Renal cell carcinoma
Kidney cancer is where anti-angiogenic drugs and immunotherapy came together, and where a Nobel-winning oxygen-sensing pathway yielded a drug, belzutifan.
Overview
Renal cell carcinoma is a cancer of the kidney's tubules, increasingly found by chance on scans done for other reasons. Three quarters are clear-cell tumours defined by loss of the VHL gene, which leaves the oxygen-sensing HIF-2α switch permanently on and makes the tumour intensely vascular and immune-infiltrated. That biology explains the whole modern treatment story: anti-VEGF pills (2005-2012), immunotherapy (2015 onward), their combination (2018 onward), and the first HIF-2α inhibitor, belzutifan (2021).
For metastatic disease, four immunotherapy-based first-line regimens have survival benefit: nivolumab-ipilimumab (CheckMate 214, durable remissions in a fifth of intermediate/poor-risk patients, still visible at eight years) and three IO-TKI doublets (pembrolizumab-axitinib, nivolumab-cabozantinib, lenvatinib-pembrolizumab). Attempts to do better in first line with triplets failed on survival (COSMIC-313) or fell short (LITESPARK-012), and two trials (CONTACT-03, TiNivo-2) showed that restarting immunotherapy after it fails does not help. After surgery, adjuvant pembrolizumab (KEYNOTE-564) was the first adjuvant immunotherapy in any solid tumour to improve overall survival, and in 2026 belzutifan plus pembrolizumab (LITESPARK-022) became the first adjuvant combination, though three other adjuvant immunotherapy trials were negative.
What comes next: selecting who needs adjuvant therapy (ctDNA is weak in RCC; CAIX PET and gene signatures are candidates); CAIX theranostics with radiolabelled girentuximab; zanzalintinib and next-generation TKIs; HIF-2α combinations in the right setting; CD70 and CAIX cell therapies; treatment-free survival as an endpoint; and better management of the small renal masses that make up an increasing share of diagnoses, many of which need no treatment at all. Non-clear-cell histologies (papillary, chromophobe, translocation) remain under-served.
State of the art
- Adjuvant immunotherapy with OS benefit.
- HIF-2α inhibition.
- Adjuvant pembrolizumab improves overall survival (KEYNOTE-564); pembrolizumab + belzutifan approved as adjuvant combination (2026).
- Belzutifan validates HIF-2α as a target in VHL disease and pretreated RCC.
- Two negative rechallenge trials (CONTACT-03, TiNivo-2) and two failed first-line intensification trials (COSMIC-313, LITESPARK-012) have sharpened the algorithm rather than widened it.
- Active surveillance and nephron-sparing approaches are standard for small renal masses.
- CAIX PET (ZIRCON) offers non-invasive diagnosis of clear-cell RCC; approval delayed by a 2025 CRL.
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.
- Four immunotherapy-based first-line regimens with survival benefit; durable remissions off treatment in ~20% with nivolumab-ipilimumab at 8 years.
Anatomy and lymph node drainage
- Renal cortex (RCC)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)
- Bladder muscle wall (muscle-invasive)
- Adrenal cortex
- Adrenal medulla and sympathetic chain (neuroblastoma)
- Developing kidney (Wilms tumour)
- Nodes: renal hilar
- Nodes: para-aortic and paracaval
- Nodes: obturator and iliac (bladder)
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)Clear-cell (~75%; VHL loss, HIF-2α driven) · Papillary type 1 (MET) and type 2 (FH, others) · Chromophobe · Translocation (TFE3/TFEB) · Collecting duct and medullary (SMARCB1) · Sarcomatoid differentiation (any histology, ~10%) · Hereditary syndromes: VHL, HLRCC (FH), BHD (FLCN), HPRC (MET)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)Papillary type 1 (MET) and type 2 (FH, others)
- 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: Neuroblastoma (paediatric), High-risk neuroblastoma, Pheochromocytoma and paraganglioma (PPGL), Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127), Metastatic pheochromocytoma and paraganglioma
Preclinical models
4 cell lines, 1 mouse models and 5 repositories are listed for this cancer.
Renal cell carcinoma causes about 430,000 cases a year worldwide, with incidence rising as imaging finds more small tumours, many of which need no treatment; ~20-30% are metastatic at diagnosis, and immunotherapy doublets now give durable remissions in about a fifth of those patients.
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.
- ~180,000 deaths a year; registry five-year survival for metastatic disease is ~15% overall, higher with modern IO regimens.
Nothing recorded yet.
- CAIX PET (89Zr-girentuximab)Phase 3
Nothing recorded yet.
Also on Nuclide: Roadmaps.
Advanced diseaseShow Hide where advanced disease can reach, and what treats itThe sites decide which scans are done at staging and follow-up, and every site listed has a treatment approach.
Most people reading this do not have advanced disease. The map describes what can happen over the whole course of the illness, across autopsy and registry series; today's staging scans find spread earlier, and each site has treatments, from focused radiotherapy for a few spots to drugs that reach the brain.
What helpsImmunotherapy doublets (nivolumab-ipilimumab or immunotherapy plus a VEGF TKI) with durable remissions in about a fifth of patients; belzutifan later; SBRT or surgery for a few sites.
Nothing recorded yet.
- A Study to Assess Safety, Tolerability and Imaging Characteristics of [68Ga]Ga-DPI-4452 and to Assess Safety, Tolerability, and Efficacy of [177Lu]Lu-DPI-4452 in Participants With Unresectable Locally Advanced or Metastatic Solid TumorsRecruiting
- A Trial to Find Out if REGN5678 (Nezastomig) is Safe and How Well it Works Alone or in Combination With Cemiplimab for Adult Participants With MetastaRecruiting
Nothing recorded yet.
Background: Oligometastatic disease. Also on Nuclide: Indications.
- Lungsmost common
- Bonecommon
Bone-destroying (lytic) lesions.
- Distant lymph nodescommon
- Livercommon
- Adrenal glandsless common
- Brainless common
- Pancreas and thyroid (late, unusual sites)rare
Renal cell carcinoma is known for late spread to odd sites years after nephrectomy.
Partial/radical nephrectomy or ablation; adjuvant pembrolizumab ± belzutifan for high risk.
IO-TKI or IO-IO doublet; belzutifan, cabozantinib, lenvatinib-everolimus later.
Active surveillance, partial nephrectomy (usually robotic), or thermal ablation depending on growth, comorbidity, and biopsy; renal mass biopsy increasingly used.
Partial or radical nephrectomy; no adjuvant therapy for low/intermediate risk.
Adjuvant pembrolizumab for 1 year (KEYNOTE-564, OS benefit); pembrolizumab + belzutifan approved 2026 (LITESPARK-022); sunitinib adjuvant rarely used.
Nivolumab + ipilimumab, or an IO-TKI doublet (pembrolizumab + axitinib, nivolumab + cabozantinib, lenvatinib + pembrolizumab); cytoreductive nephrectomy deferred or omitted (CARMENA) except in selected cases.
IO-TKI doublet (PFS benefit; OS benefit unproven in this group) or single-agent TKI (sunitinib, pazopanib) with deferred IO; active surveillance for indolent low-volume disease.
Single-agent TKI (cabozantinib, axitinib, lenvatinib + everolimus, tivozanib); belzutifan after both IO and VEGF-TKI (LITESPARK-005). Do not rechallenge PD-1 (CONTACT-03, TiNivo-2).
Metastasectomy or SBRT to limited sites with continuation of systemic therapy or observation.
Cabozantinib (PAPMET), lenvatinib + pembrolizumab (KEYNOTE-B61), or nivolumab + cabozantinib; MET inhibitors for MET-driven papillary; trials preferred.
Belzutifan for VHL-associated RCC, CNS haemangioblastoma, and pNET not requiring immediate surgery (LITESPARK-004).
Subtypes & biomarkers
top- Clear-cell (~75%; VHL loss, HIF-2α driven)
- Papillary type 1 (MET) and type 2 (FH, others)
- Chromophobe
- Translocation (TFE3/TFEB)
- Collecting duct and medullary (SMARCB1)
- Sarcomatoid differentiation (any histology, ~10%)
- Hereditary syndromes : VHL, HLRCC (FH), BHD (FLCN), HPRC (MET)
- Clear-cell vs non-clear-cell histology
- VHL
- IMDC risk
- CAIX (imaging, 89Zr-girentuximab)
- IMDC risk group (six clinical factors)
- Histology and sarcomatoid features
- VHL / HIF-2α axis (belzutifan)
- PD-L1 (not used for selection)
- CAIX (imaging; theranostic target)
- CD70 (CAR-T target)
- MET (papillary type 1)
- Gene-expression signatures (angiogenesis vs T-effector; research)
- ctDNA (low shedding; research)
How often this target appears
- 1992High-dose IL-2 approved
- 1992High-dose IL-2 approved: first immunotherapy for RCC, with rare cures
- 1993VHL gene identified; the molecular basis of clear-cell RCC
- 2001Cytoreductive nephrectomy improves survival with interferon (SWOG 8949)
- 2005Sorafenib/sunitinib: VEGF era
- 2005Sorafenib approved: first VEGF-pathway TKI in RCC
- 2006Sunitinib approved; replaces interferon
- 2009Everolimus approved second line (RECORD-1)
- 2012Axitinib approved (AXIS)
- 2015Nivolumab beats everolimus (CheckMate 025): immunotherapy returns to RCC
- 2016Cabozantinib approved (METEOR)
- 2018Nivolumab-ipilimumab first line
- 2018Nivolumab-ipilimumab first line (CheckMate 214); CARMENA questions cytoreductive nephrectomy
- 2019Pembrolizumab-axitinib and avelumab-axitinib: IO-TKI era begins
- 2021Belzutifan approved
- 2021Nivolumab-cabozantinib, lenvatinib-pembrolizumab, adjuvant pembrolizumab, belzutifan (VHL), tivozanib approved
- 2023COSMIC-313 triplet fails on OS; CONTACT-03 closes IO rechallenge; belzutifan approved after IO/TKI (LITESPARK-005); ZIRCON validates CAIX PET
- 2024KEYNOTE-564 shows OS benefit; CheckMate 214 8-year data; TiNivo-2 negative
- 2026LITESPARK-022 positive and approved (adjuvant belzutifan + pembrolizumab); LITESPARK-012 first-line triplet falls short
Dated changes read from the records linked to this indication: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 32 changes by month →- 2026-09-07This recordRenal cell carcinomaFacts on this page last checked
When this page itself was last checked or edited.
- 2026-06-12RegulatoryPembrolizumabPembrolizumab: approval (US)
Adjuvant RCC with belzutifan (LITESPARK-022)
- 2026ApprovalPembrolizumabPembrolizumab approved in US
Platinum-resistant PD-L1+ ovarian cancer; adjuvant RCC with belzutifan; with sacituzumab govitecan in 1L TNBC
- 2026GuidelineRenal cell carcinomaGuideline NCCN Kidney v3.2026: Small renal mass (<4 cm)
Active surveillance, partial nephrectomy (usually robotic), or thermal ablation depending on growth, comorbidity, and biopsy; renal mass biopsy increasingly used. (NCCN 2A)
- 2026MilestoneRenal cell carcinomaLITESPARK-022 positive and approved (adjuvant belzutifan + pembrolizumab); LITESPARK-012 first-line triplet falls short
A milestone in how this cancer is treated.
- 2024Trial resultZIRCONZIRCON reported
Met both co-primary endpoints: mean sensitivity 85.
What is in development for Renal cell carcinoma, drawn from the whole corpus: 10 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.
Drugs in phase 3 · 1
Technologies being tested · 3
Trials under way · 4
- 89Zr-TLX250 for PET/CT Imaging of ccRCC - ZIRCON-CP Study · phase 3 · Telix Pharmaceuticals (Innovations) Pty Limited
- A Study to Assess Safety, Tolerability and Imaging Characteristics of [68Ga]Ga-DPI-4452 and to Assess Safety, Tolerability, and Efficacy of [177Lu]Lu-DPI-4452 in Participants With Unresectable Locally Advanced or Metastatic Solid Tumors · phase 1/2 · Lumara Bio Oncologics GmbH
- A Trial to Find Out if REGN5678 (Nezastomig) is Safe and How Well it Works Alone or in Combination With Cemiplimab for Adult Participants With Metasta · phase 1/2 · Regeneron Pharmaceuticals
- Phase 3 Study to Assess Safety and Efficacy of 177Lu-TLX250 in Advanced Relapsed or Recurrent ccRCC · phase 3 · Telix Pharmaceuticals (Innovations) Pty Limited
Trials reported · 1
- ZIRCON · phase 3 · 2024 · completed
Ideas not yet in a trial · 1
Open problems and what is being done
Non-clear-cell histologies understudied.
No validated predictive biomarker for IO.
No predictive biomarker to choose between IO-IO and IO-TKI, or to identify the 20% who achieve durable remission.
Adjuvant therapy treats many who would never relapse; ctDNA shedding is too low for standard MRD approaches.
What is being done about thisRecurrence and residual diseaseAvailable nowNothing recorded yet.
In trialsIdeas and roadmapsNothing recorded yet.
Also on Nuclide: Indications.
Favourable-risk disease has no proven OS benefit from any first-line combination.
Non-clear-cell histologies lack dedicated phase 3 evidence.
First-line intensification (triplets) has failed twice; the next step in first line is unclear.
Treatment-free survival and de-escalation after deep response are unstudied prospectively.
Toxicity and dose reductions with lenvatinib-pembrolizumab limit real-world durability.
What is being done about thisSide effects and quality of lifeAvailable nowNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Also on Nuclide: Dosimetry.
Small renal mass overtreatment and the absence of a reliable non-invasive diagnostic (CAIX PET awaits approval).
Trials
topTrials recruiting now
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Landmark trials
Direct links plus the targets, companies, and technologies of this cancer's products.
isotopes
1fronts
2technologies
4targets
1drugs
6companies
6institutions
4pathways
1terms
2trials
5ideas
1collections
1opportunities
1key papers
1Latest papers
topQuery for this indication: (TITLE:"Renal cell carcinoma" OR ABSTRACT:"Renal cell carcinoma" OR TITLE:"RCC" OR ABSTRACT:"RCC") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Renal cell carcinoma, not a curated reading list.
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