First-in-Class Drug Shows Activity in Advanced Blood Cancers

Roxanne Nelson

April 08, 2014

SAN DIEGO — A first-in-class compound has shown activity in patients with advanced and refractory blood cancers.

Initial results with AG-221, a novel IDH2 mutant inhibitor (under development by Agios), were presented here at the at the American Association for Cancer Research 2014. The early data show that AG-221 is well tolerated, and that clinical and pharmacodynamic activity in patients with relapsed and refractory IDH2-mutant hematologic malignancies, mostly acute myeloid leukemia (AML), is promising. The effect was observed even in patients who received the lowest dose.

Of the 7 evaluable patients, 5 achieved complete remission or complete remission with incomplete platelet count recovery, which was defined as clearance of blast cells from the bone marrow and a platelet count not exceeding 100,000. Six of the 7 patients had an objective response.

"This kind of data is unheard of," said lead author Eytan M. Stein, MD, assistant attending physician in the leukemia service at the Memorial Sloan-Kettering Cancer Center in New York City. Some of the patients in the study had relapsed after bone marrow transplantation; in these patients, survival is typically very poor, he explained. "These are extremely exciting results."

The primary goal of this phase 1 study was to determine the safety and tolerability of AG-221. Dr. Stein noted that the research team was pleased to find promising clinical activity in patients with AML and IDH2 mutations.

This is early but it appears that mutant IDH2 is targetable, said John C. Byrd, MD, professor of medicine at Ohio State University Comprehensive Cancer Center in Columbus. "What impressed me is that the agent seems to be very patient-friendly, and it would make sense to move it into combination therapy," he noted.

However, there are still many questions, Dr. Byrd pointed out. "We don't know how durable the remissions are in relapsed and refractory patients or in previously untreated elderly patients."

The application of AG-221 in more aggressive mutations and possible late adverse effects also need to be explored.

"It may be able to produce long-term remissions," Dr. Byrd said. "We don't know, but the future does look interesting."

Emerging Targets

Dr. Stein and colleagues investigated the hypothesis that alterations in cellular metabolism are linked to the pathogenesis of malignancies.

Isocitrate dehydrogenase occurs in 3 isoforms: IDH1, IDH2, and IDH3. IDH is a critical metabolic enzyme in the citric acid cycle, explained Dr. Stein. IDH1 is found in the cytoplasm and peroxisomes, whereas IDH2 is found in the mitochondria. Mutations in the genes for IDH1 and IDH2 are thought to be the drivers of distinct subsets of AML. Cancer-associated IDH mutations produce 2-hydroxyglutarate (2-HG) and block normal cellular differentiation; an increase in 2-HG is thought to alter the epigenetic state of myeloid precursors.

IDH2 mutations have been identified in a wide spectrum of solid tumors and hematologic malignancies, including chondrosarcoma, glioblastoma, AML, and myelodysplastic syndrome (MDS). Mutations in IDH2 are predominantly found in hematologic malignancies, and occur in about 10% to 15% of AML patients and 5% of MDS patients.

AG-221 is an oral, potent, reversible, selective inhibitor of the mutated IDH2 protein, and is the first IDH mutant inhibitor to be tested in clinical trials. The current trial was based on preclinical work that showed that the agent reduced 2-HG levels and demonstrated a dose-dependent survival benefit. This is the first human phase 1 trial of AG-221 in patients with hematologic malignancies positive for IDH2 mutations, and the study is ongoing.

Responses and Remissions

Dr. Stein's team evaluated safety, pharmacokinetics, pharmacodynamics, 2-HG levels, and clinical activity in 21 patients with AML and 1 with MDS, all of whom tested positive for IDH2 mutations. In addition, 2 types of IDH2 mutations were identified; R140Q was found in 8 patients and R172K was found in 2 patients.

Patients received 1 of 4 doses of oral AG-221: 30 mg twice daily, 50 mg twice daily, 75 mg twice daily, or 100 mg once daily.

Dr. Stein reported the initial study results, which comprised data on 5 patients in the 30 mg group and 5 patients in the 50 mg group.

There were 5 men and 5 women, and the median age was 62.5 years. The median number of previous regimens was 2 (range, 1 - 4), and 1 patient had relapsed after allogeneic bone marrow transplantation.

Six of the 10 patients achieved an objective response; 1 patient in the 30 mg group and 2 patients in the 50 mg group achieved a complete remission, 2 patients had a complete remission but with incomplete platelet recovery, and 1 patient experienced disease progression. One patient with a complete remission was removed from study to undergo allogeneic bone marrow transplantation, and 3 patients were not evaluable because of disease-related sepsis.

Patient are currently being enrolled and are receiving higher doses of AG-221. Dr. Stein notes that they have not yet reached the maximum tolerated dose.

Pharmacodynamic evaluations showed evidence of drug uptake in the patients who responded to the drug. There was a greater than 90% reduction in levels of 2-HG in patients with R140Q mutations, and a reduction of 50% in 1 evaluable patient with an R172K mutation who had a complete remission with incomplete platelet recovery.

The drug was generally well tolerated, and no dose-limiting toxic events were reported. Two patients reported possible drug-related severe adverse events: grade 2 hyperleukocytosis and grade 3 confusion. In the 30 mg group, 3 deaths related to sepsis occurred in the 30 days after termination of the drug. One of these was possibly related to AG-221.

Future Plans and Questions

Dose escalation continues and expansion cohorts will begin in late 2014. In summary, these early data provide validation that mutant IDH2 is a therapeutic target in AML and MDS, Dr. Stein explained.

"Our future plans for AG-221 include completing the dose-escalation portion of this trial on a twice-a-day and once-a-day dosing schedule and enrolling expansion cohorts," he noted. "We hope to move AG-221 into earlier lines of treatment, and in combination with other agents. In addition, we hope to explore the activity of AG-221 in other IDH2-mutant hematologic malignancies and solid tumors."

He pointed out that another experimental agent, AG-120, is being studied in parallel phase 1 studies of the mutant IDH1 inhibitor in hematologic malignancies and solid tumors.

This study was funded by Agios Pharmaceuticals. Dr. Stein has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2014: Abstract CT103. Presented April 6, 2014.


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