# Clear cell renal cell carcinoma

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

## TL;DR

Clear cell is the common kidney cancer, driven by loss of the VHL gene that leaves the tumour behaving as if starved of oxygen and flooding itself with blood vessels. That biology explains why anti-angiogenic drugs, immunotherapy and the HIF-2 alpha blocker belzutifan all work.

## Summary

Clear cell renal cell carcinoma arises from the proximal tubule and in about nine in ten cases has lost the VHL gene on chromosome 3p, stabilising HIF-2 alpha and driving VEGF, so tumours are highly vascular; PBRM1, SETD2 and BAP1 mutations shape its behaviour. Small tumours are removed by partial nephrectomy or ablated, and some are watched. Adjuvant pembrolizumab after nephrectomy improves survival in higher-risk disease (KEYNOTE-564). Metastatic disease is treated first line with an immunotherapy doublet: pembrolizumab with axitinib or lenvatinib, nivolumab with cabozantinib, or nivolumab with ipilimumab for intermediate- and poor-risk patients; cabozantinib, axitinib, tivozanib and belzutifan follow. Belzutifan, the first HIF-2 alpha inhibitor, was approved for VHL disease in 2021 and for previously treated advanced disease in 2023. Cytoreductive nephrectomy is now reserved for selected patients after CARMENA.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: KIRC; TCGA-KIRC; kidney renal clear cell carcinoma (TCGA KIRC cohort); ccRCC; Conventional renal cell carcinoma
- Tags: subtype-page
- Group: genitourinary
- Burden: About three quarters of kidney cancers and most of the deaths; a third of patients present with or develop metastases, and immunotherapy combinations have lifted median survival in advanced disease to around four years.
- Subtypes: Sporadic clear cell (VHL-inactivated); Clear cell with sarcomatoid or rhabdoid features (aggressive, immunotherapy-responsive); VHL disease-associated (hereditary, multifocal); Clear cell papillary renal cell tumour (indolent, separate in WHO 2022)
- Biomarkers: VHL inactivation and 3p loss; PBRM1, SETD2, BAP1 mutations (prognosis); IMDC risk group (metastatic disease); Sarcomatoid features; Germline VHL testing in young or multifocal disease

## 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/clear-cell-rcc/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/clear-cell-rcc/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/clear-cell-rcc/#what-it-is [4 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/clear-cell-rcc/#finding-it [5 biomarkers]
- Treatment (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/clear-cell-rcc/#treating-it [5 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/clear-cell-rcc/#evidence [18 trials, 5 key papers, 6 milestones]
- Biology and targets (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/clear-cell-rcc/#science [23 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/clear-cell-rcc/where-you-are/
- Decisions and support (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/clear-cell-rcc/#living-with-it [20 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/clear-cell-rcc/coming/ [9 medicines, 18 trials, 3 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/clear-cell-rcc/data/ [71 connected records]

## Standard of care

- Small renal mass: Partial nephrectomy, thermal ablation or active surveillance by size, growth and patient fitness. ([Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/), [Cryoablation](https://onco.cc/terms/cryoablation/), [Active surveillance](https://onco.cc/technologies/active-surveillance/))
- Localised, higher risk: Radical or partial nephrectomy followed by one year of adjuvant pembrolizumab (KEYNOTE-564, overall survival benefit). ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-564](https://onco.cc/trials/keynote-564/))
- Metastatic, first line: Pembrolizumab plus axitinib (KEYNOTE-426) or lenvatinib, nivolumab plus cabozantinib, or nivolumab plus ipilimumab (CheckMate 214) for intermediate and poor risk; cytoreductive nephrectomy only in selected patients. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Axitinib](https://onco.cc/drugs/axitinib/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [KEYNOTE-426](https://onco.cc/trials/keynote-426/), [CheckMate 214](https://onco.cc/trials/checkmate-214/))
- Later lines: Cabozantinib, axitinib, belzutifan (LITESPARK-005), lenvatinib plus everolimus, tivozanib. ([Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Belzutifan](https://onco.cc/drugs/belzutifan/), [Everolimus](https://onco.cc/drugs/everolimus/), [HIF-2α](https://onco.cc/targets/hif2a/))
- VHL disease: Belzutifan for kidney, pancreatic and CNS tumours that would otherwise need surgery; surveillance of the kidneys with nephron-sparing surgery when tumours reach 3 cm. ([Belzutifan](https://onco.cc/drugs/belzutifan/))

## State of the art

- Immunotherapy doublets cure a small fraction of metastatic patients and control most for years, with the nivolumab-ipilimumab plateau the clearest sign of durable benefit.
- Belzutifan is the first drug to target the transcription factor at the root of the disease, forty years after VHL was mapped.
- Adjuvant pembrolizumab is the first adjuvant treatment ever to lengthen survival in kidney cancer.

## Open problems

- No validated biomarker chooses between immunotherapy doublets.
- Most metastatic patients still progress within two to three years.
- Overtreatment of small renal masses versus the risk of surveillance.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Clear-cell_renal_cell_carcinoma
- Wikipedia: https://en.wikipedia.org/wiki/Clear-cell_renal_cell_carcinoma

## Connected records

- cancers: [Chromophobe renal cell carcinoma](https://onco.cc/cancers/chromophobe-rcc/), [Clear cell papillary renal cell tumour](https://onco.cc/cancers/clear-cell-papillary-renal-cell-tumour/), [Papillary renal cell carcinoma](https://onco.cc/cancers/papillary-rcc/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/), [Renal medullary carcinoma (SMARCB1-deficient)](https://onco.cc/cancers/renal-medullary-carcinoma/), [TFE3-rearranged (translocation) renal cell carcinoma](https://onco.cc/cancers/tfe3-rearranged-renal-cell-carcinoma/)
- terms: [BAP1 loss](https://onco.cc/terms/bap1-loss/), [Cryoablation](https://onco.cc/terms/cryoablation/)
- trials: [89Zr-TLX250 for PET/CT Imaging of ccRCC - ZIRCON-CP Study](https://onco.cc/trials/nct06750419/), [89Zr-TLX250 for PET/CT Imaging of ccRCC- ZIRCON Study](https://onco.cc/trials/nct03849118/), [A Phase 1/2 Trial of ADI-270 in ccRCC](https://onco.cc/trials/nct06480565/), [A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, vs Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)-China Extension Study](https://onco.cc/trials/nct05899049/), [A Study of Subcutaneous Nivolumab Versus Intravenous Nivolumab in Participants With Previously Treated Clear Cell Renal Cell Carcinoma That is Advance](https://onco.cc/trials/nct04810078/), [A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) (MK-6482-003)](https://onco.cc/trials/nct03634540/), [AB-2100, an Integrated Circuit T Cell Therapy in Patients With Recurrent Clear-cell Renal Cell Carcinoma (ccRCC)](https://onco.cc/trials/nct06245915/), [An Investigational Scan (89Zr-DFO-GmAb PET/CT) Compared to Contrast-Enhanced CT for the Detection of Recurrent Clear Cell Renal Cell Cancer After Surgery Comparing Carbonic Anhydrase IX (CAIX) PET CT to Conventional PET CT for Post-Op Staging in Kidney Cancer](https://onco.cc/trials/nct06447103/), [CARMENA](https://onco.cc/trials/carmena/), [CheckMate 025](https://onco.cc/trials/checkmate-025/), [CheckMate 214](https://onco.cc/trials/checkmate-214/), [Dual-target CD70/CAIX CAR-NK Cells for Advanced Clear Cell Renal Cell Carcinoma](https://onco.cc/trials/nct07551349/), [KEYNOTE-426](https://onco.cc/trials/keynote-426/), [KEYNOTE-564](https://onco.cc/trials/keynote-564/), [Phase 3 Study to Assess Safety and Efficacy of 177Lu-TLX250 in Advanced Relapsed or Recurrent ccRCC](https://onco.cc/trials/nct07197580/), [REGN15505 (PSMAx4-1BB) Alone or in Combination With Cemiplimab or REGN4336 (PSMAxCD3) in Adult Patients With Metastatic Castration-Resistant Prostate ](https://onco.cc/trials/nct07594106/), [Study of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma](https://onco.cc/trials/nct07011719/), [Study of Orellanine in Metastatic Clear-Cell or Papillary Renal Cell Carcinoma](https://onco.cc/trials/nct05287945/)
- key papers: [CheckMate 214: nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma](https://onco.cc/key-papers/paper-checkmate-214-nejm-2018/), [CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer](https://onco.cc/key-papers/paper-clear-nejm-2021/), [KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma](https://onco.cc/key-papers/paper-keynote-426-nejm-2019/), [KEYNOTE-564: a year of pembrolizumab after kidney cancer surgery](https://onco.cc/key-papers/paper-keynote-564-nejm-2021/), [WHO classification of tumours of the urinary system and male genital organs, 2022: renal, penile and testicular tumours](https://onco.cc/key-papers/paper-who-2022-gu-moch-eur-urol-2022/)
- drugs: [Axitinib](https://onco.cc/drugs/axitinib/), [Belzutifan](https://onco.cc/drugs/belzutifan/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Everolimus](https://onco.cc/drugs/everolimus/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Sunitinib](https://onco.cc/drugs/sunitinib/)
- targets: [ARHGEF10L](https://onco.cc/targets/arhgef10l/), [ARHGEF12](https://onco.cc/targets/arhgef12/), [ATG7](https://onco.cc/targets/atg7/), [CHD4](https://onco.cc/targets/chd4/), [CLTC](https://onco.cc/targets/cltc/), [HIF-1α (HIF1A)](https://onco.cc/targets/hif1a/), [HIF-2α](https://onco.cc/targets/hif2a/), [KDM5C](https://onco.cc/targets/kdm5c/), [MSN](https://onco.cc/targets/msn/), [PTPRK](https://onco.cc/targets/ptprk/), [RANBP2](https://onco.cc/targets/ranbp2/), [RAP1GDS1](https://onco.cc/targets/rap1gds1/), [RNF213](https://onco.cc/targets/rnf213/), [VHL](https://onco.cc/targets/vhl/)
- technologies: [Active surveillance](https://onco.cc/technologies/active-surveillance/), [Thermal ablation (RFA, microwave, cryo)](https://onco.cc/technologies/thermal-ablation/)
- people: [Eric Jonasch](https://onco.cc/people/eric-jonasch/)

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JSON: https://onco.cc/api/v1/entities/clear-cell-rcc.json