Idasanutlin (RG-7388) is a potent (Kd = 0.15 nM), selective small-molecule MDM2 antagonist that has demonstrated tolerable safety and encouraging clinical activity in an open-label, phase 1/1b trial in patients with AML, alone and in combination with cytarabine (composite CR rate, 35.6%). 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[1].
Potent MDM2 inhibitor with an IC50 = 6 nM in binding assay and 30 nM in cancer cell proliferation assay. Induces p53 stabilisation, cell cycle arrest and apoptosis in cancer cells expression wildtype p53. Displays inhibition of tumor growth in the SJSA1 tumor xenograft model. Also inhibits MDR-1 at high concentrations.
Adverse events (AEs) reported across treatment cohorts included gastrointestinal events, hematologic events or events related to infections or infestations. Grade ≥3 AEs included hypokalemia, diarrhea, nausea and febrile aplasia or neutropenia. No unexpected toxicities were reported with the combination regimen compared with other relapse regimens containing cytarabine[2].
[1] M. Konopleva. “Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial.” Blood advances 6 1 (2022): 4147–4156.
[2] Pau Montesinos. “MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia.” Future oncology 16 13 (2020): 807–815.
