A novel inhibitor of the mutant IDH2 enzyme, enasidenib, was well tolerated and offered durable responses in a phase I trial of relapsed or refractory acute myeloid leukemia (AML) patients with an IDH2 mutation (abstract 7004).
Mutations in IDH2 occur in approximately 12% of AML patients, and this causes a block in myeloid differentiation. “Enasidenib induced differentiation of leukemic cells in preclinical and also [earlier] clinical studies,” said Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.
Stein presented results of a phase I trial that included 113 patients in a dose-escalation cohort of enasidenib, and 126 patients in an expansion cohort. Patients had relapsed/refractory AML with an IDH2 mutation; the full phase I population had a median age of 70 years, and most had an ECOG performance status of 0–1 (81%).
The overall response rate among 176 evaluable patients at all doses of enasidenib was 40.3%; there were 34 complete remissions (CRs; 19.3%), and another 12 patients (6.8%) had a CR with either incomplete platelet recovery or incomplete hematologic recovery. Eleven patients (6.3%) had a partial remission, and 14 patients (8%) achieved a morphologic leukemia-free state. Another 85 patients (48.3%) had stable disease.
The study determined a phase II dose of 100 mg per day; of the 109 phase I patients treated at that dose, the overall response rate was 38.5%, with a CR rate of 20.2%.
Enasidenib was generally well tolerated, Stein said. The most common treatment-related grade 3/4 adverse events included hyperbilirubinemia (12%), thrombocytopenia (6%), and anemia (5%); no other treatment-related grade 3/4 adverse event occurred in more than 3% of patients.
The median overall survival (OS) in the study was 9.3 months, among 176 evaluable patients. Patients with CR had a median OS of 19.7 months, while those with a non-CR response had a median OS of 13.8 months; those with no response had a median OS of 7 months.
“Enasidenib induced durable complete remissions,” Stein said. “Unlike cytotoxic chemotherapy, responses to enasidenib may require several treatment cycles and responses can improve over time with continued treatment.” He noted that differentiation of myeloblasts, rather than cytotoxicity, appears to drive the clinical efficacy of the agent. The phase II study of enasidenib has enrolled over 90 patients as of mid-April 2017.
Jeffrey E. Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, was the discussant for the session. He said that the median OS seen in this study represents a strong signal of improvement over conventional regimens in this setting.
“This drug is a very promising drug as a single agent, and has a clear path of development as a single agent in relapsed disease, as well as combination therapy,” he said. He said some of the outstanding questions with enasidenib include what is driving resistance, as well as whether predictors of response might be identified.