Rapid Readout: AGILE: ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation

OncLive® Rapid Readout from AGILE: ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation

Segment Description: Pau Montesinos, MD, PhD, discusses the AGILE phase 3 clinical trial for newly diagnosed patients with acute myeloid leukemia with an IDH1 mutation that was presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition in 2021, from study designs to data results. (Abstract 697)

Segment Body Content:

• Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6%–10% of patients with acute myeloid leukemia (AML). Ivosidenib—an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme—is FDA-approved for adults with relapsed/refractory mIDH1 AML and adults with newly diagnosed mIDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy (IC). Data from a phase 1b study of 23 patients with newly diagnosed mIDH1 AML showed a favorable safety profile and encouraging clinical activity of ivosidenib + azacitidine (IVO+AZA; NCT02677922).

Methods

• In this global, double-blind, randomized, placebo-controlled, phase 3 study, patients were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA), and stratified by region and de novo vs secondary AML.
• Key eligibility: untreated AML (WHO criteria), centrally confirmed mIDH1 status, not eligible for IC, ECOG 0-2.
• Primary endpoint: event-free survival (EFS; time from randomization until treatment failure, ie, failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause).
• Key secondary endpoints: CR rate, overall survival (OS), CR + CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR).

Results

• From March 19, 2018, to March 18, 2021, 146 patients were randomized: 72 to IVO+AZA (median [interquartile range] age, 76.0 [70.5–79.5] years) and 74 to PBO+AZA (median [interquartile range] age, 75.5 [70.0–80.0] years). Fifty-four (75.0%) patients had de novo AML vs 18 (25.0%) with secondary AML in the IVO+AZA arm. Sixteen (22.2%) patients receiving IVO+AZA had poor-risk genetics per ELN guidelines vs 20 (27.0%) patients receiving PBO+AZA. Thirty-nine (26.7%) patients remain on treatment (27/72 patients in the IVO+AZA arm vs 12/74 patients in the PBO+AZA arm).
• EFS was statistically significant (HR = 0.33 [95% CI 0.16, 0.69]; P = 0.0011) in favor of the IVO+AZA arm. Median OS with IVO+AZA was 24.0 months vs 7.9 months with PBO+AZA (HR = 0.44 [95% CI 0.27, 0.73]; P = 0.0005). CR rate with IVO+AZA was 47.2% (34/72 patients; 95% CI 35.3%, 59.3%) vs 14.9% (11/74 patients; 95% CI 7.7%, 25.0%) with PBO+AZA (P < 0.0001). Median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PBO+AZA. CR+CRh rate with IVO+AZA was 52.8% (38/72 patients; 95% CI 40.7%, 64.7%) vs 17.6% (13/74 patients; 95% CI 9.7%, 28.2%) with PBO+AZA (P < 0.0001). The CR rate by 24 weeks for IVO+AZA vs PBO+AZA was 37.5% and 10.8%, respectively. ORR with IVO+AZA was 62.5% (45/72 patients; 95% CI 50.3%, 73.6%) vs 18.9% (14/74 patients; 95% CI 10.7%, 29.7%) with PBO+AZA (P < 0.0001). All reported P-values are 1-sided.
• Common all-grade adverse events (AEs) occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA 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%).
• Sixty-six (93.0%) patients receiving IVO+AZA vs 69 (94.5%) patients receiving PBO+AZA experienced a grade ≥ 3 AE. Common grade ≥ 3 AEs occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA 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%).
• Frequency of all-grade differentiation syndrome (DS) as assessed by investigators was 14.1% with IVO+AZA vs 8.2% with PBO+AZA, and that of grade ≥ 3 DS was 4.2% with IVO+AZA vs 4.1% with PBO+AZA.
• Based on the recommendation of the Independent Data Monitoring Committee, further enrollment into the study was prematurely discontinued due to evidence of benefit.

Conclusions

• IVO+AZA significantly improved EFS, OS, and clinical response (CR, CR+CRh, ORR) compared with PBO+AZA in patients with IC-ineligible, newly diagnosed mIDH1 AML. The safety profile of IVO+AZA was favorable and consistent with previous studies. These data demonstrate the clinical benefit of IVO+AZA in this difficult-to-treat AML population.