Promising OS Benefit With Ivosidenib in IDH1-Mutated R/R AML Leads to FDA Approval

July 23, 2018

Strong efficacy and safety outcomes with this agent, which targets the molecular driver of an AML subset, have led to its approval in IDH1-mutated R/R disease.

Ivosidenib (Tibsovo), an oral, targeted, small-molecule inhibitor of mutant IDH1, was approved by the US Food and Drug Administration (FDA) on July 20 for patients with advanced IDH1-mutated relapsed or refractory acute myeloid leukemia (AML), with IDH1 mutations detected in blood or bone marrow samples using an FDA-approved test. The approval represents the first targeted treatment for patients in this disease setting.

IDH1 mutations occur in 6% to 10% of patients with AML. According to estimates from The National Cancer Institute at the National Institutes of Health, close to 20,000 people in the United States will be diagnosed with AML in 2018, and slightly more than half will die of the disease this year.

Commenting on the approval, Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said ivosidenib “is associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

Ivosidenib was safe and produced durable remissions in some patients with relapsed or refractory AML, according to results of a phase I dose-escalation multicenter study published in late June in the New England Journal of Medicine. The investigators found that in patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500-mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events. This dosage was also associated with transfusion independence, durable remissions, and molecular remissions, with some patients achieving complete remissions.

For the multicenter study reported in NEJM, investigators enrolled 258 patients between March 2014 and May 2017 (ClinicalTrials.gov identifier: NCT02074839). Ivosidenib was administered orally as a single agent.

Lead author Courtney DiNardo, MD, an assistant professor at The University of Texas MD Anderson Cancer Center, Houston, said in the trial’s primary analysis cohort of 125 patients with IDH1-mutated relapsed or refractory AML treated at the recommended 500-mg daily dose, ivosidenib yielded an overall response rate (ORR) of 41.6% and a complete remission (CR) rate of 21.6%.

DiNardo and coauthors found 30.4% of the 125 patients were in CR but with blood counts not fully restored. The overall survival (OS) rate was 50.1% at 18 months, as compared with historical OS of less than 5 months for patients with relapsed AML and two prior therapies. Dr. DiNardo said among patients achieving CR or CR with partial hematologic recovery, 21% had no residual detectable IDH1 mutations.

In the primary efficacy population (125 patients), the researchers found that transfusion independence was attained in 29 of 84 patients (35%). Patients who responded had fewer infections and febrile neutropenia episodes compared with those who did not respond.

Robert Collins, MD, Professor of Internal Medicine and Director of the Bone Marrow Transplant Program at UT Southwestern Medical Center, Dallas, Texas, believes this is an important study. “Current chemotherapy approaches to AML are very nonspecific and have low cure rates, as well as being very toxic. This study reports remarkable results with a new drug that specifically targets a mutant enzyme that is the molecular driver of a subset of AML cases,” Dr. Collins told Cancer Network.

He explained that because the drug is a highly targeted therapy, side effects have been minimal, and the new findings represent a significant advance for patients with IDH1-mutated AML. “It is also a major advance in terms of suggesting the great potential of other specifically targeted drugs that are in development for other subtypes of AML,” he said.