EHA 2024 – Syndax sets up another menin inhibitor battle

Syndax is ahead in the race for approval of a menin inhibitor monotherapy, and on Friday at the EHA meeting the group made its case for combinations. Here, Syndax intends to start a pivotal combo trial in first-line AML by the end of the year, giving it an edge over its rival Kura, which is yet to disclose pivotal combo plans for its contender, ziftomenib.

At EHA efficacy data on Syndax’s revumenib looked similar to those released earlier this year on Kura’s ziftomenib, although with different combos used it’s tricky to directly compare the studies. However, adverse events with revumenib once again raised eyebrows, with cases of differentiation syndrome and QTc prolongation seen.

Differentation

Two trials testing revumenib combos were presented at EHA: Beat AML, an investigator-sponsored "master trial", one of whose cohorts tests revumenib plus Venclexta and azacitidine in first-line NPM1 mutated or KMT2A rearranged AML; and Syndax's Augment-102, evaluating revumenib plus fludarabine/cytarabine chemo in relapsed/refractory acute leukaemia patients with NPM1 mutations, or KMT2A or NUP98 rearrangements.

In terms of the combos' composition, Syndax’s approach differs from that of Kura, which has so far tested ziftomenib with chemo in first-line AML, and with Venclexta and azacitidine in relapsed disease, in its Komet-007 trial. In January, Kura released combo data from 15 patients.

Kura’s update was notable for highlighting no differentiation syndrome events of any grade, and no evidence of QTc prolongation. Both side effects have previously been seen with menin inhibitors. Kura, which abandoned ziftomenib monotherapy in KMT2Ar patients, has previously said combos could reduce the incidence of differentiation syndrome, particularly in this cohort.

However, the Beat AML trial's revumenib cohort found a 15% rate of differentiation syndrome, suggesting that this issue might not be entirely resolved with combos. There was better news in Augment-102, with no cases of differentiation syndrome, although QTc prolongation was seen.

As for efficacy, Beat AML showed a 96% composite complete remission rate among 24 evaluable patients in two dose cohorts, down slightly from 100% among 13 patients reported at last year’s ASH meeting. This composite looks at standard complete responses, as well as those with lesser complete remissions such as those with incomplete platelet recovery.

Combo data with Syndax’s revumenib

CRc=composite complete remission (includes CR, CRh, CRp & CRi). Source: EHA.

In first-line disease ziftomenib plus chemo previously produced a 100% complete response rate, but only among five patients.

Meanwhile, Augment-102 found a 52% composite complete remission rate among 27 patients. The ORR with ziftomenib plus Venclexta and azacitidine in a similar relapsed setting was 53% among 15 subjects.

Syndax and Kura are still nailing down the ideal dosing regimens for their combos, so both companies clearly still have work to do here. And Kura hopes to take ziftomenib/Venclexta/azacitidine into front-line AML; ven/aza is becoming an increasingly popular first-line therapy thanks to its lower intensity compared with chemo and its relatively favourable tolerability in older patients.

As for monotherapy, both companies are pursuing relapsed/refractory AML, with Syndax expecting an FDA decision on revumenib in KMT2Ar acute leukaemia by 26 September. In the larger NPM1m relapsed setting Syndax is due to report pivotal monotherapy data in the fourth quarter, and Kura in early 2025.

Getting into the front line will be key to expanding the market for these projects; for now, though, it is hard to call a combo winner.