Enasidenib and ivosidenib monotherapy have demonstrated induction of clinical responses in patients with mutant IDH (mIDH) relapsed/refractory acute myeloid leukemia (AML), whereas azacitidine (AZA) monotherapy prolongs survival in older patients with the newly diagnosed (ND) AML. Based on these results and coupled with preclinical evidence of synergy with combination of mIDH inhibitors plus AZA, an ongoing phase 1b/2 study evaluated the efficacy and safety of this combination in ND AML; results of the phase 1b portion were reported at ASH 2017.
Eligible patients with mIDH ND AML were aged ≥18 years, were required to be ineligible for intensive chemotherapy per investigator assessment, and could have antecedent hematologic disorders but prior use of hypomethylating agents was not allowed. The treatment regimen included enasidenib in dose-escalation cohorts of 100 mg or 200 mg once daily for patients with mIDH2 AML, and ivosidenib 500 mg once daily for patients with mIDH1 AML in continuous 28-day cycles; all patients received AZA 75 mg/m2 daily for 7 days per cycle, administered subcutaneously. Efficacy was assessed per International Working Group criteria for AML; overall response rate (ORR) included complete remission (CR), CR with incomplete hematologic recovery, partial remission (PR), and morphologic leukemia-free state (MLFS).
At data cutoff (September 1, 2017), a total of 17 patients had received ≥1 doses of combination therapy (enasidenib 100 mg + AZA, 3; enasidenib 200 mg + AZA, 3; ivosidenib 500 mg + AZA, 11). Eleven patients remained on study at data cutoff. The median age in the enasidenib + AZA cohort was 68 years (range, 64-79 years); in the ivosidenib + AZA cohort, it was 76 years (range, 72-88 years). Overall, the median number of enasidenib treatment cycles was 9 (range, 1-13), and the median number of ivosidenib treatment cycles was 3 (range, 1-13). Two enasidenib-treated patients discontinued treatment due to progressive disease; 1 of these (200-mg arm) was fatal (lung infection).
The most common treatment-emergent adverse events (TEAEs) with all regimens were grade 1 and 2 gastrointestinal events. In the enasidenib + AZA cohort, the most common TEAEs were nausea and hyperbilirubinemia (n = 4 each); the most common enasidenib-related TEAEs were nausea (n = 3), vomiting (n = 3), and hyperbilirubinemia (n = 2). In the ivosidenib + AZA cohort, TEAEs (any grade) included nausea (n = 8), constipation (n = 6), fatigue (n = 5), and diarrhea (n = 4); ivosidenib-related TEAEs of any grade occurring in >1 patient were fatigue (n = 4) and nausea (n = 6); there was 1 death due to pneumonia that was not considered treatment-related. Of note, IDH differentiation syndrome occurred in 1 patient each in the enasidenib 200-mg and ivosidenib arms.
In terms of response, ORR was 4/6 in the combined cohort receiving enasidenib + AZA; the best responses in the cohort receiving enasidenib 100 mg + AZA were 2 CRs, whereas that in the cohort receiving enasidenib 200 mg + AZA was 1 PR. The ORR was 8/11 patients in those receiving ivosidenib + AZA; 1 responder attained CR, 1 attained PR, 2 attained MLFS; 3 maintained stable disease.
In conclusion, the preliminary results of the phase 1b portion of the ongoing phase 1b/2 study support the tolerability of the combination of enasidenib or ivosidenib + AZA in patients with ND AML, with encouraging clinical activity. This combination is currently being evaluated in 2 randomized studies, including the phase 2 expansion portion of the current study and the phase 3 AGILE study of ivosidenib + AZA.
- DiNardo CD, et al. 2017 ASH. Abstract 639.