In a phase III trial, a combination of ivosidenib and azacitidine was found superior in treating AML as compared to azacitidine alone in terms of event-free survival, the trial’s primary endpoint.

The combination treatment also extended overall survival to a median of two years compared to just eight months among those receiving azacitidine alone, a three-fold increase in survival duration.

Ivosidenib is currently approved by the U.S. Food and Drug Administration (FDA) for treating relapsed or refractory AML and for newly diagnosed patients who are over age 75 or ineligible for chemotherapy and have an IDH-1 mutation.

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 IDH-1 gene.

Ivosidenib is targeted at IDH-1 mutations, present in about 10% of patients with AML, and works by causing leukaemia cells to return to healthy cell functioning, rather than eliminating them altogether.

As a result, it does not cause the same degree of myelosuppression (a decrease in the production of blood and immune cells in the bone marrow) as other combination therapies, researchers explained.

After the 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 AML patients ineligible for intensive chemotherapy throughout much of the world.

Although the new trial does not directly compare the ivosidenib-azacitidine combination 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 AML patients with IDH-1 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 Stephane de Botton, MD, PhD, of Institut Gustave Roussy in France.

“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 IDH-1 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 favour of the ivosidenib arm, with a hazard ratio of 0.33.

Median overall survival was approximately three times longer in the ivosedinib arm, at 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 and just 16% of those receiving azacitidine alone.

The trial also found a favourable 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 azacytidine alone.

Source: American Society of Haematology