Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial.

Abstract

The phase 3 MIRROS (MDM2 antagonist Idasanutlin in Relapsed or Refractory acute myeloid leukemia [AML] for Overall Survival) trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory (R/R) AML. Adults (n = 447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 IV on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine; stratified hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.81-1.45; P = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23; 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML.

• Authors: Marina Y Konopleva, Christoph Röllig, Jamie Cavenagh, Dries Deeren, Larisa Girshova, Jürgen Krauter, Giovanni Martinelli, Pau Montesinos, Jonas A Schäfer, Oliver Ottmann, Mario Petrini, Arnaud Pigneux, Alessandro Rambaldi, Christian Recher, Rebeca Rodriguez-Veiga, David Taussig, Norbert Vey, Sung-Soo Yoon, Marion Ott, Susanne Muehlbauer, Benjamin M Beckermann, Olivier Catalani, Magali Genevray, Kirsten Mundt, Candice Jamois, Pierre Fenaux, Andrew H Wei
• Journal: Blood advances (Blood Adv) Vol. 6 Issue 14 Pg. 4147-4156 (07 26 2022) ISSN: 2473-9537 [Electronic] United States
• PMID: 35413116 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Pyrrolidines
• RG7388
• para-Aminobenzoates
• Cytarabine

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Cytarabine
• Humans
• Leukemia, Myeloid, Acute
• Pyrrolidines
• para-Aminobenzoates (therapeutic use)