Ivosidenib in Combination with Azacitidine Demonstrates Threefold Improvement in Overall Survival for Previously Untreated IDH1-Mutant AML in Phase 3 AGILE Trial Published in NEJM

Recently, Servier announced the publication in The New England Journal of Medicine (NEJM) of the results from a Phase 3 clinical trial evaluating its oral type 1 isocitrate dehydrogenase (IDH1) inhibitor, ivosidenib, in combination with chemotherapy for the first-line treatment of patients with acute myeloid leukemia (AML) carrying IDH1 mutations. The trial met its primary endpoint as well as all key secondary endpoints, including overall survival (OS). The press release noted that these results represent a significant advancement for newly diagnosed AML patients with IDH1 mutations.

AML is a rapidly progressing blood and bone marrow cancer and the most common acute leukemia affecting adults. Most AML patients will eventually relapse, and the prognosis for relapsed or refractory AML is poor, with a five-year survival rate of approximately 29.5%. Additionally, IDH1 mutations are present in about 6% to 10% of AML cases.

Ivosidenib was initially developed by Agios and has been approved in the United States as a monotherapy for adult patients with relapsed or refractory AML carrying the IDH1 mutation, as well as for previously untreated AML patients aged ≥75 years or those with comorbidities who are ineligible for intensive induction chemotherapy and carry the IDH1 mutation. It has also recently been approved for the treatment of patients with IDH1-mutant cholangiocarcinoma who have been previously treated. China's CStone Pharmaceuticals holds the development rights for this targeted therapy in Greater China. It was also approved in China in February this year for the treatment of recurrent or refractory acute myeloid leukemia.

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AGILE Study is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate the efficacy and safety of ivosidenib in combination with azacitidine versus placebo in combination with azacitidine in adult patients with newly diagnosed AML carrying an IDH1 mutation.

The study data showed that, compared with azacitidine plus placebo treatment, ivosidenib plus azacitidine treatment improved patients' event-free survival (EFS) and OS.

Patients in the Ivosidenib plus Azacitidine group achieved a statistically significant improvement in EFS [HR=0.33, 95% CI 0.16, 0.69; one-sided P=0.0011].

Ivosidenib in combination with azacitidine significantly improved OS (HR=0.44, 95% CI 0.27, 0.73; one-sided P=0.0005). The median OS was 24.0 months in the ivosidenib combination therapy group and 7.9 months in the placebo plus azacitidine group.

The complete response (CR) rate of Ivosidenib combined with Azacitidine was 47.2% (n=34/72), while the CR rate of placebo combined with Azacitidine was 14.9% (n=11/74) (P<0.0001).

The CR+CRh rate (complete remission + complete remission with partial hematologic recovery) was 52.8% (n=38/72) in the ivosidenib plus azacitidine group and 17.6% (n=13/74) in the placebo plus azacitidine group (P<0.0001).

The objective response rate (ORR) for ivosidenib combined with azacitidine was 62.5% (n=45/72), compared to 18.9% (n=14/74, P<0.0001) for placebo combined with azacitidine.

Dr. Claude Bertrand, Executive Vice President of Servier's R&D Department, stated that Servier has made oncology its focus and is allocating over 50% of its R&D budget to fighting cancer. This strategy is currently bringing new treatment options to patients with difficult-to-treat cancers.

References:

[1] Phase 3 AGILE Data of TIBSOVO® (ivosidenib tablets) in Combination with Azacitidine for Patients with Previously Untreated IDH1-mutated Acute Myeloid Leukemia Published in the New England Journal of Medicine. Retrieved April 21, 2022, from https://www.servier.us/phase3-agile-nejm

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