DSP-5336 is Well-Tolerated in R/R MLLr and NMP1-Mutant Acute Leukemia

Naval G. Daver, MD

Personalizing therapy for patients with acute myeloid leukemia (AML) by identifying targetable aberrations is of the utmost importance, according to Naval G. Daver, MD. Menin inhibitors, including DSP-5336, seem particularly effective in mixed lineage leukemia rearranged (MLLr) and NPM1-mutated disease, potentially impacting 25% to 30% of the relapse population.

DSP-5336 is a Menin inhibitor being developed for patients with AML, particularly in those with MLLr or NPN1-mutated relapsed disease. An ongoing phase 1/2 study (NCT04988555) aims to establish safety, efficacy, pharmacokinetic, and pharmacodynamic data of the agent among patients with relapsed/refractory AML.

The study has already shown promising activity, with a focus on safety. Findings have shown a lack of differentiation syndrome and no cardiac effects observed with DSP-5336. The safety profile of DSP-5336 appears favorable, with no dose-limiting toxicities observed in the 45 treated patients.

Six responders, including complete response (CR), CR with incomplete hematologic recovery (CRi), or CR with partial recovery of peripheral blood counts (CRh), were reported. Notably, at the highest dose level of 200 mg twice daily, 3 out of 4 evaluable patients achieved a CR/CRi, showing promise for further activity.

Looking ahead, Menin inhibitors could become standard-of-care. Daver, associate professor in the Department of Leukemia at MD Anderson Cancer Center, advised community oncologists to consider Menin inhibitor studies for patients with AML with specific genetic aberrations, emphasizing the potential for improved outcomes and quality-of-life.

In an interview with Targeted Oncology^TM, Daver discussed the first-in-human, phase 1/2 study of DSP-5336 in patients with relapsed or refractory AML.

Acute myeloid leukemia (AML) cells in blood flow - isometric view 3d illustration: © LASZLO - stock.adobe.com

Targeted Oncology: Please provide an overview on the phase 1/2 study of DSP-5336 in R/R acute leukemia.

Daver: DSP-5336 is a Menin inhibitor. This is an important group of drugs that we are developing in acute myeloid leukemia, especially patients with MLL-rearranged or NPN1-mutated, relapsed disease. There are now 5 different Menin inhibitors that are in clinical development. The ones most ahead are from Syndax and Kura [Oncology]. These studies started almost 3 years ago, and these are showing good activity, about 30% to 35% CR/CRi/CRh rate in relapsed/refractory MLL-rearranged or NPM1-mutated AML.

There are newer ones, [including] DSP-5336 [which] appears to be quite well tolerated. This is 1 of the key distinguishing features with this Menin inhibitor. The [adverse] effects we have seen with the other Menin inhibitors are differentiation syndrome. It's important to note that the mechanism of action of all of these drugs is by releasing differentiation and allowing normal differentiation of abnormal blast premature cells to normal neutrophils monocytes. But in some cases, that differentiation can happen too rapidly and aggressively, leading to clinical negative manifestations, such as shortness of breath, fever, liver enzyme abnormalities, kidney enzyme abnormalities. We luckily have not seen significant clinical differentiation syndrome effects [with this agent], and that includes in patients who have achieved clinical response.

The other [adverse] effect that we are always cautious of is a cardiac or QT prolongation. This is something that has been seen in a number of drugs that have been developed in the AML field. The 3 inhibitors some of the IDH inhibitors, and also it's seen with the Syndax drug, although the rates are not very high and clinically, it is manageable. It is something that we watch out for because we have not seen that with the DSP-5336. No cardiac effects, no QTc prolongation.

Can you discuss the safety observed with this agent?

Safety wise, this agent looks good. We have treated close to 45 patients now in a dose-escalation phase 1B study with no dose-limiting toxicities, and we continue to escalate. The maximum tolerated dose or the recommended phase 2 dose have not yet been selected. At the recent dose levels, we've started seeing responses. In total, we've had 6 responders, including CR, CRi, or CRh. In the study, these were all in patients who had target aberrations, which are expected to be sensitive to Menin, such as the MLL rearrangement or the NPM1. Most exciting is that at the recent highest dose level cohort of 200 milligram [twice daily], we had 3 out of 4 evaluable patients who have achieved a CR/CRi. This is looking to be entering the dose where we hopefully will continue to see more activity.

In the context of unique challenges posed by relapsed/refractory acute leukemia, how does this potential mechanism of action offer promise vs other therapies?

In general in the AML field, I think for most AMLs, the direction of movement is towards personalizing therapy by identifying targetable aberrations and finding drugs that can work effectively in that setting specifically rather than mutation or target agnostic broad treatments. In AML, we have had success with this with FLT3 inhibitors targeting FLT3 mutations, IDH inhibitors targeting IDH1 and IDH2 mutations, [and more], so I think the Menin inhibitors are similar where they seem to work well in those with MLL-rearranged and NPM1-mutated [disease].

The reason these patients are sensitive is that they have upregulation of enzymes which lead to the blockage of differentiation and by blocking this pathway, they start having a normal differentiation process. This seems to be much more sensitive and doable in those who have this MLL rearrangement with NPM1. [There are] other subsets and fusions which are not as common but may also be sensitive to this. We are starting to find [them and they are] small, rare, 1% to 2%, but many of them which could also be potentially benefited by the Menin inhibitor. At the end of the day in relapsed AML, this could have an impact in somewhere between 25% to 30% of the relapse population, which is quite a big chunk.

Please explain the methods and design of the study.

For the primary design of the DSP-5336 study, this is a dose-escalation phase 1/1b study. As a first-in-human trial, the first thing is to identify safety, as well as potentially any toxicity, as well as doing a robust [pharmacokinetic and pharmacodynamic] analysis. We have a total of 6 to 8 dose-escalations planned with the cautious approach and looking closely for dose-limiting toxicities before going to the next dose level. We do have the ability to backfill additional patients on to the dose levels that have already been proven safe so that any patient who is referred to the study does have an opportunity to get enrolled, whether it is on the active cohort or on the prior safe cohort.

The primary objectives are mainly safety, but of course, also preliminary data on efficacy as well as pharmacokinetic and pharmacodynamics. We're also putting a lot of time and effort early on in phase 1 on azole interactions, which is something that has always been an issue with AML drugs and something that was an afterthought. From the beginning of the study, we have a separate arm for patients so that by the end of the phase 1, we will know if there's an impact of azole and if there is, what is the optimal dose adjustment for that.

How do you think these results might impact the future landscape?

The field of Menin inhibitors is close to becoming something that is going to be a standard-of-care, hopefully even by next year if things go well. We may see some of these enter the commercial [United States] market. These will be initially a single-agent in relapse where even though the response rates are heartening in the 35% to 40% range and better than what you would get with any standard-of-care in a third-, fourth-line relapse MLL where historically our group published the expected response rate would be 10% to 15%, even in relapsed/refractory NPM1 for salvage would probably be 15% to 20%, they are definitely higher and it is over well tolerated, but the survival is still only 7 to 8 months. As a single agent and salvage, that may be a good approach for the initial approval, but I do think that the eventual use of these drugs as is happening with the FLT3 and IDH inhibitors will be the frontline setting in combinations where we can use these drugs to enhance the depth of response, the depth of remission, and eventually, the overall survival and cure rate. That goes for studies combining the Menin inhibitors with the [hypomethylating agents and] venetoclax [Venclexta], with intensive chemotherapy with FLT3 inhibitors, which are ongoing.

Though the study is ongoing, do you have any advice for community oncologists?

If they have a patient with AML with the MLL rearrangement, also called a KMT2A rearrangement, or an NPM1 mutation who have relapsed after any frontline standard therapy, early on in that first salvage, ideally, I would consider going to ClinicalTrials.gov, or calling their local leukemia expert, whoever they work with. They can even always reach out to us either way. But these Menin inhibitor studies that are now open in more than 50 centers in the United States, so there's a good chance that they are going to be open [near you] and would be a wonderful opportunity.

We are seeing young patients now who are 3 years out who were told they were going to go to hospice with no opportunity for survival who have gone on Menin inhibitors and are post-transplant or even without transplant and alive with good quality-of-life. There is always a lag between seeing the signals, which around 2 and a half years ago, there was a lot of excitement and signals, to commercial use and expansion of the drug. There are many patients in that window who I think could benefit by identification of the appropriate target and getting them to the clinical trial centers so they do not lose the opportunity before the drug is approved. I would definitely look for those aberrations and refer those patients.

REFERENCE

Daver N, Zeidner JF, Yuda J, et al. Phase 1/2 first-in-human study of the menin-MLL inhibitor DSP-5336 in patients with relapsed or refractory acute leukemia. Blood. 2023;142(suppl 1): 2911. doi:10.1182/blood-2023-179252