The FDA has approved ivosidenib (Tibsovo®, Servier Pharmaceuticals) in combination with azacitidine (Vidaza®, Celgene) for patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML) who are at least 75 years old or who have comorbidities preventing them from receiving intensive induction chemotherapy.
"Mutant IDH1 catalyzes the production of D-2-hydroxyglutarate, leading to disruption in cellular metabolism and epigenetic regulation and contributing to oncogenesis," wrote Pau Montesinos, MD, PhD, Attending Physician at the University Hospital La Fe in Valencia, Spain, and Co-Chairman of the Spanish PETHEMA AML and Acute Promyelocytic Leukemia (APL) group, and colleagues, in their published results of the AG120-C-009 trial (NCT03173248), on which the approval was based. "Ivosidenib—a first-in-class, oral, potent, targeted small-molecule inhibitor of mutant IDH1—has shown clinical activity as a single agent in studies involving patients with hematologic and solid-tumor cancers."
In this phase 3, multicenter, double-blind, placebo-controlled trial, 146 patients were enrolled and randomized 1:1 to receive either 500 mg of ivosidenib or a matched placebo orally once per day of each 28-day cycle, in combination with 75 mg/m2 of subcutaneous (SC) or intravenous (IV) azacitidine per day for the first week of each cycle, or until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. Eligible patients were newly diagnosed with AML with an IDH1 mutation and had at least one of the following medical conditions that made then ineligible for intensive chemotherapy: ≥75 years old, an Eastern Cooperative Oncology Group (ECOG) performance status of 2, severe pulmonary or cardiac disease, hepatic impairment, creatinine clearance <45 mL/minute, or other comorbidity. The primary end point was event-free survival, with secondary end points of complete remission rate and overall survival.
At a median follow-up of 12.4 months, event-free survival was significantly prolonged in the ivosidenib/azacitidine group compared with the placebo/azacitidine group (hazard ratio for treatment failure, relapse from remission, or death: 0.33). The probability of remaining event-free was significantly increased in the ivosidenib/azacitidine arm compared with placebo/azacitidine at the 6-month mark (40% vs 20%) and at the 12-month mark (37% vs 12%). Complete remission at the 12-month mark was reported at 88% with ivosidenib/azacitidine compared with 36% with placebo/azacitidine. Overall, complete remission, or complete remission with partial hematologic recovery, was reported in 53% of patients receiving ivosidenib/azacitidine, compared with 18% of patients receiving placebo/azacitidine. The median time to complete remission was 4.3 months in the ivosidenib arm compared with 3.8 months in the placebo arm. Overall survival saw a median of 24.0 months in the ivosidenib arm compared with 7.9 months in the placebo arm.
The most common adverse reactions in ≥25% of patients in any trial of ivosidenib in combination with azacitidine, or as monotherapy, were diarrhea, fatigue, edema, nausea, vomiting, decreased appetite, leukocytosis, arthralgia, dyspnea, abdominal pain, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, and myalgia. In addition, the prescribing information for ivosidenib has a boxed warning for differentiation syndrome, which can be fatal.
"In our trial, ivosidenib and azacitidine significantly improved event-free survival, response, and overall survival as compared with placebo and azacitidine in patients with newly diagnosed IDH1-mutated AML who were ineligible for induction chemotherapy," concluded Dr. Montesinos and colleagues in their report. "This clinical benefit is supported by favorable health-related quality of life, incidences of transfusion independence, and the expected constellation of adverse events associated with treatment for acute leukemia."
The recommended dose of ivosidenib is 500 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. In combination with azacitidine, start ivosidenib on day one of each 28-day cycle with administration of 75 mg/m2 of SC or IV azacitidine per day for the first week of each cycle. Treatment is recommended for a minimum of six months to allow time for clinical response for patients without unacceptable toxicity or progression of disease.
For More Information
Clinicaltrials.gov (2022). Study of AG-120 (ivosidenib) vs. placebo in combination with azacitidine in patients with previously untreated acute myeloid leukemia with an IDH1 mutation (AGILE). NLM identifier: NCT03173248.
US Food and Drug Administration (2022). FDA approves ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-combination-azacitidine-newly-diagnosed-acute-myeloid-leukemia
Image Credit: Prof Osaro Erhabor. Licensed under CC BY-SA 4.0