Chicago, IL—Ivosidenib is a potent oral inhibitor of the IDH1 mutation. In a new study presented at ASCO 2018, ivosidenib achieved durable remissions and molecular remissions in some patients with advanced relapsed or refractory acute myeloid leukemia (AML) and IDH1 mutation. In this phase 1 clinical trial, approximately 33% of the patients who received this drug became transfusion-independent. At a dose of 500 mg daily, ivosidenib has been associated with a low frequency of grade ≥3 treatment-related adverse events.
Ivosidenib is the second IDH inhibitor to be studied in patients with AML. The first agent is the IDH2 inhibitor enasidenib (Idhifa), which was approved by the FDA in August 2017 for adults with relapsed or refractory AML and IDH2 mutation. Ivosidenib is the first IDH1 inhibitor being investigated in AML.
"Both responders and those who didn't respond to ivosidenib achieved transfusion independence. Ivosidenib was well-tolerated, and adverse events were managed with standard of care. There are multiple ongoing studies of this drug," said lead investigator Daniel A. Pollyea, MD, MS, Clinical Director, Leukemia Services, University of Colorado School of Medicine, Aurora.
Study Details
Dr Pollyea's presentation was based on efficacy results in 179 patients in the dose-expansion phase of the study and an additional 35 patients enrolled in the dose-expansion phase after the manuscript was submitted to the New England Journal of Medicine. The results were published online to coincide with the presentation at ASCO 2018 (DiNardo CD, et al. N Engl J Med. 2018; 378:2386-2398).
All patients (median age, 67 years) received monotherapy with ivosidenib 500 mg once daily. Approximately 50% of the patients were male, approximately 66% of the patients had primary AML, and 33% had secondary AML. The median number of previous therapies was 2.
Approximately 60% of the patients had disease refractory to initial induction or reinduction therapy; approximately 53% had intermediate cytogenetic risk status; 30% poor risk status; and 17% had unknown cytogenetic risk. The rates of concomitant mutations were as expected, Dr Pollyea said. In addition to IDH2 mutation, approximately 7% of the patients had FLT3 mutation, 22% had NPM1 mutation, and 2% had CEBPA mutation.
In all, approximately 99% of patients had an adverse event, including IDH differentiation syndrome, prolongation of the QT interval, and leukocytosis, which were of particular interest in the study. These events were managed with appropriate supportive care, and no patients discontinued treatment or died because of these events.
At a median follow-up of 9 months, the objective response rate was 41.6%. The complete remission rate, with or without hematologic recovery, was approximately 32%, and the median time to achieving remission was 2.7 months. The median duration of response was 8.2 months.
At the time of data cutoff, 75 patients had a response. Approximately 25% of the responders subsequently had a transplant. At 12 months, 44% of the patients who achieved complete response remained in complete response.
The median overall survival was 9 months. With the 79 additional patients and further follow-up, the median overall survival for patients who achieved complete response was 18.8 months.
All patients with complete remission became transfusion-independent. Overall, 50% of the responders who did not achieve a complete response still achieved transfusion independence, and 17.5% of nonresponders achieved transfusion independence.
"Transfusion independence is a big achievement in terms of quality of life," Dr Pollyea told attendees.
Clinical Implications
Admittedly this was only a phase 1 study, but the outcomes were much better than historical outcomes in this group of very compromised patients with relapsed or refractory AML.
"Based on these data, ivosidenib is likely to become a new standard of care for relapsed or refractory patients with IDH1-mutated AML. We should carefully consider whether testing for mutation should become standard of care for all relapsed refractory patients," the formal discussant of the study, Eunice S. Wang, MD, Chief, Leukemia Service, Roswell Park Comprehensive Cancer Center, Buffalo, NY, stated.
EDITOR'S NOTE: Based on these results, on July 20, 2018, the FDA approved ivosidenib (Tibsovo) for the treatment of adults with relapsed or refractory AML plus IDH1 mutation, as detected by an FDA-approved test. That test, the Abbott RealTime IDH1 Assay, was approved by the FDA on the same day to identify appropriate patients for ivosidenib treatment.
