AG-221 Showing Promise for Patients with Advanced Hematologic Malignancies

AG-221 Showing Promise for Patients with Advanced Hematologic Malignancies

June 16, 2015

An experimental IDH2-inhibitor is showing considerable promise for patients with advanced hematologic malignancies. Researchers presented data on 177 patients at the 20th Congress of the European Hematology Association (EHA), held June 11-14, 2015 in Vienna.

An experimental IDH2-inhibitor is showing considerable promise for patients with advanced hematologic malignancies. Researchers presented data on 177 patients at the 20th Congress of the European Hematology Association (EHA), held June 11-14, 2015 in Vienna. Investigators found that AG-221 demonstrated durable clinical activity and a favorable safety profile.

AG-221 is a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) being tested in advanced hematologic malignancies. As of May 1, 2015, 177 patients (104 in dose escalation) with advanced hematologic malignancies were treated with single-agent AG-221 and it showed durable clinical activity. The agent was found to have an overall response rate of 40% (63 of 158 response-evaluable patients) and a complete remission rate of 16% (26 of 158 response-evaluable patients).

The investigators found that patients responding to AG-221 continue to show durable clinical activity on treatment for more than 15 months, with an estimated 76% of responders staying on treatment for 6 months or longer. Lead study investigator Courtney DiNardo, MD, who is an assistant professor at the division of leukemia at University of Texas MD Anderson Cancer Center in Houston, said the clinical profile of AG-221 continues to be impressive from the perspectives of response rate, durability, safety, and unique mechanism of action. Dr. DiNardo also noted that it was encouraging to see early proof-of-concept in myelodysplastic syndrome (MDS) and untreated acute myeloid leukemia (AML).

There is an acute unmet clinical need in patients with MDS and AML. These preliminary findings offer MDS and AML patients new hope.

Currently, AG-221 is being evaluated in an ongoing phase I trial that includes a dose-escalation phase and four expansion cohorts of 25 patients each. The cohorts include patients with relapsed or refractory AML, age 60 and older and transplant ineligible; relapsed or refractory AML patients under age 60; untreated AML patients who decline standard of care chemotherapy; and patients with other IDH2-mutant-positive hematologic malignancies.

Data reported at the meeting in Vienna included patients receiving AG-221 administered from 60 mg to 450 mg total daily doses in the dose-escalation arm, and 100 mg once daily in the first four expansion arms as of May 1, 2015. The median age of these patients was 69 (range: 22 to 90 years).

Treatment with AG-221 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers. The majority of adverse events (AEs) reported by investigators were mild to moderate, with the most common being nausea, fatigue, increased blood bilirubin, and diarrhea. The majority of serious adverse events (SAEs) were disease-related. The all-cause 30-day mortality rate was 4.5%.   

 

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