Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial

Abstract

The phase III MIRROS trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia (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 intravenously 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, 1.08; 95% 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.

Drugging p53 in cancer: one protein, many targets

“…However, a phase III clinical trial (MIRROS) of idasanutlin together with cytarabine in patients with relapsed or refractory AML 79 did not meet its primary point of superiority over cytarabine plus placebo. Specifically, despite an improved overall response rate, adding idasanutlin to cytarabine did not improve OS or complete response rates in patients with relapsed or refractory AML 80 . Similarly, idasanutlin showed encouraging clinical effects in a phase I clinical trial in patients with polycythaemia vera 81 , but haematological and low-grade gastrointestinal toxicity led to frequent discontinuation of the drug in a subsequent phase II trial 82 .…”

Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing

“…CDK4 amplification resulted in high MDM2 expression regardless of MDM2 amplification in MET ex14, and this finding could suggest CDK4 as an important regulator of MDM2 . Both MDM2 inhibitors and CDK4/6 inhibitors have antitumor activity in alternate tumor types when combined with chemotherapy, 38 targeted therapy, 39 , 40 and hormonal therapy, 41 and reveal potential novel combination treatment strategies with MET TKI in MET ex14 patients with MDM2 or CDK4 co-amplification.…”

Integrated genomics approaches identify transcriptional mediators and epigenetic responses to Afghan desert particulate matter in small airway epithelial cells

“…Further investigation of dynamic P53/P63 motif-containing TREs and chromatin accessibility features identified in our study may delineate the specific factors responsible for these multiple P53/P63 roles and determine how signal-dependent responses integrate with lineage factors in determining airway epithelia response to exposures. Finally, increasing P53 activity via agents such as idasanutlin (50), which is currently in clinical development for myeloid cancers (51), is feasible and may provide another therapeutic avenue in DRRD.…”