Enasidenib Improved Overall Response Rates in Patients With Late-Stage Mutant-IDH2 R/R AML

Results from a Randomized Phase 3 Trial

In patients ≥60 years old with de novo or secondary relapsed/refractory (R/R) acute myeloid leukemia (AML), an IDH2 gene mutation, and an Eastern Cooperative Oncology Group performance status score of ≤2, the use of oral IDH2 inhibitor enasidenib was associated with improved event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement  (HI), and red blood cell transfusion independence (RBC-TI), according to a phase 3 trial recently published in Blood. 

“Approximately 40% to 60% of older patients with newly diagnosed AML will attain morphologic remission after induction with intensive chemotherapy , leaving a substantial proportion of patients with refractory disease, and most patients who attain remission eventually experience relapse. Prognosis is dismal for patients with relapsed or refractory AML, and treatment outcomes are substantially diminished with each subsequent AML salvage therapy,” Stéphane de Botton, MD, PhD, Université Paris-Saclay, Villejeuf, France, and coauthors wrote. 

This international, multicenter, randomized, open-label, phase 3 study had a primary endpoint of assessing overall survival (OS) rates among patients aged ≥60 (median: 71, ranging 60 to 86) with de novo or secondary R/R AML and an IDH2 gene mutation. Secondary endpoints included assessing EFS, TTF, ORR, HI, and TI. 

319 patients were randomized 1:1 into 2 cohorts, with 158 patients receiving 100 mg enasidenib, and 161 patients receiving conventional care regimens (CCR), including 69 who received azacitidine, 33 who received intermediate-dose cytarabine (IDAC), 37 who received low-dose cytarabine (LDAC), and 22 who received best supportive care (BSC). Patients received treatment in repeated 28-day cycles until disease progression, relapse after complete recovery (with incomplete hematologic recovery or incomplete platelet recovery), unacceptable toxicity, loss to follow-up, withdrawal of consent, or eligibility to alternative therapies. 

At the data cutoff of March 17, 2020, results showed that the primary endpoint of reaching OS was never met. On the other hand, secondary endpoints were able to be observed, demonstrating that enasidenib improved EFS (4.9 months in the enasidenib cohort vs 2.6 months in the CCR cohort, 95% CI), TTF (4.9 months in the enasidenib cohort vs 1.9 months in the CCR cohort, 95% CI), ORR (40.5% in the enasidenib cohort vs 9.9% in the CCR cohort, 95% confidence interval [CI]), HI (42.4% in the enasidenib cohort vs 11.2% in the CCR cohort, P < .001), and RBC-TI (31.7% in the enasidenib cohort versus 9.3% in the CCR cohort). 

The most common treatment-related adverse events were gastrointestinal events, cytopenias, hyperbilirubinemia, and DS. Grade ≥3 treatment-related thrombocytopenia and neutropenia. The safety measure of enasidenib 100 mg daily was consistent with that of prior studies, denoting that enasidenib had an acceptance safety profile. 

As findings were significant in testing the safety and efficacy of enasidenib, Dr. Button et al concluded, “Results from this randomized, phase 3 study support enasidenib as an appropriate oral outpatient treatment for patients with mutant-IDH2 R/R AML.” 

Source: 

de Botton S, Montesinos P, Schuh AC, et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;141(2):156-167. doi:https://doi.org/10.1182/blood.2021014901