Ivosidenib Plus Azacitidine Brings Long-Term Survival, Hematological Benefit in IDH1-Mutated AML

The phase 3 AGILE clinical trial evaluated ivosidenib plus azacitidine for newly diagnosed, isocitrate dehydrogenase 1 (IDH1)-mutated acute myeloid leukemia (AML), with promising initial results shown with this combination. In a post-hoc analysis from this trial, published in Blood Advances, investigators observed encouraging long-term benefits from the combination, which add to the positive initial findings.

“These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML,” wrote analysis first author Pau Montesinos, MD, PhD, of La Fe University and Polytechnic Hospital, Valencia, Spain.

AGILE was a placebo-controlled trial with a total cohort of 148 patients with newly diagnosed, IDH1-mutated AML unable to undergo intensive chemotherapy. Following randomization, 73 patients received ivosidenib plus azacitidine and 75 patients received placebo plus azacitidine. After a median follow-up of 12.4 months, the ivosidenib-azacitidine arm showed markedly improved overall survival (OS), event-free survival, and complete remission rates as compared with the placebo-azacitidine arm.

The subsequent post-hoc analysis of AGILE involved a long-term follow-up of the trial cohort, with a median follow-up of 28.6 months. The calculated median OS was 29.3 months in the ivosidenib-azacitidine arm versus 7.9 months in the placebo-azacitidine arm, with a hazard ratio of 0.42 (P<0.0001). Patients had faster and more durable hematologic recovery in the ivosidenib-azacitidine arm than in the placebo-azacitidine arm, and there was also more frequent achievement of transfusion independence, at 53.8% versus 17.1%, respectively (P=0.0004).

Thirty-three patients in the ivosidenib-azacitidine arm were evaluable for measurable residual disease (MRD), and 10 achieved MRD negativity by the time of long-term follow-up. The investigators found no link between patient MRD response with IDH1 variant, variant allele frequency (VAF), inferred clonality, or number of baseline comutations.

In the ivosidenib-azacitidine arm among the treatment-responsive, MRD-evaluable patients, the investigators found at the 0.1% VAF threshold, there was no significant difference in OS between MRD-negative and MRD-positive patients, but that the former had numerically longer survival. Once they applied an exploratory 1% VAF threshold, they found that MRD status then became more predictive of long-term OS.

In this long-term analysis of AGILE, the investigators found that the ivosidenib plus azacitidine combination continued to have the safety profile it presented in the initial results from the trial.