Ivosidenib Boosts OS with Azacitidine in AML

Combining the IDH1 inhibitor ivosidenib (Tibsovo; Servier) with azacitidine triples overall survival (OS) in some people with IDH1-mutant acute myeloid leukemia (AML), according to the phase III AGILE study (N Engl J Med 2022;386:1519–31). It is the first trial to show a benefit for ivosidenib in these patients.

Azacitidine, a hypomethylating agent, has long been the standard of care for patients with AML who are too old for, or unable to tolerate, intensive induction chemotherapy. The treatment landscape has changed in the last 5 years, and these patients now typically receive azacitidine in combination with the BCL2 inhibitor venetoclax (Venclexta; Genentech). In the United States, another choice for some people with IDH1-mutant disease is ivosidenib monotherapy, which was approved in 2018.

In the AGILE trial, 146 participants were randomly assigned to receive ivosidenib and azacitidine or azacitidine and a placebo. Ivosidenib–azacitidine outperformed azacitidine alone on several measures of effectiveness. Complete remissions were more than three times as common—47% versus 15%. The combination also stood out in terms of estimated 1-year event-free survival rates, which were 37% and 12%, respectively.

“The effect of the combination on this endpoint was huge,” says study co-author Stephane de Botton, MD, PhD, of Institut Gustave Roussy in Villejuif, France. In addition, OS was longer in the ivosidenib–azacitidine patients—24 months versus 7.9 months.

The overall frequency of side effects was about the same for both arms. Adverse events such as febrile neutropenia and infections occurred less often among patients who received the combination, although bleeding and neutropenia were more common.

“It's a remarkable advance,” says Mark Levis, MD, PhD, of Johns Hopkins Medicine in Baltimore, MD, who wasn't connected to the study. “This is how AML will be beaten—in pieces. A little molecularly defined subset of patients is carved off and treated.”

Aaron Schimmer, MD, PhD, of the University of Toronto in Canada, who also wasn't involved in the research, is encouraged that IDH1 mutation frequency declined much more in patients who received both drugs. Ivosidenib stimulates leukemia cells to differentiate but does not eradicate the malignant clone. However, says Schimmer, the decrease in mutation frequency “suggests that the combination is eliminating the cells rather than differentiating them.”

Ivosidenib was approved for AML in the United States based on results from a single-arm phase I trial, and it has not been okayed in most other countries. “AGILE is the first randomized trial to show an overall survival benefit” for the drug, notes Alexander Perl, MD, of the University of Pennsylvania in Philadelphia, which could lead to its approval elsewhere in the world.

But, he adds, no study has compared ivosidenib–azacitidine with azacitidine–venetoclax, creating a dilemma. Newly diagnosed patients can start treatment immediately with azacitidine–venetoclax or wait for a mutation analysis to determine their IDH1 status and candidacy for ivosidenib–azacitidine. Those results can take up to 3 weeks, depending on the assay used. Still, says Perl, doctors and patients have to face this decision because “you are awash in good treatments now for patients who used to have very poor outcomes.” –Mitch Leslie

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