Syndax switches first-line plans

Menin inhibitor players are racing to get into the front line of treatment, but the sector’s leader, Syndax, is changing its plans in one genetic subtype of acute myeloid leukaemia: patients with KMT2A rearrangements.

An investigator-sponsored phase 3 trial, Evolve-2, is already under way in unfit patients, testing Revuforj plus Venclexta and azacitidine in patients with both KMT2Ar and NPM1 mutations. In fit patients the original plan had been for two Syndax-sponsored pivotal trials combining Revuforj with intensive 7+3 chemo: one in NPM1m, and one in KMT2Ar.

The former, Reveal ND NMP1m, started in November. But Reveal ND KMT2Ar, yet to be listed on clinicaltrials.gov, has now been shelved. The focus now in fit KMT2Ar patients will be a ven/aza combo, which will be tested in an upcoming investigator-sponsored phase 2 study called Raven.

Syndax’s chief medical officer, Nick Botwood, told ApexOnco that the group had “adapted” its plans because of “evolving data”. He highlighted the investigator-led phase 2 Paradigm study, presented at ASH this year, which showed that ven/aza could be more effective than intensive chemo, as well as less toxic, in front-line fit patients. 

Paradigm didn’t focus on KMT2Ar patients, but generally the results suggest that the ven/aza backbone might “supplant intensive chemo in certain fit populations, such as those with adverse risk”, Botwood said.

Syndax’s new strategy also reflects different outcomes in patients with NPM1m versus KMT2Ar, he added. “While intensive chemotherapy has curative potential for some patients with NPM1m, the vast majority of patients with KMT2Ar will relapse after standard front-line therapies.” 

KMT2Ar only accounts for around 10% of AML, compared with 30% for NPM1m. 

Quoth the Raven

Raven hasn’t yet appeared on clinicaltrials.gov; Syndax is “working through the design, and some of the statistical considerations”, and the study, which will be run by Dr Josh Zeidner of the University of North Carolina, should start in early 2026.

The overall aim is speed, Botwood said. “We want to deliver [Raven] quickly, because that could inform clinical practice and guidelines ahead of randomised phase 3 trials reading out. We want to be first.” 

Botwood added that, at “a minimum”, the results could lead to inclusion in National Comprehensive Cancer Network (NCCN) guidelines, but that they could also support regulatory filings “given the high unmet need in this patient population”. 

The latest move marks a departure for Syndax from its menin inhibitor rivals. In the front line Kura is testing its drug Komzifti in the pivotal Komet-017 trial, which is split into intensive chemo-eligible and non-eligible portions. 

The intensive portion will enrol both NPM1m and KMT2Ar patients, and combine Komzifti with chemo. The non-intensive part will only enrol patients with NPM1m, who tend to be less fit than those with KMT2Ar disease, and give them a ven/aza combo. 

Meanwhile, Johnson & Johnson’s bleximenib is in the company-sponsored Camelot-2 study, in intensive chemo-ineligible disease (ven/aza combo), and the upcoming investigator-sponsored Hovon-181 AML study, in intensive chemo-eligible patients (chemo combo). Both studies are enrolling patients with both genetic subtypes.

Syndax still has efforts ongoing with Revuforj plus intensive chemo in fit KMT2Ar patients, with Botwood highlighting a phase 1 trial being run by the US NCI. Further into the future, he also flagged the potential to evaluate Revuforj in myeloproliferative neoplasms, based on preclinical data presented at ASH. 

Notable trials of menin inhibitors in first-line AML

Notes: *investigator-sponsored trial; **ph2 trial; others are ph3. Source: OncologyPipeline & clinicaltrials.gov.