Oncofusion

start / graph / absence-no-menin-inhibitor-trial-in-kmt2a-r-sarcoma

Analysisstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q92-kmt2a-sarcoma

No menin inhibitor has ever enrolled a KMT2A-rearranged solid tumour, and the one solid-tumour menin trial that read out was terminated for lack of efficacy

also called menin inhibitor trials in sarcoma · menin inhibitor solid tumour

Menin-blocking drugs are approved and in dozens of trials, but every one of those trials is in leukaemia. Only two have ever been opened in solid tumours - one in bowel cancer, which the company stopped because it was not working, and one ongoing in a stomach tumour - and none has ever enrolled a patient whose tumour carries a KMT2A rearrangement outside the blood.

The same thing, for a scientist

Bounded absence, measured 2026-09-21 against the ClinicalTrials.gov API v2. A query on the intervention names revumenib, ziftomenib, bleximenib, enzomenib, SNDX-5613 and KO-539 across all conditions returns a registry dominated by acute leukaemia. Exactly two registered studies name a non-haematologic condition: NCT05731947 (revumenib in colorectal cancer and other solid tumours, Syndax, phase 1/2, 41 patients actual) which is TERMINATED with whyStopped reading 'Study was terminated by sponsor after Phase 1b as pre-defined signals of efficacy were not met in the Phase 1b dose expansion cohort'; and NCT06655246 (ziftomenib plus imatinib in advanced GIST after imatinib failure, Kura, phase 1a/1b, 157 estimated) which is recruiting. Neither selects for KMT2A rearrangement. No registered study names sarcoma, soft tissue sarcoma, or KMT2A-rearranged solid tumour. The literature is consistent: `("menin inhibitor"[tiab] OR "menin inhibitors"[tiab] OR "menin inhibition"[tiab]) AND (sarcoma[tiab] OR "soft tissue"[tiab] OR "solid tumor"[tiab] OR "solid tumour"[tiab])` returns 3 records and `menin[tiab] AND sarcoma[tiab]` returns 11 - and every one of them is about EWING sarcoma or MEN1-syndrome-associated sarcoma, not about KMT2A-rearranged sarcoma. Class: `never-measured`.

Go deeper
The registry, measured

Query: intervention = revumenib OR ziftomenib OR bleximenib OR enzomenib OR SNDX-5613 OR KO-539, all conditions, ClinicalTrials.gov API v2, 2026-09-21 1.

the only non-leukaemia recordsstatusdetail
NCT05731947 revumenib in colorectal cancer and other solid tumours (Syndax, phase 1/2)TERMINATED, n=41 actualwhyStopped: "Study was terminated by sponsor after Phase 1b as pre-defined signals of efficacy were not met in the Phase 1b dose expansion cohort." Started 2023-04-04 1
NCT06655246 ziftomenib + imatinib in advanced GIST after imatinib failure (Kura, phase 1a/1b)RECRUITING, n=157 estimatedstarted 2025-03-27 2

Zero registered studies in sarcoma, soft tissue sarcoma, or any KMT2A-rearranged solid tumour. Note that the whyStopped string is only visible through the raw API - the MCP registry tool does not return that field, and this project has previously written 'the registry gives no reason' about a record that gave the reason plainly.

The only sarcoma in which menin inhibition has been tested preclinically is the wrong sarcoma, and it failed

All 11 records returned by menin[tiab] AND sarcoma[tiab] are about Ewing sarcoma (where wild-type MLL1 and menin are reported as EWSR1::FLI1-downstream dependencies) or about sarcomas arising in MEN1 syndrome patients. The Pediatric Preclinical Testing Consortium evaluated VTP-50469 against seven Ewing sarcoma xenografts: limited antitumour activity, statistically significant slowing in four models with no regression, and an in vitro IC50 of 10 nM in the MLL-rearranged leukaemia line MV4;11 against >3 µM in Ewing lines 3.

That is a three-order-of-magnitude potency gap between a KMT2A-fusion leukaemia line and a sarcoma line in which menin is a wild-type dependency - and it is the closest thing to a menin-inhibitor result in any sarcoma. It argues that menin inhibition does not transfer to mesenchymal tumours even where a menin dependency has been reported, let alone to one whose fusion lacks the binding motif.

What this implies for the index fusion, by contrast

The menin-inhibitor franchise is entirely a leukaemia franchise, and its single solid-tumour efficacy readout to date is a sponsor termination for pre-specified efficacy signals not being met. For this project that is reassuring in one sense - the drug class's activity really does appear to depend on the KMT2A-fusion context, which is what the menin-interface hypothesis predicts - and cautionary in another: the class has never been shown to work through anything other than that one context, so any future extension of it needs the interface demonstrated first, not assumed from a gene name.

Facts and figures
absence classnever-measured
what is absentany clinical trial of a menin inhibitor enrolling KMT2A-rearranged soft tissue sarcoma, or any KMT2A-rearranged solid tumour selected as such
registry queryClinicalTrials.gov API v2, query.intr = revumenib OR ziftomenib OR bleximenib OR enzomenib OR SNDX-5613 OR KO-539, all conditions
registry resultCORRECTED 2026-09-22: THREE, not two. NCT05731947 (colorectal/solid tumours, TERMINATED, n=41 actual); NCT06655246 (GIST + imatinib, recruiting, n=157 estimated); and NCT05631574 (BMF-219/icovamenib in KRAS-driven NSCLC, pancreatic and colorectal cancer, Biomea Fusion, TERMINATED, n=13 actual). The third was missed because BMF-219 and icovamenib were absent from drug_name_list. Zero in sarcoma or in any KMT2A-rearranged solid tumour still stands. AND THE TWO TERMINATIONS ARE NOT THE SAME KIND, which matters for reading the drug class: NCT05731947 stopped because 'pre-defined signals of efficacy were not met in the Phase 1b dose expansion cohort', whereas NCT05631574 stopped because 'Biomea Fusion, Inc., is no longer pursuing oncology indications for BMF-219. No safety concerns or efficacy observations led to this study closure' - a portfolio decision, not a readout. Both whyStopped strings fetched live from the v2 API by the king on 2026-09-22.
why stopped nct05731947Study was terminated by sponsor after Phase 1b as pre-defined signals of efficacy were not met in the Phase 1b dose expansion cohort.
why stopped sourceraw ClinicalTrials.gov API v2; this field is not returned by the MCP registry tool
literature query("menin inhibitor"[tiab] OR "menin inhibitors"[tiab] OR "menin inhibition"[tiab]) AND (sarcoma[tiab] OR "soft tissue"[tiab] OR "solid tumor"[tiab] OR "solid tumour"[tiab])
literature records3
bare operand controlmenin[tiab] AND sarcoma[tiab] = 11, all Ewing sarcoma or MEN1-syndrome sarcoma
date2026-09-21
toolClinicalTrials.gov API v2 and PubMed E-utilities esearch
closest preclinical resultVTP-50469 in seven Ewing sarcoma xenografts: no regression; IC50 10 nM in MV4;11 versus >3 micromolar in Ewing lines (PMID 32333633)
drug name list
[
  "revumenib",
  "ziftomenib",
  "bleximenib",
  "enzomenib",
  "VTP-50469",
  "VTP50469",
  "MI-503",
  "MI-3454",
  "SNDX-5613",
  "KO-539",
  "menin inhibitor",
  "menin inhibitors",
  "menin inhibition",
  "BMF-219",
  "icovamenib",
  "DS-1594b",
  "DS-1594",
  "BN104",
  "DSP-5336"
]
How this could bite us back
  • This is exactly the setting the brief warns about: a rare entity with no standard therapy, a gene name shared with a drugged leukaemia, and no trial. The temptation to infer a treatment recommendation is highest where the evidence is weakest, and the coordinate argument says the drug has no binding site in either defined arm of this entity.
  • Menin behaves as a tumour SUPPRESSOR in mesenchymal tissue in MEN1 syndrome, where sarcomas arise with loss of the MEN1 locus and loss of menin expression. Inhibiting menin in a mesenchymal tumour therefore carries a mechanistic risk of the wrong sign, not merely a risk of inactivity.
  • A single-arm trial in an entity with about thirty published cases and 50% metastasis at presentation could not distinguish activity from natural history whatever it showed.
Still open
  1. Did the terminated revumenib solid-tumour study enrol any KMT2A-rearranged tumour among its 41 patients, and was fusion status collected? If it was, the single most informative data point on this question already exists inside a closed trial.
  2. Is there a tumour-agnostic KMT2A-rearrangement basket anywhere in any registry? None was found under the menin-inhibitor intervention names, but a condition-side query on KMT2A-rearranged solid tumour was not run.
  3. What is the GIST rationale for ziftomenib, and does it depend on menin's wild-type function? If it does, it is the first non-fusion menin rationale to reach a patient and its result bears on how much of this drug class's activity is fusion-specific.
Every source behind this entry (4)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    Measured here 2026-09-21 against the raw ClinicalTrials.gov API v2: of the registered studies of revumenib, ziftomenib, bleximenib, enzomenib, SNDX-5613 or KO-539, the only one in a non-haematologic malignancy that has closed is NCT05731947 (revumenib in colorectal cancer and other solid tumours, Syndax, phase 1/2, 41 patients enrolled), and its whyStopped field reads that the sponsor terminated the study after Phase 1b because pre-defined signals of efficacy were not met in the Phase 1b dose expansion cohort.

    NCT05731947
    What this evidence cannot show

    A registry record, not a publication: no response data, no biomarker analysis and no per-cohort breakdown are available, and 'other solid tumours' is not enumerated in the fields read, so it is not known whether any KMT2A-rearranged tumour was enrolled among the 41. The whyStopped string is the sponsor's own wording. Read via the raw API because the MCP registry tool does not return whyStopped.

    Evidence that argues against this (1)
    • A phase 1b termination for pre-defined efficacy signals in a colorectal-dominated cohort says nothing specific about a KMT2A-rearranged tumour, because the trial was not selecting for one. It bounds the drug class's demonstrated activity, not its activity in an unselected KMT2A-rearranged solid tumour - which remains untested. Kura Oncology et al. 2025
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry

    One menin-inhibitor study in a non-haematologic malignancy is ongoing as of 2026-09-21: NCT06655246, a phase 1a/1b study of ziftomenib plus imatinib in advanced gastrointestinal stromal tumour after imatinib failure, sponsored by Kura Oncology, with an estimated enrolment of 157 and an actual start date of 2025-03-27; it does not select for KMT2A rearrangement.

    NCT06655246
    What this evidence cannot show

    A registry record with no results posted. Its rationale is a GIST-specific one and not a KMT2A-fusion rationale, so a positive result would not extend to KMT2A-rearranged sarcoma and a negative one would not exclude it.

    Evidence that argues against this (1)
    • That a company is running a menin inhibitor in a solid tumour on a non-KMT2A rationale shows the class is being explored beyond the fusion context, so the absence of a KMT2A-rearranged-sarcoma trial is a choice about a rare indication rather than a judgement that the class cannot work outside leukaemia. Syndax Pharmaceuticals 2023
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In seven Ewing sarcoma xenograft models and Ewing sarcoma cell lines, the menin-MLL1 inhibitor VTP-50469 showed limited antitumour activity - statistically significant slowing of tumour progression in four models with no evidence of regression - and an in vitro IC50 of 10 nM in the MLL-rearranged leukaemia line MV4;11 against greater than 3 micromolar in the Ewing sarcoma lines.

    PMID 32333633DOI
    What this evidence cannot show

    Ewing sarcoma, not KMT2A-rearranged sarcoma, and the menin dependency in Ewing is a wild-type MLL1/menin dependency downstream of EWSR1::FLI1 rather than a fusion-interface dependency. Xenografts in immunodeficient mice, so immune contributions are excluded. The three-order-of-magnitude IC50 gap is the load-bearing number here and comes from cell-line viability, not from target engagement.

    Evidence that argues against this (1)
    • Other groups report that Ewing sarcoma tumorigenicity IS critically dependent on MLL1 and menin, and that EWS-FLI1 and menin converge to regulate ATF4. So a genetic dependency on menin in Ewing sarcoma is on record while the pharmacological result is close to negative - the gap between genetic and pharmacological menin results is itself the finding, and it is the same gap this project has documented for menin inhibitors elsewhere. Svoboda LK et al. 2017
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Measured here 2026-09-21 by PubMed esearch with one field tag per term: ("menin inhibitor" OR "menin inhibitors" OR "menin inhibition")[tiab] AND (sarcoma OR "soft tissue" OR "solid tumor" OR "solid tumour")[tiab] returns 3 records and menin[tiab] AND sarcoma[tiab] returns 11, and every record in both sets is about Ewing sarcoma or about sarcomas arising in MEN1 syndrome rather than about KMT2A-rearranged sarcoma.

    What this evidence cannot show

    The drug-class name list was run in singular, plural and nominalised forms and with the compound codes both hyphenated and unhyphenated, because those are three and two different strings respectively; the bare operand control menin[tiab] AND sarcoma[tiab] returns 11, so the class-name list is not the limiting factor. Bounded to titles and abstracts on 2026-09-21. All 11 titles were read individually.

    Evidence that argues against this (1)
    • One of the 11 records is a paper on sarcomas arising in MEN1 patients with loss of heterozygosity at the MEN1 locus and loss of menin expression - i.e. menin acting as a tumour SUPPRESSOR in mesenchymal tissue. That is the opposite pharmacological direction from menin inhibition, and it is a reason to worry about inhibiting menin in a mesenchymal tumour rather than a reason to try it. van Leeuwaarde RS et al. 2024
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