Five-Year Follow-Up Data Confirm Long-Term Benefits of Olutasidenib in R/R IDH1+ AML

In an interview with OncLive®, Justin M. Watts, MD, reported and expanded on the significance of final 5-year results from the pivotal cohort of the phase 2 Study 2102-HEM-101 trial (NCT02719574), which evaluated olutasidenib (Rezlidhia) in patients with relapsed/refractory acute myeloid leukemia (AML).¹

Primary results from this trial supported the FDA approval of olutasidenib for patients with IDH1-mutant relapsed/refractory AML in December 2022.2 An additional 2 years of data beyond the results supporting the decision were presented at the 2024 ASCO Annual Meeting, and affirm the use of olutasidenib as a safe and effective therapy in this patient population. Responses with were maintained in heavily pretreated patients, proving to be durable, and no additional toxicity was observed compared with what was reported in the 3-year analysis.

The overall response rate (ORR) with this agent was 48% (n = 147), with 35% (95% CI, 27%-43%; P < .001) of patients achieving complete response (CR) or complete hematologic response (CRh), which was the trial’s primary end point. The composite CR rate was 45%. Patients who achieved an ORR or a CR/CRh experienced a median duration of response (DOR) of 15.5 months (range, 0-54.6) and 25.3 months (range, 1.8-54.6), respectively. Moreover, the median overall survival (OS) was 11.6 months (range, 0.2-57.1) in the total population (n = 153). For responders with a CR/CRh (n = 55), other responders (n = 20), and nonresponders (n = 78), the median OS was not reached (range, 6.3-57.1+), 13.7 months (range, 2.6-36.3), and 3.9 months (range, 0.2-32.6), respectively.

“These 5-year follow-up [data] further support [olutasidenib] as probably the best-in-class IDH1 inhibitor that we have,” said Watts, who is an associate professor of medicine in the Division of Hematology and chief of the Leukemia Section at the University of Miami Sylvester Comprehensive Cancer Center in Miami, Florida. “For a single agent to [produce these responses] in a relapsed/refractory setting, and in a disease that has multiple mutations that can drive resistance, is incredible.”

Watts also expanded on the implications of the follow-up data for responders, including considerations about the potential for a functional cure; discussed the need for more research on targeted strategies for nonresponses; and emphasized how prolonged survival outcomes with olutasidenib solidify its role as a preferred treatment option for patients with IDH1-mutant AML.

OncLive: Please provide some background on Study 2102-HEM-101. What findings have been previously reported?

Watts: This is a pivotal phase 2 trial, [which enrolled approximately] 150 patients. [Previous data on response rates and DOR] led to olutasidenib’s FDA approval. [The data reported at this year’s ASCO Annual Meeting] is the 5-year follow-up of those 150 patients. Patients had relapsed/refractory, IDH-mutant AML and [had progressed on] standard therapy, often multiple lines. The median was 2 prior lines of [therapy, including] chemotherapy, hypomethylating agents [HMAs], venetoclax [Venclexta], or prior transplant. They [received] single-agent olutasidenib as 1 pill, 150 mg twice a day, every day.

It’s very well tolerated. The response rates that were previously reported were a CR/CRh rate of 35% and an ORR of 48% in this high-risk patient population. So, almost half of patients responded. What’s more impressive than the [response rate itself] is the DOR in responders—especially among the patients [who achieved a CR/CRh. [For those with] that response, the median DOR was over 2 years, which is unheard of in relapsed/refractory AML with a single-agent targeted therapy. That held [up] with these 5-year follow-up data.

What updated efficacy findings were presented at the meeting, and why are these data so significant?

What’s so impressive about these new data is the longer look at OS. The median OS for all patients was [11.6] months. The reason it’s not higher is because [patients who] don’t respond—and half of patients didn’t respond— [have a] median of [3.9] months. Therefore, half the patients are going to do very poorly, and that drags the whole thing down. [However], patients who [demonstrated] any response, [which was approximately] 48% of patients, [had a] median OS of almost 3 years. If you look at just the patients [who achieved] a CR/CRh, it was not even reached, and the tail of the curve is sitting right above 50%.

That means that half of patients are still alive at up to 5 years out if they responded. That gives you a lot of confidence when you see a patient [with an IDH1 mutation]. You know that patient is probably going to respond, and you know that if they do respond, they’re going to be in remission for a long time. IDH1 mutations are one of the dominant drivers for the disease, and there’s not a lot of other bad mutations you don’t want to see, like FLT3 or RAS.

What are the implications of these 5-year follow-up data for responders? Are there any unanswered questions regarding the agent’s benefit in responders vs nonresponders that still need to be addressed?

If someone is 5 years out [from treatment] and there’s a tick mark, are they cured? Are they functionally cured? [We don’t] know, so we keep them on the drug. What remains to be seen is [how to proceed in] the other half of patients who don’t respond at all. Some of them may experience brief benefit [by achieving] transfusion independence or stable disease, but the median OS is [3.9] months, so what do we do with those patients? Those patients have a tougher disease, they’re not going to respond, and we’re trying to figure out who they are [on a molecular level].

They’re going to get combinations with venetoclax and a HMA in the relapsed/refractory setting, but [we’re also looking at] moving that to the frontline setting in IDH1-mutant AML. [Olutasidenib could be administered] as a triplet therapy with all 3, or sequenced in older patients, or even in younger [patients]. We need to think about this for all patients regardless of age, unless they have a core-binding factor fusion or an MLL rearrangement. If it’s a clonal hematopoiesis–driven, IDH-mutated leukemia, maybe we shouldn’t be giving them chemotherapy at all, even if they’re younger, as [these patients] tend to be resistant.

How do these data solidify the role of olutasidenib in the relapsed/refractory AML treatment paradigm?

This is an important poster on these 5-year follow-up data because of how impressive the data are. [Olutasidenib is] a bit under the radar still, because it’s the second IDH1 inhibitor. IDH1 [mutations] are not uncommon, but they are only [present in approximately] 10% of patients with AML. However, if [a patient] has IDH1-mutated AML, they will want to know about this drug.

When you compare [olutasidenib] with any other targeted therapy in relapsed/refractory AML, whether it is an IDH2, IDH1, or FLT3 [inhibitor], and [factor in] what we [currently] know about menin [inhibitors], none of them [have prolonged] the DOR and survival in responders [to this extent]. Response rates might become similar, but it’s the DOR that is so striking, and we’ve seen patients on this drug for a long time.

Dr Watts reports the following disclosures: serving in a consulting or advisory role for Aptose Biosciences, Astellas Pharma, Celgene/Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Rafael Pharmaceuticals, Reven Pharmaceuticals, Rigel, SERVIER, and Takeda; receiving research funding from Immune System Key and Takeda.

References

1. Cortes J, Jonas BA, Watts JM, et al. Olutasidenib for mutated IDH1 acute myeloid leukemia: Final five-year results from the phase 2 pivotal cohort. J Clin Oncol. 2024, 42(suppl 16):6528.doi:10.1200/JCO.2024.42.16_suppl.6528
2. FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. News release. FDA. December 1, 2022. Accessed July 19, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation