# Epithelioid sarcoma

Source: https://onco.cc/cancers/epithelioid-sarcoma/  
OnCo record `epithelioid-sarcoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Epithelioid sarcoma is a rare soft tissue cancer that has lost a gene brake called SMARCB1, leaving it dependent on the enzyme EZH2. Surgery cures localised tumours. The EZH2 inhibitor tazemetostat, the first epigenetic drug approved for a solid tumour, was approved in 2020 and withdrawn worldwide in March 2026 after secondary blood cancers in a lymphoma trial, so there is no targeted drug today.

## Summary

Epithelioid sarcoma is defined by loss of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin-remodelling complex, in over 90 percent of cases. SWI/SNF loss makes cells dependent on the antagonistic polycomb repressive complex 2 and its catalytic subunit EZH2, a synthetic-lethal relationship demonstrated in preclinical models and confirmed in patients. The distal (classic) type presents as slow-growing nodules on the hands and forearms of young adults and is often misdiagnosed as a benign lesion; the proximal type, in the pelvis, perineum and trunk, is larger and more aggressive, with rhabdoid features. Both spread to lymph nodes, which is unusual for sarcomas, and to lung.

Localised disease is treated with wide resection and radiotherapy according to soft tissue sarcoma principles; sentinel node evaluation is considered because of nodal spread. Conventional chemotherapy (anthracycline, ifosfamide, gemcitabine-docetaxel) has modest activity. Tazemetostat received FDA accelerated approval in January 2020 for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection, on the basis of the single-arm EZH-202 cohort (objective responses in a minority, but durable, with a benign safety profile). The confirmatory randomised trial EZH-301 adds tazemetostat to doxorubicin in the first line; it was meant to decide whether the accelerated approval would be converted, but Ipsen withdrew the drug in all indications on 9 March 2026 after the SYMPHONY-1 follicular lymphoma trial's data monitoring committee flagged secondary haematologic malignancies (18 of 318 patients, 5.7%, per the FDA safety communication).

Beyond EZH2, checkpoint inhibitors have produced occasional responses (SWI/SNF-deficient tumours are immunogenic in some settings), and combinations of tazemetostat with doxorubicin or immunotherapy are the main directions.

## Fields

- Kind: Cancer
- Last checked: 2026-09-10
- Tags: nci-coverage; rare; sarcoma
- Group: sarcoma
- Burden: Under one case per million people per year; the distal type peaks in young adults aged 20 to 40, the proximal type in older adults.
- Subtypes: Distal (classic) type; Proximal type (large cell, rhabdoid features)
- Biomarkers: SMARCB1/INI1 loss by immunohistochemistry (diagnostic); CD34 and cytokeratin co-expression; Regional lymph node status; Tumour size and depth (proximal vs distal)

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/epithelioid-sarcoma/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/epithelioid-sarcoma/#overview [4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/epithelioid-sarcoma/#what-it-is [2 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/epithelioid-sarcoma/#finding-it [4 biomarkers]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/epithelioid-sarcoma/#treating-it [2 settings, 2 decisions with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/epithelioid-sarcoma/#evidence [5 trials, 3 key papers, 6 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/epithelioid-sarcoma/#science [2 targets, 2 pathways]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/epithelioid-sarcoma/where-you-are/
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/epithelioid-sarcoma/#living-with-it [12 questions, 4 red cards]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/epithelioid-sarcoma/coming/ [3 medicines, 5 trials, 5 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/epithelioid-sarcoma/data/ [25 connected records]

## Standard of care

- Localised: Wide resection with negative margins plus radiotherapy for large, deep or close-margin tumours; lymph node assessment considered because of nodal spread. ([Limb-salvage surgery and endoprosthetic reconstruction](https://onco.cc/technologies/limb-salvage-surgery/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/))
- Advanced or metastatic: Anthracycline-based chemotherapy; tazemetostat (accelerated approval 2020, EZH-202) was withdrawn from all markets in March 2026 after SYMPHONY-1 showed excess secondary blood cancers, so the EZH2 option is gone; clinical trial enrolment encouraged. ([Tazemetostat](https://onco.cc/drugs/tazemetostat/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/))

## State of the art

- Tazemetostat was the first EZH2 inhibitor and the first epigenetic drug approved for a solid tumour, and epithelioid sarcoma is the disease that made the SWI/SNF-EZH2 synthetic lethality a clinical reality; its withdrawal in March 2026 for secondary haematologic malignancies leaves the target validated and the disease without a drug.
- The 2020 approval rested on a single-arm cohort; the randomised EZH-301 confirmatory trial with doxorubicin never got to answer whether the benefit held in first line.
- Nodal spread and frequent misdiagnosis of distal lesions mean that expert pathology review and sarcoma-centre referral change outcomes.
- SMARCB1 loss links this tumour to ATRT, poorly differentiated chordoma and renal medullary carcinoma, allowing shared trials across rare SWI/SNF-deficient cancers.

## Open problems

- No approved targeted therapy since the March 2026 withdrawal: next-generation PRC2 inhibitors such as rinzimetostat (EED) are being tested in other cancers, and whether one can be brought to epithelioid sarcoma is open.
- The EZH-301 doxorubicin combination and immunotherapy combinations were still recruiting when tazemetostat was withdrawn; their read-outs would show whether the EZH2 axis is worth revisiting.
- Checkpoint inhibition has a signal but no approval: talimogene laherparepvec with pembrolizumab gave a 35% objective response rate across 20 patients with advanced sarcoma of mixed histology (Kelly and colleagues, JAMA Oncol 2020), and the AcSe rare-sarcoma basket gave 6.2% at week 12 across 97 patients (Blay and colleagues, Lancet Oncol 2023).
- Late diagnosis of distal lesions mistaken for warts or granulomas.
- Proximal-type disease remains chemoresistant and rapidly progressive.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Epithelioid_sarcoma
- NCI PDQ: soft tissue sarcoma: https://www.cancer.gov/types/soft-tissue-sarcoma
- EZH-202 (Lancet Oncol 2020): https://doi.org/10.1016/S1470-2045(20)30451-4
- EZH-301 on ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04204941
- Ipsen withdrawal notice (9 March 2026): https://www.globenewswire.com/news-release/2026/03/09/3252192/0/en/update-ipsen-voluntarily-withdraws-tazverik-tazemetostat-in-follicular-lymphoma-and-epithelioid-sarcoma.html
- FDA safety communication on the Tazverik withdrawal (11 May 2026): https://www.fda.gov/drugs/drug-alerts-and-statements/fda-alerts-health-care-providers-and-patients-about-increased-risk-new-blood-cancers-tazverik
- T-VEC plus pembrolizumab in sarcoma (JAMA Oncol 2020): https://doi.org/10.1001/jamaoncol.2019.6152
- AcSe pembrolizumab in rare sarcomas (Lancet Oncol 2023): https://doi.org/10.1016/S1470-2045(23)00282-6

## Connected records

- cancers: [Alveolar soft part sarcoma](https://onco.cc/cancers/alveolar-soft-part-sarcoma/), [Atypical teratoid/rhabdoid tumour (ATRT)](https://onco.cc/cancers/atrt/), [Malignant peripheral nerve sheath tumour (MPNST)](https://onco.cc/cancers/malignant-peripheral-nerve-sheath-tumour/), [Perivascular epithelioid cell tumour (PEComa)](https://onco.cc/cancers/pecoma/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/), [Synovial sarcoma](https://onco.cc/cancers/synovial-sarcoma/)
- technologies: [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Limb-salvage surgery and endoprosthetic reconstruction](https://onco.cc/technologies/limb-salvage-surgery/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/)
- targets: [EZH2](https://onco.cc/targets/ezh2/), [SMARCB1](https://onco.cc/targets/smarcb1/)
- drugs: [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Tazemetostat](https://onco.cc/drugs/tazemetostat/)
- companies: [Ipsen](https://onco.cc/companies/ipsen/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/), [Rare cancers](https://onco.cc/terms/rare-cancers/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/)
- key papers: [Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab: A Phase 2 Clinical Trial](https://onco.cc/key-papers/paper-kelly-jama-oncol/), [Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial](https://onco.cc/key-papers/paper-blay-lancet-oncol/), [Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study](https://onco.cc/key-papers/paper-gounder-lancet-oncol/)
- trials: [A Study of ONO-4538HSC in Pediatric Patients With Malignant Solid Tumors and in Patients With Epithelioid Sarcoma.](https://onco.cc/trials/nct07734116/), [Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma](https://onco.cc/trials/nct00112463/), [Evaluate the Safety and Clinical Activity of HH2853](https://onco.cc/trials/nct04390737/), [MASCT-I Combined With Doxorubicin and Ifosfamide for First-line Treatment of Advanced Soft Tissue Sarcoma](https://onco.cc/trials/nct06277154/), [Tazemetostat with doxorubicin as front-line therapy for advanced epithelioid sarcoma (EZH-301 run-in)](https://onco.cc/trials/tazemetostat-doxorubicin-es/)

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JSON: https://onco.cc/api/v1/entities/epithelioid-sarcoma.json