Menin Inhibitors May Shape the Future of AML Treatment

A slew of new drugs have been approved in the past decade within the acute myeloid leukemia (AML) space and more are coming down the pipeline. Specifically, investigators believe Menin inhibitors may become the next class of targeted agents for patients with AML.

Menin is a protein which is a part of the pathogenesis of a certain subtype of AML and acute lymphoblastic leukemia (ALL) that has rearrangements in the MLL locus. The use of Menin inhibitors aims to target NMP1 mutations, KMT2A rearrangements, and KMT2Ar rearrangements.

According to Eytan M. Stein, MD, early data from clinical trials have shown Menin inhibitors to lead to promising safety and efficacy and improvements in overall response for patients with relapsed/refractory AML. Still, further research is needed to examine the impact on Menin inhibitors combined with standard of care agents.

“We need those clinical trials because number 1, we have to be sure that the combination of these Menin inhibitors with the standard of care is safe…but then you also want to see that they lead to greater effectiveness and that somehow, they're not antagonistic and theoretically end up being worse than giving either agent alone,” said Stein, hematologic oncologist and director of the Program for Drug Development in Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, in an interview with Targeted Oncology™.

Developing agents and trials will only continue to improve patient outcomes. For Stein, he believes that menin inhibitors may even be the next class of drugs approved for the treatment of a certain AML and ALL.

In the interview, Stein discussed the benefits and potential use of Menin inhibition for patients with AML.

Targeted Oncology: Can you provide some background on Menin inhibitors and their mechanism of action?

Stein: Menin is a protein that is uniquely involved in the pathogenesis of acute leukemias that harbor a rearrangement in the MLL gene locus and in patients with NPM1 mutations. When you have those diseases, the interaction of Menin with some other proteins leads to the development of that leukemia. Therefore, if you can take an inhibitor of Menin to block that protein interaction, what ends up happening is that the leukemia essentially melts away.

What I talked about during a presentation [at 10th Annual Meeting of the Society of Hematologic Oncology] was a number of current Menin inhibitors including a couple of Menin inhibitors that are in clinical development, 1 from Syndax Pharmaceuticals and 1 from Kura Oncology.

What current treatment options are available for patients with AML? How does Menin inhibition fit into this landscape?

The way we currently treat AML outside of a clinical trial is that for 1 group of patients, typically those patients who are a little bit younger, we will give those patients some intensive induction chemotherapy. Then for patients who may be a little bit older, we give them the combination of a hypomethylating agent, which is typically azacytidine, with the BCL2 inhibitor, venetoclax. Menin inhibitors now are being developed in the setting of patients who have relapsed and refractory acute myeloid leukemia. They've gotten that treatment regimen paradigm that I just described, and it either didn't work or it worked for a brief period of time, and then the patient ended up relapsing. These drugs are currently in clinical trials in the relapsed and refractory setting as single agents.

However, there's a lot of effort now. When you have a drug that looks to be effective in the relapsed and refractory setting, you don't want to wait for a patient to relapse to give them that drug. You want to move it up into earlier lines of therapy. When you move it up into earlier lines of therapy, you want to combine it with the standard of care agent. Now, some of the new clinical trials that are being done are combining Menin inhibitors, and specifically the Syndax drug, with that intensive induction chemotherapy and with the combination of azacitidine and venetoclax.

What are some benefits that Menin inhibition provides compared with other agents in space?

Menin inhibitors are unique because they act as what's called differentiation agents. Differentiation is when you've got an abnormal cell, or leukemia cell, and instead of trying to kill that cell, which is what most of our therapies do, you try to rehabilitate that cell and turn it back into a normal cell. That's a different way of thinking about treating leukemia and treating cancer. There are other examples of differentiation therapy in patients with acute myeloid leukemia, but this would be the first differentiation therapy for patients with AML or ALL that has a rearrangement of the MLL gene or an NPN1 mutation.

What can be done to further integrate these agents into future therapeutic approaches?

We need clinical trials that combine Menin inhibitors with standard of care agents. That's going to be the next generation of clinical trials that comes. We need those clinical trials because number 1, we have to be sure that the combination of these Menin inhibitors with the standard of care is safe. That's obviously the most important thing. But then you also want to see that they lead to greater effectiveness and that somehow, they're not antagonistic and theoretically, end up being worse than giving either agent alone.

What unmet needs still exist in this space?

Unfortunately, all of AML is an unmet need. Despite the fact that we've had a number of different drug approvals and patients are living longer and having a better quality of life than they did 10 years ago, most patients will still end up dying of acute myeloid leukemia. A lot of patients still are not cured. Therefore, we need to make these trials and develop therapies that improve patients' survival even longer, and that's what we're trying to do. That's what is happening with Menin inhibitors, and hopefully there are going to be other drugs coming down the pipeline.

What advice do you have for oncologists who want to learn more about the use of Menin inhibitors in AML?

The key takeaways are that Menin inhibitors are exciting. I think they are going to be the next drugs that are approved for the treatment of a certain subset of acute myeloid leukemia and perhaps acute lymphoblastic leukemia. If you have a patient with an MLL rearrangement or an NTP1 mutation that is relapsed or refractory, go to ClinicalTrials.gov, look up Menin inhibitors, and look for the closest clinical trial in New York to your location.