ATLANTA (FRONTLINE MEDICAL NEWS) – Enasidenib, a first-in-class oral, selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2) protein, shows promise both as monotherapy in older adults with untreated mIDH2 acute myeloid leukemia (AML), and in combination with azacitidine in patients with newly diagnosed AML, according to preliminary data from two phase 1/2 studies.

Of 239 patients aged 60 years and older from the AG221-C-001 phase 1 study of enasidenib monotherapy, 38 had previously untreated mIDH2 AML and were included in the current analysis, Daniel A. Pollyea, MD , reported at the annual meeting of the American Society of Hematology.

The previously untreated patients had a median age of 77 years, and at the Sept. 1, 2017, data cutoff, the median number of enasidenib treatment cycles in these patients was 6.5. Median follow-up was 8.6 months, said Dr. Pollyea of the University of Colorado, Aurora,

Overall, 7 of the 38 patients attained complete remission (CR). The median time to CR was 5.6 months. The overall response rate was 32%, Dr. Pollyea said, noting that the median duration of complete remission was not reached.

The median duration of any response was 12.2 months, he said.

Among all 38 patients, median overall survival was 10.4 months, and among responders and nonresponders it was 19.8 months and 5.4 months, respectively. Median event-free survival was 11.3 months.

Study subjects were adults aged 60 and older with previously untreated AML, who were not candidates for standard treatment. During dose-escalation they received 50-650 mg of enasidenib daily, and all patients in the expansion phase received 100 mg daily in continuous 28-day treatment cycles.

The findings are notable, because older patients with untreated AML, who are not candidates for standard induction therapy because of advanced age or health-related factors, pose a therapeutic challenge.

“We all know that older patients with newly diagnosed AML are often poor candidates for intensive chemotherapy approaches,” Dr. Pollyea said, explaining that this may be due to patient-related factors such as comorbidities that increase the risk of treatment-related mortality, or to adverse biologic features that make them less responsive to intensive chemotherapy. “The majority of older patients in this country are offered no treatment at all.”

In the current analysis, treatment was well tolerated; the rate of treatment-emergent adverse events was low, with only 2 of the 38 patients discontinuing treatment due to such an event. Serious treatment-related adverse events included isocitrate dehydrogenase (IDH) differentiation syndrome in four patients and tumor lysis syndrome in two patients. Grade 3-4 cytopenias were relatively uncommon, occurring in no more than 16% of patients.

The safety profile was similar to that reported for all patients in the phase 1 portions of the study, Dr. Pollyea noted.

These results suggest enasidenib may benefit older adults with mIDH2 AML who are not fit to receive cytotoxic chemotherapy, he said, adding that the encouraging and durable responses have prompted follow-up studies of enasidenib in older patients with previously untreated mIDH2 AML, such as the Beat AML Master Trial , and a study of enasidenib and ivosidenib (a small-molecule inhibitor of mIDH1 protein), each in combination with azacitidine in patients with newly diagnosed AML.

Combination approach

Preliminary findings from the latter trial ( AG-221-AML-005 ) were presented at the ASH meeting by Courtney D. DiNardo, MD , who is also a coauthor on the AG221-C-001 study.

Eleven of 17 patients enrolled remained on study at the Sept. 1, 2017, data cutoff, including 3 of 6 who received enasidenib at doses of either 100 mg or 200 mg, and 8 of 11 who received 500 mg of ivosidenib.

In the enasidenib-treated patients, the overall response rate was 67% at data cutoff. Of those who received 100 mg of enasidenib, two achieved CR, and of those who received 200 mg, one achieved partial remission and one had morphologic leukemia-free state. Another maintained stable disease. One patient in the 100-mg group had progressive disease, said Dr. DiNardo of the University of Texas MD Anderson Cancer Center, Houston.

The patients who received enasidenib had a median age of 68 years, and the median number of treatment cycles overall was nine.

The most common treatment-emergent adverse events were hyperbilirubinemia and nausea, each occurring in four patients. Others, of any grade, included nausea, vomiting, and hyperbilirubinemia. IDH differentiation syndrome occurred in one patient in the 200-mg arm.

In the ivosidenib patients, the overall response rate was 73%; four patients achieved CR, one achieved CR with incomplete neutrophil recovery, one achieved partial remission, and two had morphologic leukemia-free state. Three maintained stable disease.

Patients in this group had a median age of 76 years and the median number of treatment cycles was three.

The most common treatment-emergent adverse events were nausea, constipation, fatigue, and diarrhea.

One patient experienced IDH differentiation syndrome, and two patients developed pneumonia. One of the patients with pneumonia died, but the event was not considered treatment related.

The findings suggest that both enasidenib and ivosidenib in combination with azacitidine are generally well tolerated in patients with newly diagnosed AML, Dr. DiNardo said.

Both agents were shown preclinically to reduce aberrant 2-HG levels and to promote myeloid differentiation. As monotherapies, they induce clinical responses in patients with mIDH relapsed/refractory AML, she said.

Further, azacitidine monotherapy prolongs survival, compared with conventional care, in older patients with newly diagnosed AML, she explained. She said that combinations of mIDH inhibitors and azacitidine in vitro showed synergistic effects on releasing differentiation block in mIDH leukemia models, providing a clinical rationale for combining these agents for the treatment of AML.

The current findings represent the initial results of the phase 1b portion of an ongoing phase 1b/2 study. “Preliminary efficacy results with these combination regimens are encouraging,” Dr. DiNardo said. “Phase 1b confirms the recommended monotherapy doses of enasidenib 100 mg, ivosidenib 500 mg as safe and effective in combination with azacitidine.”

These treatments will move forward for additional study in combination regimens, she said, noting that the evaluation of mIDH inhibitors plus azacitidine continues in two currently enrolling randomized studies, including the expansion phase of the current study and the phase 3 AGILE study of ivosidenib plus azacitidine in newly diagnosed AML patients not suitable for intensive therapy.

Both studies were sponsored by Celgene, the maker of enasidenib. Dr. Pollyea reported ties to Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis, and Agios. Dr. DiNardo reported ties to Novartis, AbbVie, Celgene, Agios,and Daiichi Sankyo.

SOURCE: Pollyea D et al. ASH 2017 Abstract 638 ; DiNardo C et al. ASH 2017 Abstract 639


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