‘Admirable’ overall survival attainable in AML with enasidenib
CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.
Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.
“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”
Mutations in IDH2 occur in approximately 12% of AML patients.
Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.
Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.
Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).
The clinical and translational papers were published simultaneously in Blood.
Study design
The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.
Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.
Four expansion arms were added, with 126 patients.
Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.
The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.
Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.
The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.
Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.
The MTD was not reached at doses up to 650 mg/day.
Baseline characteristics
Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.
The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.
Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).
There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).
The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.
SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.
Safety
The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).
