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Clinical Trial
. 2025 Oct 28;9(20):5177-5189.
doi: 10.1182/bloodadvances.2025016399.

Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML

Pau Montesinos  1 , Dylan M Marchione  2 , Christian Recher  3 , Michael Heuser  4 , Susana Vives  5 , Ewa Zarzycka  6 , Jianxiang Wang  7 , Marta Riva  8 , Rodrigo T Calado  9 , Andre C Schuh  10 , Su-Peng Yeh  11 , Adriana E Tron  2 , Jianan Hui  2 , Diego A Gianolio  2 , Sung Choe  2 , Prapti Patel  2 , Stéphane De Botton  12 , Courtney D DiNardo  13 , Hartmut Döhner  14
Affiliations
Clinical Trial

Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML

Pau Montesinos et al. Blood Adv. .

Abstract

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (n = 73) or placebo-azacitidine (n = 75). Median OS was significantly longer with ivosidenib (29.3 months; 95% confidence interval [CI], 13.2 to not reached) than with placebo (7.9 months; 95% CI, 4.1-11.3; hazard ratio, 0.42 [95% CI, 0.27-0.65]; P < .0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; P = .0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy-ineligible patients with IDH1-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03173248.

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Conflict of interest statement

Conflict-of-interest disclosure: P.M. reports consulting or advisory roles with Servier, Bristol Myers Squibb (BMS), and Novartis; participation in speakers’ bureaus for Servier, BMS, Jazz Pharmaceuticals, Sanofi, AbbVie, and Teva Pharmaceuticals; research funding from BMS, AbbVie, and Daiichi Sankyo; travel, accommodations, or expenses from Pfizer. C.R. reports consulting or advisory roles with AbbVie, Amgen, Astellas, BMS, Boehringer, Jazz Pharmaceuticals, Johnson & Johnson, and Servier; research funding from AbbVie, Amgen, Astellas, BMS, IQVIA, and Jazz Pharmaceuticals; and support for attending meetings and/or travel from AbbVie, Novartis, and Servier. M.H. reports research funding to institution from AbbVie, Bayer Pharma AG, Jazz Pharmaceuticals, Glycostem, Karyopharm, PinotBio, Servier, and Toray; honoraria from Astellas, Daiichi Sankyo, Janssen, Miltenyi, Otsuka, Qiagen, and Servier; and consulting roles with AbbVie, AvenCell, Ascentage Pharma, BMS, Janssen, Jazz Pharmaceuticals, LabDelbert, Novartis, Pfizer, and Servier. S.V. reports travel, accommodations, and expenses from Astellas Pharma, Pfizer, Servier, AbbVie, and Jazz Pharmaceuticals; research funding from Astellas Pharma; consulting or advisory roles (without honoraria) with Astellas Pharma, Pfizer, Servier, AbbVie, and Jazz Pharmaceuticals. J.W. reports consulting or advisory role with AbbVie. R.T.C. reports honoraria from Novartis and Alexion Pharmaceuticals. A.C.S. reports clinical trials/research support: AbbVie, Amgen, Astellas, BMS, GlycoMimetics, J&J, Kite/Gilead, Loxo, Novartis, Pfizer, Servier, and Syndax; and participation on advisory board for AbbVie, Amgen, Astellas, BMS, Jazz, Kite/Gilead, Novartis, Paladin, Phebra, Pfizer, Servier, and Teva. S.P.Y. reports honoraria from AbbVie, Amgen, Astellas Pharma, Bayer, BMS, Janssen, Novartis, Sanofi, and Takeda; and consulting or advisory roles with AbbVie, Chugai Pharma, Janssen, Novartis, Pfizer, and Sanofi. D.M.M., A.E.T., J.H., D.A.G., S.C., and P.P. are employees of Servier BioInnovation. S.D.B. reports honoraria from BMS, AbbVie, Servier, Jazz Pharmaceuticals, Astellas Pharma, and Loxo; consultancy or advisory roles with Servier, BMS, GlaxoSmithKline, Syndax, and Remix; participation in speakers’ bureaus for Servier, BMS, Jazz Pharmaceuticals, Astellas Pharma, and AbbVie; research funding from Forma and Auron; and travel, accommodations, or expenses from AbbVie and Servier. C.D.D. reports honoraria from AbbVie/Genentech, Astellas, BMS, Fogham, Notable Labs, ImmuneOnco, Servier, Novartis, and Takeda; and has received consultancy fees from Schrödinger. H.D. reports consulting or advisory roles with AbbVie, AstraZeneca, Gilead, Janssen, Jazz, Pfizer, Servier, Stemline Therapeutics, and Syndax; travel, accommodations, and expenses from AbbVie and Servier; and research funding from Amgen, BMS, Novartis, Pfizer, Jazz Pharmaceuticals, AbbVie, and Kronos Bio. The remaining authors declare no competing financial interests.

The current affiliation for M.H. is Department of Internal Medicine IV, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Patient disposition in the ITT population.
Figure 2.
Figure 2.
OS in patients treated with ivosidenib + azacitidine or placebo + azacitidine in the ITT population. (A) Kaplan-Meier estimates of OS with a median follow-up of 28.6 months. (B) OS rates at 12, 24, and 36 months.
Figure 3.
Figure 3.
Hematology outcomes for patients treated with ivosidenib + azacitidine or placebo + azacitidine in the ITT population. Mean ± standard error hemoglobin (A), platelet counts (B), and neutrophil counts (C) over time. BL, baseline; C1D8, cycle 1 day 8.
Figure 3.
Figure 3.
Hematology outcomes for patients treated with ivosidenib + azacitidine or placebo + azacitidine in the ITT population. Mean ± standard error hemoglobin (A), platelet counts (B), and neutrophil counts (C) over time. BL, baseline; C1D8, cycle 1 day 8.
Figure 4.
Figure 4.
Red blood cell and platelet transfusion independence in the ITT population. (A) Rate of conversion to red blood cell and platelet transfusion independence. (B) Maintenance of red blood cell and platelet transfusion independence from baseline.
Figure 5.
Figure 5.
OS in MRD-evaluable patients treated with ivosidenib + azacitidine according to MRD status (n = 33). (A) OS in MRDneg vs MRDpos patients. (B) OS in patients with MRD<1% vs patients with MRD≥1%. NE, not evaluable.
See this image and copyright information in PMC

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