Combined therapy with enasidenib and azacitidine resulted in significantly improved response rates and durations in older patients with newly diagnosed IDH2-mutated acute myeloid leukemia (AML), and was generally well-tolerated, according to updated results from a phase 2 study presented at the virtual 2020 ASCO Annual Meeting.

“As many in the audience are now very well aware, IDH2 mutations are one of the most common recurrent mutations in AML and overall occur in approximately 15% of patients,” said Courtney DiNardo, MD, MSCE, during her presentation.

“Given potential for complimentary activity as well as evidence of synergistic results in in vitro models, a phase 1/2 study was initiated to evaluate the combination of targeted therapy with enasidenib in combination with azacitidine for newly-diagnosed older unfit patients with IDH2 mutations,” Dr DiNardo explained.

“Today we will provide updated results from the randomized phase 2 trial portion that was previously presented at ASH 2019, which is the subsequent 2:1 randomized comparison of the combination of enasidenib and azacitidine versus azacitidine monotherapy,” she continued.

All patients received azacitidine subcutaneously at 75 mg/m2 for 7 days of each 28-day cycle. Those randomized to the combination therapy arm also received enasidenib at 100 mg orally once daily continuously.

The primary end point of the trial was overall response rate (ORR). Key secondary end points included duration of response (DOR), overall survival (OS), event-free survival (EFS).

A total of 101 patients (median age, 75 years) were enrolled and randomized to combination therapy (n = 68) or azacitidine monotherapy (n = 33). The most common reasons for treatment discontinuation was disease progression.

The median number of treatment cycles was 10 (range, 1-26) in the combination therapy arm and 6 (range, 1-28) in the azacitidine monotherapy arm. A total of 7 patients in the azacitidine monotherapy arm received subsequent treatment with enasidenib.

The ORR was 48% with combination therapy compared to 14% with azacitidine alone. Median OS was 22 months in both of the treatment arms (HR, 0.99; 95% CI, 0.52, 1.87; P = .97). Median EFS was 17.2 months and 10.8 months, respectively (HR, 0.59; 95%CI, 0.30, 1.17; P = .13).

The most common treatment-related grade 3-4 adverse events (AEs) with enasidenib plus azacitidine were thrombocytopenia (37% vs 19% with azacitidine monotherapy), neutropenia (35% vs 22%, respectively), anemia (19% vs 22%, respectively), and febrile neutropenia (15% vs 16%, respectively). Grade 3-4 infections were reported in 18% and 31% of patients in each arm, respectively.

“Ultimately, this study demonstrates the favorable responses seen with the pairing of azacitidine with this targeted IDH2 mutation-specific treatment,” concluded Dr DiNardo.—Alexis V. Hyams

DiNardo CD, Schuh AC, Stein EM, et al. Effect of enasidenib (ENA) plus azacitidine (AZA) on complete remission and overall response versus AZA monotherapy in mutant-IDH2 (mIDH2) newly diagnosed acute myeloid leukemia (ND-AML). Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 7501.