Addition of Ivosidenib to Azacitidine Improves Outcomes in Newly Diagnosed IDH1-Mutant AML

Hartmut Dohner, MD

The combination of ivosidenib (Tibsovo) and azacitidine (Vidaza) elicited a clinically meaningful benefit across end points compared with azacitidine alone among patients with newly diagnosed IDH1-mutant acute myeloid leukemia (AML) who were ineligible for intensive induction chemotherapy. Findings from the phase 3 AGILE trial (NCT03173248) were presented in a poster at the 2022 ASCO Annual Meeting.

Conversion to and maintenance of transfusion independence rates were reported for both cohorts. Among patients in the ivosidenib/azacitidine (n = 71) and the azacitidine/placebo group (n = 74), 39 and 40 patients, respectively, had transfusion independence at baseline. Among those who received the investigative combination, 46.2% maintained red blood cell/platelet transfusion independence vs 17.5% in the placebo plus azacitidine group (1-sided P = .0032). Further, maintenance of transfusion independence was superior with the ivosidenib/azacitidine vs azacitidine/placebo (69.7% vs 61.8%, respectively).

Transfusion independence was defined as a period of at least 56 days with no transfusion after the start of the study.

“Approximately 6% to 10% of patients with AML have somatic mutations in the IDH1 gene. Ivosidenib is a potent oral targeted inhibitor of IDH1. [Data from the] AGILE study showed benefits of ivosidenib plus azacitidine compared with placebo plus azacitidine in patients with newly diagnosed IDH1-mutated AML,” Hartmut Dohner, MD, medical director, deputy director, professor, principal investigator at Ulm, Baden-Wurttemberg in Germany, said during a presentation of the findings.

The multicenter, double-blind, randomized, placebo-controlled, phase 3 AGILE trial aimed to evaluate the efficacy and safety of ivosidenib plus azacitidine compared with placebo plus azacitidine in adult patients with newly diagnosed, previously untreated IDH1m AML who were ineligible for intensive induction chemotherapy.

Enrollment within the trial was open to patients aged 18 years who met at least one of the following criteria: an ECOG performance status score of 2, severe cardiac disorder, severe pulmonary disorder, creatinine clearance less than 45 mL/minute, bilirubin more than 1.5 times the upper limit of normal, or had another comorbidity judged incompatible with intensive IC by the investigators.

Along with this, patients must have had previously untreated AML with at least 20% leukemic blasts in the bone marrow, an IDH1 mutation, and adequate hepatic and renal function.

Patients were randomized 1:1, to receive the combination of oral ivosidenib at 500 mg plus subcutaneous or intravenous azacitidine at 75 mg/m2, or a matching placebo. Patients were assessed for red blood cell and/or platelet transfusion history at the time of screening and follow-up. Further, bone marrow and peripheral blood samples were obtained at the time of screening, weeks 9, 17, 25, 33, 41, 53, every 24 weeks after, as well as at the end of treatment and during EFS follow-up.

The primary end point of the trial was EFS with key secondary end points including overall survival (OS), rate of complete remission (CR), rate of CR and complete remission with partial hematologic recovery (CRh), and overall response rate (ORR).

Previously reported findings showed the median overall survival for patients who received the combination of ivosidenib and azacitidine to be 24 months vs 7.9 months with placebo (HR, 0.44, 95% CI, 0.27-0.73; P = 0.0005). Improvements were also seen in event-free survival (EFS; HR,0.33, 95% CI, 0.16-0.69; P = 0.0011). This extended to CR/CRh rates which were 52.8% vs 17.6%, respectively.

Results from the sub-analysis of the trial demonstrated that in the ivosidenib plus azacitidine and placebo plus azacitidine arms, a total of 4.2% and 5.5% of patients received concomitant granulocyte colony-stimulating factor.

The combination of ivosidenib plus azacitidine demonstrated rapidly increased mean neutrophil counts from baseline (0.99 x 109/L) (2.05 x 109/L) and week 5 (4.07 x 109/L), before generally stabilizing to a normal range by the end of the study (last available cycle value; approximately 2.0 x 109/L), showing that they recovered more rapidly compared with the placebo combination.

Along with increased blood counts, there was a rapid decrease in the mean bone marrow blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17 in the ivosidenib plus azacitidine treated patients and were maintained for 149 weeks. The decline in bone marrow blasts was slower in the patients who were administered placebo plus azacitidine (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively).

The mean platelet count recovered from baseline values in the ivosidenib plus azacitidine and placebo plus azacitidine arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population.

Febrile neutropenia and infection rates also were reduced when patients were administered ivosidenib and azacitidine, and within the placebo plus azacitidine arm, the mean neutrophil counts initially declined before recovering to near-normal levels after 36 to 40 weeks at a slow pace.

In terms of safety, fewer adverse events (AEs) of febrile neutropenia were demonstrated in the ivosidenib plus azacitidine arm (28.2%) vs the placebo plus azacitidine arm (34.2%). Additionally, infections were found in 28.2% vs 49.3% of patients who received ivosidenib plus azacitidine vs placebo plus azacitidine.

In the combination arm, anemia of any grade occurred in 22 patients (31%) and grade 3 or higher occurred in 18 (25.4%) vs 28.8% and 26% in the placebo plus azacitidine arm. Thrombocytopenia of any grade was reported in 20 patients (28.2%) and thrombocytopenia grade 3 or higher in 17 patients (23.9%) compared with 15 (20.5%) in the placebo plus azacitidine arm.

Non-hematological AEs of any grade in the ivosidenib plus azacitidine vs placebo plus azacitidine arm included nausea (42.3% vs 38.4%), vomiting (40.8% vs 26%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), constipation (26.8% vs 52.1%), pneumonia (23.9% vs 31.5%), and more. Grade 3 or higher non-hematological in each arm included nausea (2.8% vs 4.1%), vomiting (0% vs 1.4%), diarrhea (1.4% vs 6.8%), pyrexia (1.4% vs 2.7%), constipation (0% vs 1.4%) and pneumonia (22.5% vs 28.8%).

Reference

Dohner H, Montesinos P, Vives Polo S et al. Hematologic improvements with ivosidenib + azacitidine compared to placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2022;40(suppl 16):7042. doi:10.1200/JCO.2022.40.16_suppl.7042