azacitidine or matched placebo plus azacitidine. The primary endpoint of EFS was defined as time from randomization to treatment failure, relapse from remission, or death from any cause.
The estimated probability that a patient would remain event free at 12 months was three times as high in patients assigned to the combination compared to those assigned to placebo plus azacitidine (37% vs. 12%). The percentage of patients with complete remission was 38% for the combination and 11% for placebo with azacitidine.
Median overall survival (OS) was also more than three times longer (24.0 vs. 7.9 months; HR for death = 0.44; 95% CI 0.27-0.73; p=0.001).
“This is the first randomized study showing improvements in OS using the combination of azacitidine with a targeted therapy for an actionable mutation in unfit AML,” Dr. Montesinos said. “Unfortunately, other attempts with targeted therapies have failed in this difficult-to-treat setting.”
The researchers wrote that this clinical benefit is also supported by “favorable health-related quality of life, incidences of transfusion independence, and the expected constellation of adverse events (AEs) associated with treatment for acute leukemia.”
The most common grade 3 or higher AEs were febrile neutropenia (28% for the combination and 34% for azacitidine alone) and neutropenia (27% vs. 16%). Infection of any grade occurred in 28% of patients assigned to ivosidenib plus azacitidine and 49% of patients assigned to placebo and azacitidine.
Dr. Montesinos said that current standard of care for the majority of unfit patients with AML is azacitidine plus venetoclax, which does not target a specific subgroup of patients harboring selected mutations. This regimen can be initiated without waiting for mutational status, he said.
“Instead, we need to carefully assess clinical characteristics and performance status of patients in order to safely initiate venetoclax and azacitidine, as this therapy is quite effective to induce initial complete remissions, but there is substantial myelotoxicity,” Dr. Montesinos said.
Future availability of ivosidenib plus azacitidine may offer an additional pathway for IDH1-mutated AML.
“Although a potential disadvantage could be the need of molecular screening before starting frontline therapy for all patients, there are several features making this new regimen an attractive option in this setting,” Dr. Montesinos said. “In my opinion, the more relevant advantage is that ivosidenib plus azacitidine looks less myelosuppressive, and potentially leads to fewer episodes of infections in this frail population.”
Dr. Montesinos said that real-life experience with the combination will help physicians to position this new regimen among other first-line options.
Any conflicts of interest declared by the authors can be found in the original article.
Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386:1519-1531.