Olutasidenib Shows Durable and Manageable Responses in AML

Recent data from the phase 1/2 Study 2102-HEM-101 (NCT02719574) supported the approval of olutasidenib (Rezlidhia) for patients with relapsed/refractory acute myeloid leukemia (AML) that harbor an IDH1 mutation.¹ In a discussion with Targeted OncologyTM, Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, broke down the Study 2102-HEM-101 data.

Cortes initially presented these data at the 2022 American Society of Hematology (ASH) meeting where he discussed the exciting implications of the durable response data with a manageable toxicity profile. Looking at 153 patients with relapsed/refractory AML, the phase 1 study eventually went to a phase 2 cohort of the open-label, multicenter trial, that decided on a dose of 150 mg twice daily in a continuous 28-day cycle.² Moreover, at the time of data cutoff, 21 patients (14%) of the evaluable patients was still receiving treatment.

Jorge Cortes, MD

Director

Georgia Cancer Center

Augusta University

Augusta, GA

In this discussion, Cortes highlights the manageable any grade adverse events (AEs) with the drug, including differentiation syndrome (14%), leukocytosis (13%), alanine aminotransaminase increases (8%), constipation (8%), fatigue (7%), vomiting (7%), anemia (6%). Moreover, he explains the importance of the complete responses (CRs) seen in this phase 1 study.

Please provide some background on olutasidenib and the patient population of the 2102-HEM-101 study.

This drug, it's an oral agent, it's an IDH1 inhibitor, and it was administered orally to patients on a twice daily schedule. This is based on the phase 1 study that...showed the recommended phase 2 dose. In this study, we included patients that had received prior therapy, everybody had received induction chemotherapy, and many of them had received venetoclax. This is a relatively older patient population, the median age is over 70 years old, and about a third of the patients were refractory to prior therapy. Of those who had relapsed, the great majority had relapsed within 12 months, so it's really a high-risk patient population. Most of the patients had also received intermediate cytogenetics, which is typical for the IDH-mutated population.

What was the patient response to this therapy?

What we saw was a high level of response. The response rate, the complete response [CR] plus [complete remission with partial hematologic recovery [(CRPH)], was 35%. Importantly, the CRs were 32%, so the great majority of the CRPH responses were true CRs. The other thing that is exciting about this study, is the fact that these remissions are durable. The remission duration was 28 months, which was more than 2 years of remission duration. We have some remissions that are still ongoing [at the time of cutoff] and are long term now. It is exciting to see that high level of response with durable responses, and that of course reflected in good overall survival and progression-free survival results.

What is the safety profile of this drug?

The drug has been very safe, not much in terms of toxicity. Some elements that are important to highlight [included] differentiation syndrome, as we do see that's a mechanism of action related safety profile. But in general, with close monitoring, the great majority of these [adverse events (AEs)], and these were less than 15% of patients who had these, and most of them were managed with treatment interruptions or corticosteroids, or hydroxyurea. We don't seek VTC-prolongation to any significant extent with these drugs, so it doesn't have that problem. There is some liver toxicity in 20% of the patients, but the great majority of these can be managed, again, with treatment interruptions or dose adjustments. [Moreover], there was only a handful of patients that had to discontinue because of liver toxicity.

What are the implications of these findings?

This study is important, and these findings are important because although we do have 1 IDH1 inhibitor approved, which is valuable and useful, it's certainly always good to have alternatives for patients. Some of the things that appear valuable for these drugs is the high rate of CRs, the long remission duration and a safety profile that is different. We don't have VTC-prolongation, which is part of what we have with the olutasidenib, so it gives us different options for these patients. In addition, olutasidenib is being studied in an extensive research strategy that includes single agent and combination arms as maintenance [therapy]. So, there's a whole spectrum of new roles that could be explored that could open new possibilities for patients as these data comes out.

What has been the most impactful research in the AML space?

I think that starting to learn how to incorporate the new drugs into combination therapy [is important], because we know the single agent drugs [since] we develop the drugs that way, but that's in most instances not how we're going to use these drugs. So, starting to learn and incorporate these new drugs into these combinations, to me that's remarkable, because that is the future and [we are] starting to bring them up to frontline rather than using them only for salvage [therapy]. There's a number of these approaches that are being developed, and that's a lot of what we're seeing at conferences like ASH [in recent years]. I cannot single out one of these combinations because they all have different roles depending on the mutation profile of their patient or their safety profile, their comorbidities, their fitness, but [now that we're looking at them] is critical.

^Reference:

^{1. FDA D.I.S.C.O. Burst Edition: FDA approval of Rezlidhia (olutasidenib) for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. FDA. January 1, 2023. Accessed June 20, 2023. https://tinyurl.com/yw7nfr9n}

^{2. Cortes J, Fenaux P, Yee, K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed/refractory mIDH1 acute myeloid leukemia. Results from a planned interim analysis of a phase 2 pivotal clinical trial. Blood. 2022;140(suppl 1):6193-6196. doi:10.1182/blood-2022-167330}