Enasidenib (AG-221) is a novel, small-molecule oral inhibitor of mutated IDH2 (mIDH2) proteins that is currently indicated for the treatment of adult patients with mIDH-positive relapsed or refractory (R/R) acute myeloid leukemia (AML). The phase 1 AG221-C-001 study demonstrated the clinical efficacy of enasidenib in patients with mIDH2 R/R AML. Given the limited treatment options for older patients with untreated AML, the current analysis sought to evaluate the clinical outcomes for older patients with previously untreated mIDH2 AML who received enasidenib monotherapy in the AG221-C-001 study.1
Both the dose-escalation and expansion cohorts included patients aged ≥60 years with previously untreated AML who were not candidates for standard treatment and had an Eastern Cooperative Oncology Group performance status of 0 to 2. In the dose-escalation phase, patients were treated with enasidenib 50 mg to 650 mg daily, whereas patients in the expansion phase received enasidenib 100 mg daily in continuous 28-day treatment cycles. The overall response rate (ORR) included complete remission (CR), CR with incomplete count recovery (CRi), CR with incomplete platelet recovery (CRp), and morphologic leukemia-free state (MLFS), per modified International Working Group 2003 response criteria for AML. Data cutoff for this analysis was October 14, 2016.
A total of 239 patients received enasidenib monotherapy in the phase 1 dose-escalation and study expansion, of which 38 patients had previously untreated mIDH2 AML. The median age of analysis patient set was 77 years (range, 58-87 years); 19 patients had intermediate cytogenetic risk by National Comprehensive Cancer Network classification and 10 had poor-risk cytogenetics. The median number of enasidenib treatment cycles was 6.5 (range, 1-35), and median follow-up was 8.6 months (range, 0.5-34.3 months).
In the efficacy analysis, an ORR of 32% (95% confidence interval [CI], 17.5-48.7) was reported, including 7 (18%) patients who achieved CR, 1 with CRi/CRp, 1 partial response, and 1 MLFS. Notably, 18 patients achieved stable disease. The median time to CR was 5.6 months (range, 3.4-12.9 months), the median duration of CR was not reached (NR; 95% CI, 3.7-NR), and the median duration of any response was 12.2 months (95% CI, 2.9-NR). At data cutoff, 3 patients proceeded to transplant and remained in remission. In the overall cohort (n = 37), the median overall survival (OS) was 11.3 months (95% CI, 5.7-17.0) and median event-free survival was 5.7 months (95% CI, 3.1-16.0). The median OS in responders (n = 14) was not reached (95% CI, 10.4-NR).
The most common treatment-emergent adverse events (TEAEs), regardless of grade, were fatigue (43%), nausea (41%), and decreased appetite (41%). The most frequent treatment-related TEAEs of any grade, occurring in ≥10% of patients, were hyperbilirubinemia (32%) and nausea (24%); grade 3/4 TEAEs occurred in 13% and 0%, respectively. Serious treatment-related TEAEs reported in >1 patient were IDH differentiation syndrome (n = 4; 11%) and tumor lysis syndrome (n = 4; 11%). Treatment-related TEAEs led to treatment discontinuation in 2 (3%) patients due to cardiac tamponade and thrombocytopenia. The safety profile was similar to that observed in the total study population of 239 patients.
These results suggest that enasidenib monotherapy may improve clinical outcomes by inducing durable hematologic responses in older, difficult-to-treat patients with previously untreated mIDH2 AML who were not candidates for standard treatment.
- Pollyea DA, et al. 2017 ASH. Abstract 638.