Ivosidenib Demonstrates Durable Responses in R/R AML

Angelica Welch

Daniel A. Pollyea, MD

Daniel A. Pollyea, MD

Ivosidenib induced an overall response rate (ORR) of 41.6% (95% CI, 32.9-50.8) in patients with IDH1-positive relapsed/refractory acute myeloid leukemia (AML), according to a phase I dose-expansion study presented at the 2018 ASCO Annual Meeting and published simultaneously online in the New England Journal of Medicine.1,2

A once daily 500 mg dose of the IDH1 inhibitor demonstrated a median progression-free survival (PFS) of 8.2 months, a complete remission (CR) or CR with partial hematologic recovery (CRh) of 30.4% (95% CI, 22.5-39.3), and a CR rate of 21.6% (95% CI, 14.7-29.8). The primary efficacy endpoint of the study was CR of CRh, a protocol-defined endpoint.

“In this population of IDH-positive relapsed/refractory AML patients, ivosidenib was able to achieve durable responses,” said lead author Daniel A. Pollyea, MD, assistant professor of Medicine at the University of Colorado Cancer Center and clinical director of Leukemia Services at the CU School of Medicine. “For the first time, we are able to tell you that the median overall survival for patients who achieved a CR is 18.8 months.”

Ivosidenib is an investigational first-in-class, oral, potent, reversible, targeted inhibitor of the mutant IDH1 enzyme. The investigators of this phase I dose-expansion and dose-escalation study of ivosidenib monotherapy aimed to establish safety and efficacy in patients with IDH1-mutated AML.

Of the 258 IDH1-mutated patients enrolled on the trial, 179 patients were relapsed or refractory. The reported outcomes were based on the primary efficacy group of 125 patients, which were made up of cohorts 1 and 4 of the dose expansion, as well as 33 additional patients from the dose escalation.

The median duration of response (DOR) for patients who received a CR was 10.1 months (95% CI, 6.5-22.2), and 8.2 months (95% CI, 5.6-12.0) for patients that received a CR or a CRh. Median DOR for all patients that responded was 6.5 months (95% CI, 5.5-10.1). Of the patients who achieved a CR or CRh, 21% (7) had no residual detectable IDH1 mutations, investigators reported.

The most common adverse event (AEs) of any grade were diarrhea (33.5%), leukocytosis (31.3%), nausea (31.3%), febrile neutropenia (29.1%), and fatigue (28.5%).

The AE profile was not unexpected in this population, Pollyea said, but there were a few toxicities that warrant further discussion.

“For a drug that has a mechanism of action that is very novel, and involves induction of differentiation, you could expect that the side effect profile might be different or unusual,” said Pollyea. “We did find that to be the case in the context of this study.”

Grade ≥3 leukocytosis was reported in 14 patients (8%), and was managed with hydroxyurea in all cases. Eighteen patients (10%) had ≥3 ECG QT prolongation, with no fatalities. Additionally, 19 patients (10.6%) had IDH differentiation syndrome (IDH-DS) of any grade. Grade ≥3 IDH-DS was observed in 9 patients (5%). IDH-DS was managed with corticosteroids and diuretics, and no instances lead to a dose reduction, permanent treatment discontinuation, or death.

“The majority of these patients did end up having a response, so the message is that supportive care and continued treatment can allow for patients who are experiencing differentiation syndrome to ultimately respond,” said Pollyea.

IDH1 mutations occur in 6% to 10% of patients with AML, and mutations in IDH1 and IDH2 are often present in patients with relapsed/refractory AML. In August 2017, the FDA approved the IDH2 inhibitor enasidenib (Idhifa) as a treatment for patients with relapsed or refractory IDH2-mutated AML based on findings from a phase I/II study.

There are several other studies investigating the use of ivosidenib in patients with AML and other advanced hematologic malignancies.

“This single-agent oral therapy was able to completely eradicate evidence of the IDH1 clone in 23% of patients who had achieved a CR, and that did correlate with better clinical outcomes,” concluded Pollyea.


  1. Pollyea DA, Dinardo CD, de Botton S, at al. Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/refractory acute myeloid leukemia (R/R AML): Results of a phase 1 study. J Clin Oncol.2018;36(suppl_abstr 7000).
  2. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. [published online June 2, 2018] N Engl J Med. doi: 10.1056/NEJMoa1716984.
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