MDM2 Inhibitor May Improve Response in AML

Marina Konopleva, MD

Investigators are hopeful that idasanutlin, a novel small molecule that targets the MDM2 protein, can improve the efficacy of chemotherapy in patients with relapsed/refractory acute myeloid leukemia (AML). This agent is being tested in combination with cytarabine, which is commonly used as a first or second salvage therapy in this patient population.

“Relapsed AML is a difficult disease to tackle, especially because salvage therapy response rates drop from about 75% in newly diagnosed patients to 40% in the first salvage population and the second salvage population [has response rates of] about 15% to 20%, so it’s hard to cure anybody at this stage,” said Marina Y. Konopleva, MD, PhD, professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

Figure. Idasanutlin With Cytarabine in Relapsed/Refractory AML

The international phase III MIRROS clinical trial (NCT02545283) is currently enrolling patients with relapsed/refractory AML, according to Konopleva, who is the principal investigator at MD Anderson. Participants must have experienced 1 or 2 relapses. They also must have received no more than 2 prior induction regimens, and 1 or both must have included cytarabine with an anthracycline. Those who qualify will be randomized to either idasanutlin with cytarabine or cytarabine with a placebo (Figure).Notably, the primary endpoint is overall survival (OS) and will be assessed in a subset of the patient population with TP53 wild type, with OS in the overall population as a secondary endpoint. Assessing the TP53 wild-type population as the primary endpoint is important because idasanutlin’s mechanism of action depends on p53, which is encoded by TP53.

Idasanutlin inhibits the MDM2 protein, which degrades p53, a known tumor growth suppressor, Konopleva said. The drug binds to MDM2 to prevent the interaction between the 2 proteins, resulting in the continued activation of p53 and tumor-cell apoptosis.¹

“Patients who have high [expression of] MDM2 will have degraded p53, which means there are very low levels of active p53 available for any active function, and they may not be able to respond to chemotherapy,” Konopleva said. Patients with a TP53 gene mutation generally do not have the functional p53 protein, but they will not be excluded from the MIRROS study.

Idasanutlin has previously demonstrated efficacy in combination with cytarabine in a phase Ib study to determine the appropriate dosage. Seventy-five patients with AML were treated with the combination, and results included 6 complete responses (CRs) in the dose escalation arm (n = 23), 5 CRs in the subsequent expansion cohort (n = 21), and 8 CRs in a bridging arm to determine the safety and pharmacokinetics of a spray-dried powder formulation of idasanutlin (n = 32).2 According to Konopleva, the objective response rate was 33% and responses tended to be durable, with a median duration of response of about 6.4 months (range, 1.1-11.9).

Secondary endpoints included complete remission, complete remission with incomplete platelet (CRp) or hematologic recovery (Cri), and composite complete remission (CRc, CR + CRp + Cri). Five of 22 patients with AML who achieved a CRc (23%) proceeded to hematopoietic stem cell transplant after the therapy. These data demonstrated that idasanutlin with cytarabine is a promising combination therapy for patients with relapsed/refractory AML, the investigators said.²

No statistically significant association between TP53 mutation status and response was seen in the phase Ib study, but there was a trend suggesting TP53 mutation status was a negative predictive biomarker (P = .08). MDM2 protein expression displayed a pronounced association with CRc when analyses were restricted to patients with TP53 wild type only (P = .0021).²

“Clinically, the bigger problem is the TP53- mutant population, because there’s no approved drug there, and the gene is essential to have the chemotherapy work,” Konopleva said. “In the wild-type TP53 population, once [patients] relapse, there are not many drugs approved for second salvage, and for first salvage, you can still try chemotherapy. But if the treatment duration is too short, then there isn’t as much time for the chemotherapy to work.”

The main adverse event (AE) shown in the phase Ib study for idasanutlin was gastrointestinal toxicity in the form of diarrhea, which was generally manageable and increased with higher dosage.² Konopleva said that based on AEs noted in other studies of idasanutlin in solid tumors, myelosuppression is expected to occur in the phase III trial.

Konopleva is hopeful that if idasanutlin and cytarabine yield a higher response rate in the MIRROS study than cytarabine alone, the combination could become a standard of care for patients with AML with TP53 wild type as first or second salvage therapy.

Idasanutlin is being developed by Roche, based in Basel, Switzerland, and Genentech, based in San Francisco, California.

References

1. Idasanutlin. Genentech website. biooncology.com/pipeline-molecules/idasanutlin.html. Accessed June 4, 2018.
2. Martinelli G, Pappayannidis C, Yee K, et al. Phase 1b results of idasanutlin + cstarabine (ara-C) in acute myeloid leukemia (AML) patients (pts). Presented at: 21st Congress of the European Hematology Association; June 3-7, 2016; Copenhagen, Denmark. Abstract S504. learningcenter. ehaweb.org/eha/2016/21st/135260/cristina.pappayannidis. phase.1b.results.of.idasanutlin.2B.cytarabine.28ara-c29.in.html.