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Ivosidenib plus Azacitidine versus Placebo plus Azacitidine in Patients with Newly Diagnosed AML with an IDH1 Mutation

Conference Correspondent

The isocitrate dehydrogenase 1 (IDH1) inhibitor ivosidenib is approved for patients with relapsed/refractory acute myeloid leukemia (AML) with an IDH1 mutation and newly diagnosed AML with an IDH1 mutation who are ineligible for intensive induction chemotherapy. AGILE was a global, double-blind, randomized, placebo-controlled, phase 3 study that evaluated ivosidenib plus azacitidine (IVO + AZA) versus placebo plus azacitidine (PBO + AZA) in patients with newly diagnosed with AML with an IDH1 mutation.

From March 19, 2018, to March 18, 2021, the study enrolled newly diagnosed previously untreated patients with AML, with centrally confirmed IDH1 mutation status, who were not eligible for intensive chemotherapy and had Eastern Cooperative Oncology Group performance status 0-2. Eligible patients were randomized 1:1 to receive ivosidenib (500 mg once daily) + AZA (75 mg/m2 subcutaneously or intravenously, days 1-7 of 28-day cycles), or placebo (PBO) + AZA; stratification was by region and de novo versus secondary AML. The primary end point was event-free survival (EFS); key secondary end points were complete response (CR) rate, overall survival (OS), CR + CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR).

A total of 146 patients were randomized to the study; 72 patients to the IVO + AZA arm and 74 to the PBO + AZA arm. The baseline characteristics were well-balanced. In the IVO + AZA arm, the median age was 76.0 years; 75% of patients had de novo AML, 25% had secondary AML, and 22.2% of patients had poor-risk genetics per European LeukemiaNet guidelines. At the time of current analysis, of the 39 patients who remain on treatment, 27 patients were in the IVO + AZA arm and 12 patients were in the PBO + AZA arm.

In the intent-to-treat population, the IVO + AZA arm was associated with a statistically significant longer EFS (hazard ratio [HR], 0.33; P = .0011) versus PBO + AZA. The EFS benefit with IVO + AZA therapy translated into a significant OS improvement (median OS, 24.0 months vs 7.9 months; HR, 0.44; P = .0005). Clinical responses were significantly higher with IVO + AZA therapy compared with PBO + AZA in terms of CR rate (47.2% vs 14.9%; P <.0001), CR + CRh rate (52.8% vs 17.6%; P <.0001), and ORR (62.5% vs 18.9%; P <.0001). The median time to CR was 4.3 months in the IVO + AZA arm versus 3.8 months in the IVO + AZA arm; the CR rate by 24 weeks was 37.5% and 10.8%, respectively.

In the IVO + AZA versus PBO + AZA cohorts, the most common treatment-emergent adverse events (TEAEs; any grade; >20% incidence) were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%). Grade ≥3 TEAEs occurred in 93.0% of patients in the IVO + AZA cohort versus 94.5% in the PBO + AZA cohort; common grade ≥3 adverse events (>20%) included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%). Incidence of differentiation syndrome—any grade; investigator-assessed—was higher in the IVO + AZA arm versus IVO + AZA (14.1% vs 8.2%). Health-related quality-of-life results favored IVO + AZA across all subscales, with clinically meaningful improvements in Global Health Status/QoL and Fatigue subscales over time in the IVO + AZA arm. Based on these results, the Independent Data Monitoring Committee recommended discontinuation of further enrollment into the study due to evidence of benefit.

In conclusion, the randomized phase 3 AGILE study demonstrated that IVO + AZA therapy accorded clinical benefit in terms of significant improvement in EFS, OS, and clinical response compared with PBO + AZA in newly diagnosed patients with AML with an IDH1 mutation who were ineligible for intensive chemotherapy; the safety profile for the active combination was deemed favorable.

Source: Montesinos P, et al. ASH 2021; abstr 697.

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