Tibsovo Plus Vidaza Is Beneficial for Patients With IDH1-Mutant Acute Myeloid Leukemia

Findings from the phase 3 AGILE trial showed significant benefit with Tibsovo (ivosidenib) plus Vidaza (azacytidine) compared to placebo in patients who had newly diagnosed IDH1-mutant acute myeloid leukemia (AML).

Results from AGILE supported the recent Food and Drug Administration (FDA) approval of Tibsovo in combination with Vidaza as a treatment option for patients with previously untreated IDH1-mutated AML aged 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy. The supplemental new drug application was reviewed as part of the FDA's Real-Time Oncology Review (RTOR) pilot program, which gets safe and effective therapies to patients sooner.

Earlier findings AGILE findings showed the median survival for patients who received the combination of Tibsovo and Vidaza to be 24 months compared to placebo. Improvements were also seen in event free survival (time from treatment until any complications or events that the therapy was meant to delay) and complete remission plus complete remission with partial hematologic recovery rates was 52.8% compared to17.6% with placebo.

“Approximately 6% to 10% of patients with acute myeloid leukemia have somatic mutations in the IDH1 gene. (Tibsovo) is a potent oral targeted inhibitor of mIDH1. And the AGILE study showed benefits of (Tibsovo) plus (Vidaza) compared with placebo plus (Vidaza) in patients with newly diagnosed IDH1-mutated AML,” Dr. Hartmut Dohner, 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 (meaning neither patients nor their clinicians knew which treatment was being administered), randomized, placebo-controlled, phase 3 AGILE trial aimed to evaluate the efficacy and safety of Tibsovo plus Vidaza compared with placebo plus Vidaza 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 (which indicates some degree of impairment to perform daily functions), severe cardiac disorder, severe pulmonary disorder, creatinine clearance less than 45 mL/minute, bilirubin greater 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 20% or more leukemic blasts in the bone marrow, an IDH1 mutation and adequate hepatic and renal function.

Patients were randomly assigned to receive the combination of oral Tibsovo at 500 mg plus subcutaneous or intravenous Vidaza at 75 mg/m2 (72 patients), or a matching placebo (74 patients). 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 nine, 17, 25, 33, 41, 53, every 24 weeks after, as well as at the end of treatment and during event-free survival follow-up.

The primary end point of the trial was EFS with key secondary end points including overall survival (time from treatment until death of any cause), rate of complete remission (no signs of cancer left after treatment), rate of complete remission and complete remission with partial hematologic recovery (CRh), and overall response rate (percentage of patients whose disease shrinks as a result of treatment).

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

The combination of Tibsovo plus Vidaza demonstrated rapidly increased mean neutrophil counts from baseline (0.99 x 109/L) (2.05 x 109/L) and week five (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 nine and 17 in the Tibsovo plus Vidaza treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the patients who were administered placebo plus Vidaza (53.7%, 34.6% and 19.6% at baseline, week nine and week 17, respectively).

The mean platelet count recovered from baseline values in the Tibsovo plus Vidaza and placebo plus Vidaza arms (71.0 and 92.6 x 109/L, respectively) as early as week nine 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 Tibsovo and Vidaza, and within the placebo plus Vidaza 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 Tibsovo plus Vidaza arm vs 17.5% in the placebo plus Vidaza arm achieved red blood cell/platelet transfusion independence compared.

In regard to safety, fewer side effects of febrile neutropenia were demonstrated in the Tibsovo plus Vidaza arm (28.2%) compared to the placebo plus Vidaza arm (34.2%). Additionally, infections were found in 28.2% vs 49.3% of patients who received Tibsovo plus Vidaza compared to placebo plus Vidaza.

In the combination group, 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 Vidaza 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 Vidaza arm.

Non-hematological side effects of any grade in the Tibsovo plus Vidaza vs placebo plus Vidaza 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%).

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