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ASH 2023 – J&J makes menin a three-horse race

But JNJ-75276617 still has much to prove.

Three horses racing

When data first emerged on Johnson & Johnson’s JNJ-75276617, in an ASH abstract, it looked like the group’s menin inhibitor rivals didn’t have too much to worry about. Updated phase 1 results in relapsed/refractory AML, presented today, suggest that the project might not be all that different from Syndax’s revumenib and Kura’s ziftomenib.

Interestingly, JNJ-75276617 showed similar efficacy across both genetic subtypes in which menin inhibitors are being trialled, patients with KMT2A rearrangements or NPM1 mutations; ziftomenib monotherapy has not shown activity in the former.

There are still unanswered questions, including which dose J&J will take forward; the recommended phase 2 dose has not yet been determined.

And, as with the other menin inhibitors, there are worries about side effects. Neutropenia was one of the most common adverse events seen with JNJ-75276617, occurring in 12% of patients. 

While Kura has not reported this as a common adverse event with ziftomenib, it has also been seen with revumenib, notably in the KMT2Ar cohort of the Augment-101 trial: an ASH abstract details a 14% rate of grade 3-plus febrile neutropenia. More revumenib data are due to at a late-breaking ASH session on Tuesday

As for other notable side effects, rates of differentiation syndrome (DS) appear lower overall with JNJ-75276617 than the other two projects. There was one DS-related death with JNJ-75276617 once-daily dosing, but after the study switched to twice-daily and step-up dosing DS became “manageable”, according to Dr Elias Jabbour of MD Anderson Cancer Center, who presented the data.

There was also one case of QTc prolongation classed at a dose-limiting toxicity.

Perhaps things will become clearer once an ideal dose for JNJ-75276617 is nailed down, but for now menin inhibition has become a three-horse race.

 

Cross-trial comparison of menin inhibitors

CompanyJohnson & JohnsonSyndaxKura
ProjectJNJ-75276617RevumenibZiftomenib
Trial75276617ALE1001Augment-101Komet-001
SubgroupNPM1m    KMT2Ar    NPM1mKMT2Ar*NPM1mKMT2Ar
Data cut off25 Oct 202331 Mar 202224 Jul 202312 Apr 2023Feb 2023 – monotherapy 
cohorts 
discontinued 
in this 
setting
ORR50%**42%**36%63%45%
CR at RP2D^21%**27%23%35%
QTc prolongationNot givenNot split out***23% (14% at gr3+)None reported         
Differentiation syndrome12% (5% at gr3+)None at gr3+27% (16% at gr3+)20% (5% at gr3+)
Neutropenia12% (11% at gr3+)Not split out14% gr3+ 
febrile 
neutropenia
Not given
SourceASH 2023ASH 20222 Oct 2023
event/
ASH 2023 
abstract
EHA 2023

Notes: *the registrational cohort includes 8 patients with ALL, with the remaining 49 having AML; **in 45-130mg BID cohorts (RP2D not yet determined); ***across both cohorts and all doses grade 3+ QTc prolongation was seen in 13% of patients at ASH 2022; ^CR defined as CR+CRh.

Tags

Molecular Drug Targets