Patients with newly diagnosed, IDH2-mutated acute myeloid leukemia (AML) had significantly improved overall response rates (ORRs) with the combination of enasidenib plus azacitidine compared with azacitidine alone, according to results of the phase Ib/II AG221-AML-005 trial.
In the study, published in Lancet Oncology, about three-quarters (74%) of the patients randomly assigned to enasidenib plus azacitidine had a response compared with only about one-third (36%) of patients assigned to azacitidine alone (odds ratio [OR] = 4.9; 95% CI 2.0-11.9; p=0.0003).
Enasidenib is an oral IDH2 inhibitor, and IDH2 mutations occur in about 8-19% of patients with AML. Enasidenib is currently approved in the U.S. as a single agent for adult patients with relapsed or refractory IDH2-mutated AML.
“This study demonstrates that the combination of azacitidine with enasidenib represents another effective hypomethylating agent–based combination for intensive chemotherapy–ineligible patients with newly diagnosed AML,” said study researcher Courtney D. DiNardo, MD, of University of Texas MD Anderson Cancer Center.
Preclinical data suggests that combining azacitidine and enasidenib “enhances apoptosis versus azacitidine alone, and is associated with greater-than-additive increases in hemoglobin and reduced leukemic stem cell and progenitor cell populations.”
The open-label, phase Ib/II trial was designed to assess the proper dose, safety, and antitumor activity of the combination in newly diagnosed disease. The study included 107 patients from 43 clinical sites in 12 countries.
In the phase Ib portion, patients received oral enasidenib 100 mg per day or 200 mg per day plus subcutaneous azacitidine 75 mg/m2 per day for seven days of each 28-day cycle. In phase II, patients were randomly assigned 2:1 to enasidenib plus azacitidine or azacitidine alone. The primary endpoint was overall response rate in the intention-to-treat population at a prespecified interim analysis.
Of the 107 patients enrolled, six were enrolled in the phase Ib portion with half receiving 100 mg enasidenib and half receiving 200 mg enasidenib. No dose-limiting toxicities were found. The 100 mg dose was selected for phase II.
“The combination of enasidenib with azacitidine compared to azacitidine alone demonstrated significant improvements in clinical response, including a higher rate of patients attaining complete remissions (CRs) with full hematologic recovery,” Dr. DiNardo said.
At data cutoff for the interim analysis, 24 patients were still receiving their assigned treatment. The primary endpoint was met as the overall response rate was significantly higher in the combination group compared with azacitidine alone.
The CR rate was also significantly higher for patients assigned to the combination (OR=8.7; 95% CI 2.7-27.3; p<0.0001), as was the rate of CR plus CR with incomplete blood count or platelet recovery (CRi).
The estimated median event-free survival (EFS) was not significantly different for combination therapy compared with azacitidine alone (15.9 vs. 11.9 months; hazard ratio [HR] = 0.59; 95% CI 0.30-1.13; p=0.11). Neither was the overall survival (OS; 22.0 vs. 22.3 months; HR=0.99; 95% CI 0.52-1.87; p=0.97). A post-hoc analysis showed that median OS was not yet reached in patients assigned to the combination who had a morphological complete remission.
“While the OS was not different between arms, the OS endpoint may be confounded by the high rate of subsequent therapy, including approximately one-third of patients in the azacitidine-only arm receiving subsequent enasidenib therapy once discontinuing trial therapy,” Dr. DiNardo noted.
Common treatment-related grade 3/4 adverse events with the combination included thrombocytopenia (37%), neutropenia (37%), anemia (19%), and febrile neutropenia (16%). Similar rates of serious treatment-related adverse events were reported in the two study arms (43% vs. 44%). No treatment-related deaths occurred.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacytidine versus azacytidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomized, phase 2 trial. Lancet Oncol. 2021;22(11):1597-1608.
Perspectives
"This trial raises an important question about what is the best frontline treatment for patients who are newly diagnosed with AML and are ineligible for intensive chemotherapy (IC). In a subset analysis of the phase III VIALE-A study,1 patients with IDH2 mutations did extremely well when treated with the combination of azacitidine and venetoclax compared to the overall study population with a complete response (CR) with or without count recovery (CRi) rate of over 80%.2 In the precision medicine AG221-AML-005 study targeting IDH2, the combination of azacitidine and enasidenib as compared with azacitidine alone in IDH2-mutated, IC-ineligible patients, the combination demonstrated an improved overall response rate (74%) over single-agent azacitidine (36%). The CR/CRi rate was 57% in the combination arm, and while there was an improvement in median EFS of 15.9 months (95% CI 13.0-not reached) versus 11.9 months (95% CI 8.2-15.5), this did not result in an OS difference (acknowledging that the study was not powered to detect this endpoint). There were significant grade 3 and 4 adverse events in both arms, with differentiation syndrome being unique to the combination arm.
"Until a larger study can demonstrate an OS benefit in this subset of patients, azacitidine plus venetoclax appears to be a very effective frontline therapy for this patient population. The use of enasidenib as effective salvage in the azacitidine alone arm in the study may have confounded the results, but also shows the effectiveness of using IDH2-targeted therapy as a salvage option. This study shows that using either strategy as a frontline option for IC-ineligible patients is feasible, but until we have a head-to-head combination study, it remains an open question whether targeted therapy should be “saved” for salvage therapy versus being used up front. Use of an azacitidine-only control arm in studies of IC-ineligible patients, such as this one, greatly limits any conclusions we can draw given that azacitidine plus venetoclax is now the standard of care for this patient population."
Uma Borate, MD
The Ohio State University
Dr. Borate is a paid consultant for AbbVie, Genentech, and Bristol Myers Squibb.
References
- DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629.
- Pollyea DA, Dinardo CD, Arellano ML, et al. Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with IDH 1/2 mutations. Blood. 2020;136(Suppl 1):5-7.
