AG-221 Sparks Durable Remissions in IDH2-Mutated AML

The novel drug AG-221 generated durable remissions in patients with acute myeloid leukemia (AML) by targeting a mutation of the IDH2 gene in a small, first-in-man study that represents a new, chemotherapy-free approach for attacking the malignancy. Eytan M. Stein, MD, reported these findings during a press briefing at the 56th Annual Meeting of the American Society of Hematology (ASH).

The agent, which inhibits the IDH2-mutant enzyme, demonstrated tolerability and efficacy in treating patients with AML—whether previously treated or not—and with myelodysplastic syndromes among participants withIDH2-positive disease, Stein, of Memorial Sloan Kettering Cancer Center, said.

If left unchecked, theIGH2mutation leads to increased production of an oncometabolite known as 2-hydroxyglutarate (2-HG), preventing immature white blood cells from developing into healthy adult infection-fighting white cells. In turn, this increased production allows immature leukemic white cells to accumulate and crowd out normal red cells and platelets, resulting in the development of AML, ASH experts explained in a press release.

For patients with AML or pre-leukemia (including myelodysplastic syndrome [MDS], chronic myelomonocytic leukemia, and myeloproliferative neoplasms) who are affected by the mutation, AG-221 could eventually represent a better-tolerated alternative to conventional chemotherapy, ASH stated. Up to 13% of patients with AML and up to 6% of patients with MDS harborIDH2mutations, Stein said.

“These early results in this hard-to-treat population demonstrate that, when we inhibit mutant IDH2, we can transform leukemia cells into healthy, normal adult white blood cells and eradicate disease without the use of traditional chemotherapy,” Stein said. “This approach to treat leukemia is revolutionary and represents the future of treatment for hematologic diseases. Our goal is to treat patients with therapy that is targeted to the specific genotype of their disease, thereby increasing efficacy, extending patients’ life spans, and minimizing toxicity.”

The primary objectives of the ongoing trial are safety and determination of maximum tolerated dose, and to select a dose and schedule for the expansion cohorts and future phase II studies. Secondary objectives include clinical activity assessed by investigators using International Working Group Criteria, pharmacokinetics, and pharmacodynamics.

As of October 1, 2014, 73 patients with IDH2-mutant AML or pre-leukemia were enrolled in the study, Stein said. Of those patients, 55 have relapsed or refractory AML and 13 have undergone prior bone marrow transplant, making them unlikely to respond to chemotherapy, he said.

Initially, the study tested the use of the oral agent once or twice daily at escalating doses up to 150 mg and 200 mg, respectively, for 28-day cycles. More recently, four additional dose cohorts were added, with the highest cumulative daily dose being 300 mg, and four expansion cohorts were added at a daily dose of 100 mg, Stein said. The lowest dose being tested is 60 mg. A maximum tolerated dose has not been reached, he said.

Bone marrow examinations are incorporated into the trial on days 15, 29, and 57 of treatment, and every 56 days thereafter.

Among the 45 patients who have been on the study long enough to be evaluable, responses have been observed in 25 patients (56%), including various classifications of complete remission in 15 patients and partial remissions in 10 participants, Stein reported. There have been no relapses in patients who have experienced a complete remission, according to a press release from Agios Pharmaceuticals, Inc, which is developing the drug in collaboration with Celgene.

In addition, 17 patients have experienced stable disease, and two patients have had disease progression while participating in the study.

Responses have been durable, Stein said, with some patients who have experienced partial response being on the study as long as 9 months so far, and some patients with complete response being on the study as long as 7 months to date.

Therapy has been well tolerated, with the majority of reported adverse events (AEs) being grades 1 and 2, most typically including nausea, pyrexia, diarrhea, and fatigue—AEs that might have come from the disease itself, Stein noted.

Thirteen patients have experienced 21 severe AEs that were possibly or probably treatment related, Stein added. The most common severe AEs have included tumor lysis syndrome and leukocytosis, although leukocytosis appears to be a differentiation effect of the drug, and all the patients who experienced it went on to achieve complete or partial remission, he said.

There have been 11 deaths reported, nine unrelated to the study drug and two possibly related. One death was due to hypoxia (in a patient who also had unrelated sepsis and fungal pneumonia) and the other to atrial flutter, Stein reported.

Preliminary pharmacokinetic analysis of the 30 mg through 75 mg twice-daily and 100 mg once-daily doses demonstrated excellent exposure to AG-221, high accumulation after multiple doses, and a mean plasma half-life of greater than 40 hours, the authors wrote in the abstract presented at ASH. Pharmacodynamic evaluation demonstrated sustained plasma 2-HG inhibition of up to 97% in patients with anIDH2R140Q mutation, and up to 50% in patients with anIDH2R172K mutation, after multiple doses, they wrote.

AG-221 is “well tolerated in patients with advanced hematologic malignancies, and triggers the differentiation of leukemic blast cells that ultimately leads to objective durable responses, including complete remissions,” the authors wrote in their abstract. “These data provide continued validation of mutantIDH2as a therapeutic cancer target.”

Eventually, AG-221 might be applicable as a treatment for other tumor types, including glioblastoma, Stein added.

_REFERENCE:

_{Stein EM, Altman JK, Collins R, et al. AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies. Paper presented at: 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, CA. Abstract 115.}