ASH 2014: High Hopes for AG-221 in Advanced Leukemia
Although the data are preliminary, single-agent AG-221 therapy targeted to the IDH2 mutation holds great promise as a nonchemotherapy approach for the treatment of advanced hematologic malignancies, including relapsed/refractory acute myelogenous leukemia (AML) and untreated AML. The findings were presented at the 56th Annual American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 115).
In an updated analysis of a dose-expansion phase I trial that now includes a total of 73 patients with advanced hematologic cancer, AG-221 was well tolerated and achieved > 90% inhibition of its target (2-hydroxyglutarate [2-HG]) in patients with an IDH2 mutation.
In 45 evaluable patients with the IDH2 mutation, overall response rate was 56%. Fifteen patients achieved complete response (including 9 complete responses with incomplete platelet or hematologic recovery), 10 had partial response, and 17 had stable disease throughout the treatment period. Moreover, responses were durable, lasting as long as 9 months on study. No patient in complete response has relapsed.
“These findings were achieved in patients unlikely to respond to other chemotherapies,” noted lead author Eytan Stein, MD, Memorial Sloan Kettering Cancer Center, New York.
New Therapeutic Target?
“These data provide continued validation of mutant IDH2 as a therapeutic target in AML and myelodysplastic syndromes. What we have learned with additional experience is that responses have been durable. It’s only an interim analysis and it’s very early, but my dream is that this becomes a treatment for IDH2 mutation–positive patients. This treatment has minimal toxicity and could be an alternative to chemotherapy,” Dr. Stein said.
About 15% to 20% of AML patients harbor the IDH2 mutation, which leads to overproduction of 2-HG, thereby preventing immature white blood cells from maturing into normal white blood cells. AG-221 is a first–in-class, potent oral inhibitor of the IDH2 mutant enzyme; this novel agent takes the brakes off of undifferentiated white blood cells and allows them to mature as normal cells, acting in a similar manner as all-trans retinoic acid and arsenic trioxide (Trisenox) in acute promyelocytic leukemia (APL), he explained.
Study Details
The updated analysis Dr. Stein presented at the 2014 Annual Meeting of the American Society of Hematology was based on a total of 73 patients and four additional dose-expansion cohorts.
The cohort of 73 patients included 55 with relapsed/refractory AML, 5 with untreated AML, 6 with myelodysplastic syndrome, and 6 with “other” advanced cancers. The median age of all patients was 67 years (range = 33–90 years). At the time of the presentation, 45 patients were evaluable for response, and the maximum tolerated dose had not yet been reached.
AG-221 was very well tolerated. Cancer-related symptoms, not attributable to this drug, were mild to moderate and included nausea, fever, diarrhea, and fatigue. One case of dose-related grade 5 hypoxia was reported in a patient with unrelated fungal pneumonia and sepsis. The 60-day all cause mortality rate was 13.7%.
The majority of serious adverse events were disease-related. Thirteen patients developed 21 potentially treatment-related serious adverse events.
Eleven deaths were reported, nine of them unrelated to treatment; two deaths due to sepsis/hypoxia and atrial flutter were possibly treatment-related, he said.
Encouraging Results
“These results are fantastic,” said David Steensma, MD, a hematologist at Dana-Farber Cancer Institute and Harvard School of Medicine, Boston. “We have long wanted agents for AML like we have for APL: nonchemotherapy approaches that release cells stuck in immature stages. Unfortunately, IDH2 is only present in about 20% of AML.”
Dr. Steensma said that if further studies bear out these encouraging results, AG-221 could be transformative, allowing patients with advanced leukemia a chance for curative transplant. He also said AG-221 may be useful in other malignancies that harbor IDH2 mutations.
AG-221 is being developed by Agios Pharmaceuticals in collaboration with Celgene.
Dr. Stein reported consultancy with Janssen Pharmaceuticals. For full disclosures of the study authors, view the study abstract.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
