ASH 2024 – J&J mounts its first-line menin challenge

Earlier this year Kura impressed with its menin inhibitor ziftomenib in first-line AML, in combination with chemotherapy, and data presented on Saturday at ASH reinforced this result in more patients.

Meanwhile, Johnson & Johnson is also targeting newly diagnosed patients with its contender, bleximenib. That company’s first-line dataset, presented in the same session at ASH, looked impressive – although perhaps not quite as impressive as ziftomenib’s.

Still, the usual caution about cross-trial comparisons applies, and both projects look to have dialled down or eliminated the risk of QTc prolongation and differentiation syndrome. These side effects are seen with menin inhibitor monotherapy in relapsed/refractory leukaemia.

Cross-trial comparison of menin inhibitors in first-line AML at ASH 2024

Notes: *all CRs; **gr3, managed & patient remained on treatment; ziftomenib efficacy data at 200-600mg once daily; bleximenib efficacy data at ≥50mg twice daily. Source: ASH 2024.

While no cases of differentiation syndrome were seen in Kura’s February update, there was one in the latest cut of the Komet-007 trial; however, the lead investigator, Dr Amer Zeidan of Yale University, noted that, although this was a grade 3 it was successfully managed, and the patient remained on therapy.

Ziftomenib’s previous datacut involved just five front-line patients, and showed efficacy of 100% in both genetic subtypes of KMT2A-rearranged and NPM1-mutated disease. This has waned slightly in the KMT2Ar cohort, but that’s to be expected as more patients have been treated – and it’s notable that all responses were complete (rather than complete remission with partial haematological recovery).

Both groups already have phase 3 front-line trials in the works: Zeidan mentioned in his ASH presentation that Kura planned to start the Komet-17 study in mid-2025. It will enrol both fit and unfit patients with first-line AML and KMT2Ar or NPM1m. Fit patients will receive ziftomenib plus chemo, while the unfit cohort will get the menin inhibitor plus Venclexta and azacitidine.

Meanwhile, J&J told ApexOnco that it was planning a phase 3 trial, called Camelot-3, of bleximenib plus Venclexta/azacitidine in newly diagnosed, chemo-ineligible (unfit) patients.

The menin leader, Syndax, is also looking at its drug Revoforj in first-line disease, and has so far reported data with a Venclexta/azacitidine combo, from the investigator-sponsored Beat-AML trial.

On the data available so far it seems that front-line disease could develop into another menin inhibitor battleground.