Idasanutlin Added to Cytarabine Fails to Improve OS in Relapsed/Refractory AML: MIRROS Trial

Despite improvements in overall response rate (ORR), the phase 3 MIRROS trial found that adding idasanutlin to cytarabine did not improve overall survival (OS) or complete remission (CR) rates in patients with relapsed/refractory acute myeloid leukemia (AML). 

“Idasanutlin is a potent, 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%),” Marina Y. Konopleva, MD, University of Texas MD Anderson Cancer Center, Houston, and colleagues wrote in a study in Blood Advances.

The phase 3 MIRROS trial enrolled 447 adults with AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen. Patients had an Eastern Cooperative Oncology Group performance status ≤2 and were enrolled regardless of TP53 mutation status.

Patients were randomly assigned in a 2:1 ratio 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 end point, OS in the TP53WT-ITT population, was not met. The median OS was 8.3 months with idasanutlin-cytarabine vs 9.1 months with placebo-cytarabine (stratified hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.81 to 1.45; P = .58). The CR rate, a key secondary endpoint, was 20.3% vs 17.1%, respectively (odds ratio [OR], 1.23; 95% CI, 0.70 to 2.18).

The overall response rate (ORR) was 38.8% in the idasanutlin arm vs 22% in the placebo arm (OR, 2.25; 95% CI, 1.36 to 3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87% 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 [OS] or CR rates in patients with [relapsed/refractory] AML,” Dr Konopleva and colleagues concluded. 

Source:

Konopleva MY, Röllig C, Cavenagh J, et al. Idasanutlin Plus Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia: Results of the MIRROS Trial. Blood Advances. Published online April 12, 2022. doi:10.1182/bloodadvances.2021006303