Summary
Results of the phase II open-label trial were presented at the 2020 ASCO Annual Meeting (Abstract 7501). On their own, both drugs induce overall response rates of around 30 percent and complete remission rates of about 20 percent, but combining the two enhances cell differentiation and, as indicated by the new findings, may complement each other and further improve rates.
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Original Article
New Combination Regimen Boosts AML Remission
Oncology Times
By Kurt Samson
Combined treatment with enasidenib and the hypomethylating agent azacitidine significantly improved complete remission (CR) and overall response rates (ORR) compared with azacitidine alone in a group of 101 newly diagnosed acute myeloid leukemia (AML) patients with an IDH2 mutation.
Results of the phase II open-label trial were presented at the 2020 ASCO Annual Meeting (Abstract 7501). On their own, both drugs induce overall response rates of around 30 percent and complete remission rates of about 20 percent, but combining the two enhances cell differentiation and, as indicated by the new findings, may complement each other and further improve rates.
An oral small molecule inhibitor of mutant IDH2 proteins, enasidenib was approved by the FDA in 2017 for patients with IDH2-mutated relapsed/refractory AML. Azacitidine is a widely used treatment for older AML patients with the mutation who are ineligible, or opt not to, undergo intensive chemotherapy.
“The combination of the two drugs may provide patients with a new option,” said investigator Courtney Dinardo, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center.
In the trial, patients who were not candidates for intensive chemotherapy, with poor ECOG functional status scores and intermediate- or poor-risk cytogenetics, were randomized to receive either both agents or just to azacytidine in 28-day cycles. They were given SC azacitidine 75 mg/m2/d x 7 d/cycle, while patients in the combination therapy group received 100 mg of enasidenib.
The primary endpoint was ORR (CR, CR with incomplete recovery, partial remission, morphologic leukemia-free state). Other endpoints include duration of response (DOR), overall and event-free survival (OS, EFS), safety, and mIDH2 variant allele frequency (VAF).
The median age was 75 years and most subjects had intermediate-risk cytogenetics. In all, 21 patients in the combination arm and one in the azacytidine alone arm participated for the length of the study. The most common reason for discontinuing treatment was disease progression, which occurred in 31 percent of the patients in the combination arm and 52 subjects treated with azacitidine alone.
“We have learned that the combination of azacitidine plus enasidenib is associated with significantly improved complete remission and overall response rates compared to azacitidine alone,” DiNardo said.
“The remissions are deep, with significant decrease in mutant IDH2 allele frequency than with azacitidine alone,” she told Oncology Times. “Additionally, the responses are independent of signaling pathway co-mutations like FLT3-ITD or KRAS or NRAS, which were associated with lack of response to enasidenib monotherapy in the previous phase I study.”
A total of 21 percent of subjects given azacitidine alone received subsequent enasidenib treatments.
The median overall survival rate was 22 months in both groups, while the median event-free survival rate was found to be 17.2 months in the combination subjects compared to 10.8 months in those treated with azacitidine monotherapy.
The maximal mIDH2 VAF change from baseline was 83.4 percent with both agents, but just 17.7 percent with azacitidine alone.
No baseline co-mutation predicted primary resistance, and the most commonly reported adverse events (category 3 or 4) in the combined arm were thrombocytopenia in 37 percent of patients, neutropenia in 35 percent, anemia in 19 percent, and febrile neutropenia in 15 percent, DiNardo explained. In the azacitidine subjects, the rates were 19 percent, 22 percent, 22 percent, and 16 percent.
A total of 18 patients in the combination therapy group developed grade 3-4 infections, as did 31 percent of those in the azacitidine alone arm.
“Combining enasidenib with azacitidine resulted in significantly improved response rates and durations, and was generally well-tolerated,” said DiNardo. “There are no new safety concerns.”
Azacitidine has been the standard of care in older AML patients, yielding clinical response rates of about 20 percent and around 30 percent overall survival response. Median overall survival is currently around 1 year.
“It was thought that combining enasidenib with azacitidine for the treatment of newly diagnosed patients with AML might improve upon expectations with either agent on their own. This is what we have found,” DiNardo stated. “My next step is working to determine the best way to combine or sequence azacitidine with enasidenib and venetoclax—another very powerful and effective new therapy for AML.”
Kurt Samson is a contributing writer.