Early IDH1 Inhibitor Data Promising in AML

The IDH1 inhibitor AG-120 has shown a favorable safety and efficacy profile in patients with IDH1 mutation positive advanced hematologic malignancies, including acute myeloid leukemia (AML), according to early data from a phase I dose-escalation study.

The data, which was presented at the 2014 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, showed investigator assessed objective responses in seven out of 14 evaluable patients (50%), including four complete remissions, with responses observed across the four dose levels tested. Early evidence of durability was demonstrated, with one patient remaining stable on study.

"We are highly encouraged to see the early favorable safety profile and clinical activity of AG-120, which includes four patients who achieved complete remission," Daniel Pollyea, MD, clinical investigator at the University of Colorado School of Medicine, said in a statement. "For the first time in decades, we have the potential to offer certain AML patients an improved targeted treatment for this fatal disease that has historically had limited treatment options. I am hopeful that in the future we clinicians will be able to offer well tolerated and highly effective targeted therapies for our patients who have AML harboring an IDH mutation."

As of October 17, 2014, the ongoing phase I trial of AG-120 had enrolled 17 patients with a documented IDH1 mutation whose cancer relapsed or failed to respond to at least one prior treatment regimen. At the time of the data cut, 14 patients with relapsed and/or refractory AML were evaluable; three patients recently initiated therapy and were not evaluable.

An analysis conducted at the data cutoff showed the majority of adverse events (AEs) reported by investigators to be grade 1 and 2 and most commonly included nausea, fatigue and dyspnea.

Serious AEs were reported in 8 patients and were primarily related to disease progression. There were 6 patient deaths, but all were unrelated to study drug. Five deaths occurred after discontinuation of AG-120 due to progressive disease and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

One patient had a dose limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction subject to treatment protocol. This patient is in complete remission and remains on AG-120. Dose escalation continues in a once-daily regimen. The maximum tolerated dose has not been achieved.

"These data show very promising evidence of clinical activity for AG-120 in AML patients with an IDH1 mutation," Chris Bowden, MD, chief medical officer of Agios Pharmaceuticals, the company developing the agent, said in a statement "Together with the data we reported from our ongoing phase I study of AG-221 in advanced hematologic cancers, our lead investigational medicine and an IDH2-mutant inhibitor, we believe IDH inhibitors could potentially change the treatment paradigm for AML patients with these mutations. We look forward to moving rapidly into multiple expansion cohorts in the first half of 2015 to further characterize the potential of AG-120."

In April, data were announced at the 2014 AACR Annual Meeting that showed that AG-221 demonstrated responses in six out of seven AML patients (86%). AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein and is also being evaluated for patients with AML who have an IDH2 mutation.

Safety data as of April 25, 2014, showed that AG-221 is well tolerated in patients with relapse or refractory AML, with the majority of adverse events being mild to moderate. No dose-limiting toxicities were reported.

“These patients have no good treatment options. We give them chemotherapy but it is not very effective and has substantial toxicity. AG-221 represents the opportunity to treat them in a way that doesn’t compromise their immune system. These responses are kind of unheard of in AML,” lead author Eytan M. Stein, MD, Memorial Sloan Kettering Cancer Center, said during the 2014 AACR Annual Meeting.

Both AG-221 and AG-120 are also being studied in patients with solid tumors, including glioma, for patients with IDH2 and IDH1 mutations, respectfully.

Agios said it expects to present data from the AG-120 phase I advanced solid tumor trial at a medical conference in 2015.