# Group trials by broken mechanism, not by organ or single mutation

Source: https://onco.cc/ideas/idea-bio2-mechanism-defined-baskets/  
OnCo record `idea-bio2-mechanism-defined-baskets` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Rare cancers often share a broken cellular machine even when they arise in different organs. Grouping patients by that shared fault makes trials possible.

## Summary

Tumour-agnostic approvals so far follow single alterations such as NTRK fusions or mismatch repair deficiency. Many rare cancers instead share mechanism classes (SWI/SNF complex loss including SMARCB1 and SMARCA4, chromatin regulator loss, fusion-driven transcription factor addiction, metabolic enzyme mutations) that could define baskets with dozens of contributing diagnoses and a common therapeutic hypothesis such as EZH2 or PRMT5 dependence.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Mechanism-class baskets, for example SWI/SNF-deficient tumours treated with an EZH2 inhibitor, show consistent response across contributing histologies, justifying mechanism-level rather than mutation-level approvals.
- Rationale: Tazemetostat activity in SMARCB1-deficient epithelioid sarcoma is proof that a chromatin mechanism class can be targeted, and synthetic lethal relationships in this space are well mapped in cell line dependency data. Mechanism classes are far more prevalent than any single alteration.
- Proposed test: A basket trial enrolling by mechanism class with pre-specified histology-level Bayesian borrowing; kill the class hypothesis if response is confined to one histology.
- Maturity: early-clinical
- Actor: research

## Sources

- Bottleneck evidence (Rare and paediatric cancers without markets): Gatta et al., Rare cancers are not so rare: the rare cancer burden in Europe (EJC 2011): https://doi.org/10.1016/j.ejca.2011.08.008

## Connected records

- ideas: [PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma](https://onco.cc/ideas/idea-mtap-prmt5-mesothelioma/)
- collections: [DepMap (Cancer Dependency Map)](https://onco.cc/collections/depmap/), [OncoKB](https://onco.cc/collections/oncokb/)
- cancers: [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- targets: [EZH2](https://onco.cc/targets/ezh2/), [IDH1 / IDH2](https://onco.cc/targets/idh/), [KMT2A (MLL) rearrangement](https://onco.cc/targets/kmt2a/)
- terms: [Gene fusion](https://onco.cc/terms/gene-fusion/), [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- trials: [NCI-COG Pediatric MATCH (APEC1621)](https://onco.cc/trials/pediatric-match/), [Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)](https://onco.cc/trials/nct03213665/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications](https://onco.cc/key-papers/paper-ezh2-sarcoma-bmc-med-2011/), [Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer](https://onco.cc/key-papers/paper-ezh2-ovarian-mol-cancer-ther-2018/), [Rare cancers are not so rare: the rare cancer burden in Europe](https://onco.cc/key-papers/paper-gatta-eur-j-cancer/), [Targeting EZH2 in SMARCB1-deficient sarcomas: Advances and opportunities to potentiate the efficacy of EZH2 inhibitors](https://onco.cc/key-papers/paper-ezh2-sarcoma-biochem-pharmacol-2023/)

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