Kura leaves some combo questions unanswered

First the good news for Kura: initial results from a combination trial of the group’s menin inhibitor ziftomenib didn't find any cases of differentiation syndrome, the side effect that has previously caused consternation.

However, as expected, the early efficacy data were tricky to interpret. Notably, Kura didn't disclose how ziftomenib performed in one subtype of patients studied, relapsed/refractory AML subjects who had progressed on a previous menin inhibitor. Investors seemed happy to overlook this, though, sending Kura up 11% in early trading this morning.

Komet-007

True, the main question many wanted answered with the latest data, which come from the first 20 patients enrolled into the Komet-007 trial, was whether combining ziftomenib with other agents could cut rates of differentiation syndrome.

Here the study was a success: Kura said no differentiation syndrome events of any grade were reported. During a conference call today to discuss the data the group’s chief executive, Troy Wilson, cautioned that there would likely be some differentiation syndrome seen in future updates, however.

This on-target side effect has been particularly problematic in patients with KMT2A rearrangements. In today’s Komet-007 update 9 patients had this AML subtype; the other 11 had NPM1 mutations.

Komet-007 included first-line as well as relapsed/refractory patients, with ziftomenib being combined with different agents in each setting.

In patients with adverse-risk first-line disease, where ziftomenib was combined with 7+3 chemotherapy, the result was emphatic, with complete responses in all five subjects. This surpassed a benchmark cited by Kura today, a 32-33% CR/CRi rate with 7+3 chemo in an adverse-risk population.

Although impressive, this result came in a handful of subjects – only one had KMT2Ar disease – and will need to be confirmed in more patients.

Komet-007 efficacy data

Notes: all patients received 200mg; dose escalation is ongoing or planned; *all complete responses. Source: company presentation.

In relapsed/refractory disease, where ziftomenib was combined with Venclexta plus azacitidine, the picture was less clear. Kura gave an ORR of 53% among 15 patients, but didn't break this down by genetic subtype.

Instead, the company preferred to focus on a subset of 9 menin inhibitor-naive relapsed/refractory patients, where seven of the eight responses occurred. Kura said five of these seven responses were complete, giving a CR/CRh rate of 56% in these menin inhibitor-naive patients.

When asked for more details in menin-experienced patients, a spokesperson for Kura told ApexOnco that the company wanted to preserve some data for a medical meeting.

However, the group did present results today in Venclexta failures, a subset of patients with particularly poor prognosis. Here CR/CRh rates were 30% overall.

Next steps

Dose escalation is continuing, so the picture looks likely to evolve. Kura also plans to move the combo of ziftomenib and Venclexta/azacitidine into front-line use – relevant because this doublet has been used in newly diagnosed patients in recent years. Kura expects to start dosing here mid-year, once it’s nailed down its recommended phase 2 dose.

Kura’s main menin inhibitor rival, Syndax, has previously reported a CR/CRh rate of 85% with its project revumenib plus Venclexta and azacitidine in first-line disease, among 13 patients in the Beat AML trial – providing Kura with a bar to clear.

Kura today claimed that ziftomenib was “definitely” the best-in-class menin inhibitor, but in reality it still has work to do to prove this.