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The FDA has approved a supplemental new drug application for ivosidenib as a single agent for the first-line treatment of adult patients with IDH1-mutant acute myeloid leukemia, as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive chemotherapy.
The FDA has approved a supplemental new drug application (sNDA) for ivosidenib (Tibsovo) as a single agent for the first-line treatment of adult patients with IDH1-mutant acute myeloid leukemia (AML), as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive chemotherapy.1
The approval is based on findings from a phase I trial in which ivosidenib induced a 28.6% (95% CI, 13.2-48.7) complete response (CR) rate and a CR plus CR with partial hematologic recovery (CRh) rate of 42.9% (95% CI, 24.5-62.8), stated Agios, the developer of ivosidenib, in a press release. The median durations of CR and CR+CRh were not estimable, and 41.7% (n = 5) of patients who achieved CR/CRh remain on ivosidenib as of the data cutoff.
“The phase I results for Tibsovo demonstrated that this oral, single-agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation,” Gail J. Roboz, MD, professor of medicine, Director of the Leukemia Program and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, said in a press release. “Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics and prior treatment with hypomethylating agents.”
The agency’s decision took place more than a month before the action date, which was June 21, 2019. The sNDA had been accepted under the FDA’s Real-Time Oncology Review pilot program, which is designed to have a more efficient review process to make therapies more quickly available to patients.
Agios submitted data from a phase I dose escalation/expansion study examining ivosidenib monotherapy in patients with IDH1-positive hematologic malignancies. Study results from the data cutoff date of May 11, 2018, were presented in December 2018 at the ASH Annual Meeting.2 At the cutoff, 258 patients had received treatment, including 34 patients with untreated AML. Of this group, 9 were from the dose-escalation phase and 25 were from the expansion phase.
Among these 34 AML patients, 79.4% had secondary AML and 20.6% had de novo AML. The median patient age was 76.5 years (range, 64-87). Patients received 500 mg of ivosidenib daily, and the median treatment duration was 4.3 months (range, 0.3-40.9).
Results also showed that 58.3% of patients who achieved a CR or CRh were in remission at 1 year after receiving ivosidenib. The median time to CR/CRh was 2.8 months (range, 1.9-12.9). Also, among 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41.2% were independent of RBC and such transfusions during any 56-day postbaseline period. Moreover, of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 54.5% of them remained transfusion independent during the similar period.
Among all responders, the median time to first response was 1.9 months (range, 0.9-3.6). The estimated 12-month durations of response were 59.5%, 66.7%, and 77.8%, in the ORR, CR/CRh, and CR populations, respectively.
There were patients across all categories of responders who achieved transfusion independence (no transfusions for ≥56 consecutive days on treatment). Sixty-four percent (9 of 14) of the CR/CRh group had IDH1 mutation clearance, including all 4 patients who achieved a CRh.
Regarding safety, adverse events (AEs) across all grades occurring in >20% of patients were diarrhea (52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), and edema peripheral (26.5%). QTc interval prolongation also occurred in patients treated with ivosidenib. IDH-differentiation syndrome (IDH-DS) across all grades occurred in 25% (n = 7) of patients, of which 6 patients (86%) recovered.
The FDA previously approved ivosidenib in July 2018 for the treatment of adult patients with relapsed/refractory IDH1-mutant AML.3 The approval was based on a single-arm phase I study of 174 patients with IDH1-positive relapsed/refractory AML. In the study, the CR rate was 24.7% (95% CI, 18.5-31.8) and the CRh rate was 8% (95% CI, 4.5-13.1). The median duration of CR plus CRh was 8.2 months (range, 5.6-12). Among the CR/CRh population, the median time to best response was 2.0 months (range, 0.9-5.6).