In the phase III AGILE trial, the combination of ivosidenib and azacitidine was found to be superior in treating newly diagnosed patients with IDH1-mutated acute myeloid leukemia (AML) compared to azacitidine alone in terms of event-free survival, the study’s primary endpoint. The combination also extended overall survival to a median of 2 years compared to 8 months among those receiving azacitidine alone—a threefold increase in survival duration. These results were presented by Montesinos et al at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 697).

Ivosidenib is currently approved by the U.S. Food and Drug Administration (FDA) for treating IDH1-mutated AML, either in the relapsed or refractory setting, or for newly diagnosed patients older than age 75 or who are ineligible for chemotherapy. The results of the new study suggest that combining ivodidenib with azacitidine offers a promising option for newly diagnosed patients with AML who have mutations in the IDH1 gene. Ivosidenib is targeted at IDH1 mutations, present in about 10% of patients with AML, and works by causing leukemia cells to return to healthy cell functioning, rather than eliminating them altogether. As a result, it does not cause the same degree of myelosuppression as other combination therapies, researchers explained.

AGILE Trial

After the AGILE trial was designed, the FDA approved venetoclax as a first-line treatment in this patient group, making the combination of azacitidine and venetoclax the current standard of care for patients with AML ineligible for intensive chemotherapy throughout much of the world. Although the new trial does not directly compare ivosidenib/azacitidine with the venetoclax/azacitidine standard of care, researchers said that the study sheds light on ivosidenib/azacitidine as a treatment option that could prove particularly useful for the hard-to-treat subset of patients with AML and IDH1 mutations, who were the target of the study.

“This high-risk population still needs improved strategies to prevent relapse or improve the response to front-line treatment,” said presenting study author Stephane de Botton, MD, PhD, of Institut Gustave Roussy. “Because of this drug’s mechanism of action, we were able to show a significant increase in the rate of complete response and improvement in symptoms without any increase in complications related to immunosuppression and infection.”

The trial enrolled 146 patients in more than 20 countries with newly diagnosed AML. All patients had IDH1 mutations and were ineligible for intensive induction chemotherapy, typically due to age or frailty. Half of the participants received ivosidenib and azacitidine, while half received azacitidine and a placebo. The primary endpoint of the AGILE trial was event-free survival, which was statistically significant in favor of the ivosidenib arm, with a hazard ratio of 0.33.

Median overall survival was approximately three times longer in the ivosedinib arm: 24 months compared with a median of 7.9 months among those receiving azacitidine alone. Patients receiving ivosidenib were also significantly more likely to achieve a complete response to treatment, which occurred in 47% of patients receiving ivosidenib vs 16% of those receiving azacitidine alone.

The trial also found a favorable safety profile for ivosidenib, with rates of adverse events similar to those seen with azacitidine alone.

“In addition, our results showed a significant improvement in quality of life with the ivosidenib combination therapy, which is a measure that is very important for patients,” said Dr. de Botton.

The study was stopped early after preliminary results indicated the ivosidenib/azacitidine combination yielded substantial benefits over azacitidine alone.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.