Clear cell renal cell carcinoma
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.
Overview
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.
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.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Adjuvant pembrolizumab is the first adjuvant treatment ever to lengthen survival in kidney cancer.
Anatomy and lymph node drainage
Renal cell carcinoma comes from the kidney's filtering cortex, urothelial cancer from the lining of the collecting system and bladder, and the adrenal on top hosts cortical and medullary (neuroblastoma) tumours.
- Renal cortex (RCC)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)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)Clear cell papillary renal cell tumour (indolent, separate in WHO 2022)
- Bladder muscle wall (muscle-invasive)
- Adrenal cortex
- Adrenal medulla and sympathetic chain (neuroblastoma)
- Developing kidney (Wilms tumour)
- renal hilar
- para-aortic and paracaval
- obturator and iliac (bladder)
Same organ: Non-muscle-invasive bladder cancer, Muscle-invasive and advanced bladder cancer, Bladder & urothelial cancer, Papillary renal cell carcinoma, Chromophobe renal cell carcinoma, Renal cell carcinoma, Wilms tumour (nephroblastoma), Neuroblastoma (paediatric), Adrenocortical carcinoma, Pheochromocytoma and paraganglioma (PPGL), Urethral cancer, Penile cancer
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- 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.
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
Partial nephrectomy, thermal ablation or active surveillance by size, growth and patient fitness.
Radical or partial nephrectomy followed by one year of adjuvant pembrolizumab (KEYNOTE-564, overall survival benefit).
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.
Cabozantinib, axitinib, belzutifan (LITESPARK-005), lenvatinib plus everolimus, tivozanib.
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.
Subtypes & biomarkers
top- 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)
- 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
How often this target appears
- 1993VHL gene identified
- 2005Sorafenib and sunitinib open the anti-angiogenic era
- 2015Nivolumab beats everolimus after anti-angiogenic therapy (CheckMate 025)
- 2018Nivolumab plus ipilimumab first line (CheckMate 214)
- 2019Pembrolizumab plus axitinib first line (KEYNOTE-426)
- 2021Belzutifan approved for VHL disease; adjuvant pembrolizumab (KEYNOTE-564)
What is in development for Clear cell renal cell carcinoma, drawn from the whole corpus: 0 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Nothing recorded in development for this cancer yet.
Open problems and what is being done
No validated biomarker chooses between immunotherapy doublets.
Most metastatic patients still progress within two to three years.
and how the field plans to fix it →What is being done about thisAdvanced and metastatic diseaseAvailable now- Thermal ablation (RFA, microwave, cryo)Standard of care
- Bone-modifying agents (bisphosphonates, denosumab)Standard of care
- DordaviproneApproved
- HIPEC / PIPAC (intraperitoneal chemotherapy)Established
- Laser interstitial thermal therapy (LITT)Established
- Liquid biopsy (ctDNA)Standard of care
In trials- ACTIONRecruiting
- CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)Phase 1
- CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)Active
- DESTINY-Breast12Positive
- DYNAMICPositive
- EF-14Positive
Ideas and roadmaps- A billion-dollar prize for the first durable cure of a lethal metastatic cancer
- A blood test for the pre-metastatic niche
- A global rapid tissue donation network for metastatic disease
- A national rapid research autopsy network for end-stage cancer
- A regulatory endpoint for drugs that block spread, not tumours
- A ring-fenced metastasis programme with metastasis-specific endpoints
Background: Blood-brain barrier (BBB), Circulating tumour DNA (ctDNA), EGFRvIII, Epithelial-mesenchymal transition & drug efflux, H3 K27M (diffuse midline glioma). Also on OnCo: Atlas of advanced disease · Invasion and metastasis.
Overtreatment of small renal masses versus the risk of surveillance.
Trials
topTrials recruiting now
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Landmark trials
Expert centres
topExpert centres
- Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer CenterBaltimore, USNewsweek oncology #10NCI comprehensivevia Pembrolizumab
- via Nivolumab, Ipilimumab
- via Belzutifan, HIF-2α
- via Nivolumab, Ipilimumab
- via Nivolumab, Ipilimumab
- via Nivolumab
- Alliance for Clinical Trials in OncologyChicago, IL, USvia Pembrolizumab
- German Hodgkin Study GroupCologne, DEvia Nivolumab
- GOG FoundationPhiladelphia, PA, USvia Pembrolizumab
- Institut Jules BordetBrussels, BEvia Pembrolizumab
- Kyoto University HospitalKyoto, JPvia Nivolumab
- via Nivolumab
- via Pembrolizumab
- National Cancer Center Hospital EastKashiwa, Chiba, JPvia Nivolumab
- SWOG Cancer Research NetworkPortland, OR, USvia Nivolumab
- Zhongshan Hospital, Fudan UniversityShanghai, CNvia Thermal ablation (RFA, microwave, cryo)
Questions to ask
topQuestions to ask your oncologist about Clear cell renal cell carcinoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example VHL inactivation and 3p loss, PBRM1, SETD2, BAP1 mutations, IMDC risk group, Sarcomatoid features, Germline VHL testing in young or multifocal disease), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Sporadic clear cell, Clear cell with sarcomatoid or rhabdoid features, VHL disease-associated.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Small renal mass
- For my situation (small renal mass), which of the standard options do you recommend and why?Why: Guideline options include: Partial nephrectomy, thermal ablation or active surveillance by size, growth and patient fitness.
Localised, higher risk
- For my situation (localised, higher risk), which of the standard options do you recommend and why?Why: Guideline options include: Radical or partial nephrectomy followed by one year of adjuvant pembrolizumab (KEYNOTE-564, overall survival benefit).
- Am I a candidate for Pembrolizumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-564 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Metastatic, first line
- For my situation (metastatic, first line), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Pembrolizumab, Axitinib, Lenvatinib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-426 and CheckMate 214 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Later lines
- For my situation (later lines), which of the standard options do you recommend and why?Why: Guideline options include: Cabozantinib, axitinib, belzutifan (LITESPARK-005), lenvatinib plus everolimus, tivozanib.
- Am I a candidate for Cabozantinib, Belzutifan, Everolimus, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
VHL disease
- For my situation (vhl disease), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Belzutifan, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No validated biomarker chooses between immunotherapy doublets”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Most metastatic patients still progress within two to three years”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
5targets
10drugs
9companies
7terms
1trials
3Latest papers
topQuery for this cancer: (TITLE:"Clear cell renal cell carcinoma" OR ABSTRACT:"Clear cell renal cell carcinoma" OR TITLE:"ccRCC" OR ABSTRACT:"ccRCC" OR TITLE:"Conventional renal cell carcinoma" OR ABSTRACT:"Conventional renal cell carcinoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Clear cell renal cell carcinoma, not a curated reading list.
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