Phase 3 AGILE results show that ivosidenib plus azacitidine has clinical activity in IDH1-mutant acute myeloid leukemia.
Significant clinical benefit has been shown with ivosidenib (Tibsovo), a potent oral targeted inhibitor of IDH1, plus azacitidine (AZA; Vidaza) vs placebo plus azacitidine in patients with newly-diagnosed IDH1-mutant acute myeloid leukemia (AML), according to findingd from the phase 3 AGILE trial (NCT03173248).1
Results from AGILE supported the recent FDA approval of ivosidenib in combination with azacitidine as a treatment option for patients with previously untreated IDH1-mutated AML aged 75 years or older or who have comorbidities that preclude use of intesive induction chemotherapy. The supplemental new drug application was reveiwed as part of the FDA's Real-Time Oncology Review (RTOR) pilot program, which gets safe and effective therapies to patients sooner.2
Earlier findings AGILE findings showed the median survival for patients who received the combination of ivosidenib and azacitidine to be 24 months vs 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) and complete remission (CR) plus CR with partial hematologic recovery rates was 52.8% vs 17.6% with placebo.
“Approximately 6% to 10% of patients with acute myeloid leukemia have somatic mutations in the IDH1 gene. Ivosidenib is a potent oral targeted inhibitor of mIDH1. And the AGILE study showed benefits of IVO plus AZA compared with placebo plus AZA in patients with newly diagnosed IDH1-mutated AML,” Hartmut Dohner, MD, medical director, deputy director, professor, principle investigator at Ulm, Baden-Wurttemberg in Germany, stated during a presentation of the poster during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.
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 1 of the following criteria: an ECOG performance status score of 2, severe cardiac disorder, severe pulmonary disorder, creatinine clearance <45 mL/minute, bilirubin >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 ≥ 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 (n = 72), or a matching placebo (n = 74). 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).
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; ̃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 BM 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 BM 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.
Additionally, there was a reduced dependence on red blood cell and/or platelet transfusion. 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 36-40 weeks at a slow pace.
Of the patients who at baseline were red blood cell/platelet transfusion-dependent, a total of 54.0% in both groups, 46.2% of patients within the ivosidenib plus azacitidine arm vs 17.5% in the placebo plus azacitidine arm achieved red blood cell/platelet transfusion independence compared (1-sided P = 0.0032).
In regard to safety, fewer adverse events 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%).
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. 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. J Clin Oncol. 2022; 40(suppl 16; abstr 7042) doi: 10.1200/JCO.2022.40.16_suppl.7042
Servier announces FDA approval of Tibsovo® (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. News release. Srvier. May 25, 2022. Accessed June 4, 2022.