What Needs to Happen Before Menin Inhibitors Move Into Frontline AML Combinations?

In an interview with CancerNetwork® at the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting, Eunice Wang, MD, chief of leukemia service at Roswell Park Comprehensive Cancer Center, discussed the regulatory path forward for menin inhibitors revumenib (Revuforj) and ziftomenib (Komzifti) in frontline acute myeloid leukemia (AML). Both agents, already approved in the relapsed/refractory setting for KMT2A-rearranged and NPM1-mutated disease, respectively, are being evaluated in registrational phase 3 trials in combination with venetoclax (Venclexta) plus azacitidine (Vidaza) or standard 7+3 induction for patients with newly diagnosed disease.

Wang explained that while overall survival (OS) remains the primary end point in most of these trials, the favorable long-term prognosis of many patients with NPM1-mutated disease complicates timely survival readouts, prompting interest in measurable residual disease (MRD)–negative complete remission as a faster surrogate end point. She also anticipated that additional approvals in combination regimens for relapsed/refractory disease may arrive before frontline indications are granted.

Transcript:

CancerNetwork: Both revumenib and ziftomenib are currently approved in the relapsed/refractory setting. What needs to happen in terms of data or regulatory review before either one moves into a frontline combination?

Wang: Both drugs are in registrational phase 3 studies combining them with venetoclax and azacitidine, or with conventional 7+3 induction, for treatment of newly diagnosed patients with KMT2A[-rearranged] and NPM1[-mutated] disease. The end points of those studies largely include [OS]; in one of the trials, investigators are looking at an earlier end point, achievement of a complete remission without evidence of measurable residual disease.

The problem holding back those trials is that patients with NPM1-mutant disease, in the upfront setting, typically do very well with therapy, with 50% of them achieving long-term survival. The barrier is determining which of those patients will do worse and might progress sooner, and how long we have to wait for [OS] data before we can act on it. If a disease has a very poor prognosis and most patients have died within a year, it is, ironically, easier to get FDA approval of a drug, because within a year or two of enrolling the trial, you can see whether there is any improvement with adding the agent. If 50% of patients are going to be cured, you may need to wait years to see that [OS] benefit or to show equivalence. Using measurable residual disease end points might be a faster way to get approval, and one of the trials is using that approach.

In the interim, combinations of the drugs in the relapsed/refractory setting may move forward more quickly, because patients with refractory disease progress more rapidly. Revumenib and ziftomenib each induce about a 20% to 23% complete remission rate with partial hematologic recovery [CR/CRh], with a [6- to 8-month; verify] overall survival. Adding conventional agents—for example, venetoclax and azacitidine—to that single-agent menin inhibitor therapy has improved response rates to the 40% to 60% range. We may see approval of combination therapy in the relapsed/refractory setting as the next step in the approval process for these drugs, before approval in the newly diagnosed setting. That is what I anticipate.