FDA Grants Ivosidenib Plus Azacitidine Approval for Newly Diagnosed AML With IDH1 Mutations


Ivosidenib plus azacitidine received FDA approval for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) harboring IDH1 mutations.

Ivosidenib (Tibsovo) plus azacitidine received FDA approval for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) harboring IDH1 mutations who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.1

The expanded approval is supported by findings from the phase 3 AGILE trial, which showed that ivosidenib plus azacitidine significantly improved event-free survival (EFS) over azacitidine alone (HR, 0.35; 95% CI, 0.17-0.72; 2-sided P = .0038).2 The addition of ivosidenib also improved median overall survival (OS) compared with azacitidine alone, at 24.0 months (95% CI, 11.3-34.1) vs 7.9 months (95% CI, 4.1-11.3), respectively (HR, 0.44; 95% CI, 0.27-0.73; P = .001).

"Today's approval builds on the established body of evidence for [ivosidenib], which is now approved across multiple IDH1-mutated cancer types," David K. Lee, chief executive officer at Servier Pharmaceuticals, stated in a press release. "As a leader in oncology pioneering the science behind targeted IDH inhibition, we are proud to bring a new therapeutic option to the acute myeloid leukemia community and remain committed to pushing the boundaries of healthcare innovation in oncology and beyond."

The global, double-blind, placebo-controlled, phase 3 trial enrolled patients with a centrally confirmed diagnosis of previously untreated IDH1-mutated AML who were not eligible for intensive chemotherapy.

To participate, patients needed to be at least 18 years of age, had an ECOG performance status of 0 to 2, acceptable hepatic and renal function, and who did not receive prior treatment with an IDH1 inhibitor or hypomethylating agent for myelodysplastic syndrome.

Patients were not candidates to receive intensive chemotherapy if they were aged 75 years or older, and had 1 of the following conditions: an ECOG performance status of 2, a severe cardiac disorder, a severe pulmonary disorder, a creatinine clearance of less than 45 mL/min, or a bilirubin level greater than 1.5 times the upper limit of the normal range.

Study participants were administered ivosidenib at a once-daily dose of 500 mg (n = 72) or matched placebo (n = 74), in combination with azacitidine at 75 mg/m2 for 7 days as part of 28-day cycles. Stratification factors included geographic region and disease status (primary vs secondary disease).

Treatment was given for a minimum of 6 cycles unless relapse, progressive disease, intolerable toxicity, or death occurred.

The primary end point was EFS, and secondary end points included complete remission (CR), OS, CR or CR with partial hematologic recovery, objective response, safety, and health-related quality of life.

The demographic and clinical characteristics of the patients at baseline were comparable across the arms. Of those in the investigative arm, 75% had primary AML and 25% had secondary AML; these rates were 72% and 28%, respectively, in the control arm. Moreover, 22% of those who received ivosidenib in combination with azacitidine had poor-risk cytogenetic characteristics vs 27% of those who received azacitidine alone.

A total of 39 patients were receiving treatment at the data-cutoff date of March 18, 2021; 38% of these patients were in the investigative arm and 16% were in the control arm.

Additional data published in the New England Journal of Medicine showed that CR was achieved by 47% (95% CI, 35%-59%) of those in the ivosidenib arm and 15% (95% CI, 8%-25%) of those in the azacitidine-alone arm (P < .001). The median duration of CR was not yet reached with ivosidenib vs 11.2 months in those who received azacitidine alone.

In those who achieved a CR, the estimated probability that a patient would remain in CR at 1 year was 88% vs 36% in the investigative and control arms, respectively. The median time to CR was 4.3 months (range, 1.7-9.2) in the ivosidenib/azacitidine arm and 3.8 months (range, 1.9-8.5) in the azacitidine-alone arm. CR or CR with partial hematologic recovery was observed in 53% (95% CI, 41%-65%) and 18% (95% CI, 10%-28%) of those in the investigative and control arms, respectively.

Moreover, 62% (95% CI, 50%-74%) of those who received ivosidenib/azacitidine experienced an objective response vs 19% (95% CI, 11%-30%) of those who received azacitidine alone (P < .001). The median duration of response was 22.1 months (95% CI, 13.0–not estimable) and 9.2 months (95% CI, 6.6-14.1), respectively.

The safety profile of the combination proved to be consistent with previously published findings. The most common toxicities that were observed in patients with newly diagnosed AML who received the regimen included nausea, vomiting, electrocardiogram QT prolonged, insomnia, differentiation syndrome, leukocytosis, hematoma, hypertension, arthralgia, dyspnea, and headache.

The select laboratory abnormalities that were experienced include decreased leukocytes, platelets, hemoglobin, neutrophils, phosphate, and magnesium, as well as increased lymphocytes, aspartate aminotransferase, alkaline phosphatase, and potassium.


  1. Servier announces FDA approval of Tibsovo (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. News release. Servier Pharmaceuticals. May 25, 2022. Accessed May 25, 2022. https://prn.to/3sX1OOw
  2. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344
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