Emerging Data With KO-539 and Other Menin Inhibitors Generate Excitement in AML

Naval Daver, MD

Investigational menin inhibitors like KO-539 have showcased early promise in KMT2A-rearranged and NPM1-mutated acute myeloid leukemia (AML), according to Naval Daver, MD, who added that next steps with these agents will be to develop effective management strategies for associated toxicities, to evaluate their use in novel combinations, and to get them approved by regulatory authorities to provide patients with more treatment options.

“At the 2021 ASH Annual Meeting, [data on] preclinical combinations of [KO-539] and various other standard-of-care agents in AML [were reported],” Daver said. “As we have seen over the past 10 or 15 years with FLT3 inhibitors, and in the past 5 to 7 years with IDH inhibitors, although they work well on their own, you can almost double response rates if you combine them with the right agents, whether [that is with] venetoclax [Venclexta], azacitidine [Onureg], or chemotherapy.”

Preclinical data showed that co-treatment with the menin inhibitor and venetoclax, a BET inhibitor, or a CDK6 inhibitor was found to be synergistically lethal against AML cells that harbored KMT2A rearrangements or NPM1 mutations. Compared with single-agent treatment with KO-539, venetoclax, or the vehicle control, the combination of KO-539 and venetoclax exerted superior in vivo anti-AML efficacy without any host toxicity in a PDX model of KMT2A-rearranged disease.

In an interview with OncLive^®, Daver, associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the encouraging early data that has been reported with KO-539 and other menin inhibitors in AML, data presented with novel KO-539 combinations in this disease, and next steps for research.

OncLive^®: Could you speak to the promise of menin inhibitors in AML?

Daver: Menin inhibitors are exciting to us. Among the targeted therapies, we have had multiple FLT3 inhibitors, and many [have been] approved. [With] emerging data, hopefully more [of these agents] will be approved. IDH inhibitors have also been a great addition to the treatment [arsenal for] patients with AML. Now, the next, third group of targeted therapies that is emerging and look to be exciting, [although] in early stages, is menin inhibitors, which can target NPM1 mutations and KMT2A rearrangements.

What are some of the menin inhibitors that have been developed for use in this disease?

We are moving into personalized therapy. Targeted therapies in AML have been talked about for 2 decades, but we now have drugs that are bearing out those successes [we dreamed of]. KO-539 is 1 of the menin inhibitors from Kura Oncology. Five of these agents are now in clinical development.

Clinical data with 1 of the menin inhibitors, SNDX-50469, showed encouraging response rates of about 40% to 45% in the relapsed/refractory [setting]. The drug from Kura Oncology, [KO-539], also appears to be a potent menin inhibitor; clinical data presented last year also showed encouraging response rates [with this agent].

What were the preclinical data reported with KO-539 during the 2021 ASH Annual Meeting?

It was shown that combining [KO-539] with drugs like venetoclax, a hypomethylating agent, or intensive chemotherapy, [was] very synergistic and could improve response rates. More importantly, [the combination] may abrogate 1 of the adverse effects that we see with menin inhibitors, namely differentiation syndrome.

When we give these drugs, they remove the differentiation blockade, so you get a rapid differentiation of the leukemic immature blast normal neutrophils, which is good, but if it happens too quickly and too much, then you could have a huge neutrophil infiltration that could affect the lungs or kidney.

If we combine [menin inhibitors] with other drugs that are cytotoxic, that suppress the emergence of such differentiation, we may [be able to] make the drug safer. We are excited to move this [approach] into the clinic; [we want to combine] these agents with venetoclax, intensive chemotherapy, and other targeted approaches. Some of those trials are already starting to enroll [patients to receive treatment with] the different menin inhibitors.

What are the next steps for research with menin inhibitors like KO-539?

With menin inhibitors, the next steps [include] 3 important [aspects]. One is to optimize the management of differentiation syndrome because we are seeing this [toxicity] and it seems to be more frequent and more potent than what has been seen with IDH [inhibitors and others; with those agents,] this effect is still manageable. [It is important to] get that expertise, so that [patients] do not have any bad outcomes with severe differentiation.

The second thing we would like to do is move [menin inhibitors] into combination [regimens] early [on] so that we do not spend many years with single agents. We know that almost all targeted therapies in all leukemias have [shown] much better [efficacy] when [they are] combined with the right drugs. Preclinical data are going to help.

The third important thing is to hopefully get multiple [menin inhibitors] approved, because each of them [comes with] some [pros] and some cons. Some [of these agents] come with gastrointestinal toxicity, some have cardiac toxicity, and some have more powerful differentiation. [If several options were available, we] could select the best one for a given patient [based on their associated toxicities]. We're hoping many of these [agents] could get approved in the next few years, and then be utilized in optimal combinations.

Reference

1. Davis JA, Fiskus WC, Daver N, et al. Clinical-stage menin inhibitor KO-539 is synergistically active with multiple classes of targeted agents in KMT2A-r and NPM1-mutant AML models. Blood. 2021;138(suppl 1):3357. doi:10.1182/blood-2021-149831