# Renal cell carcinoma

Source: https://nuclide.cc/indications/rcc/  
Nuclide record `rcc` (Indication). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

Kidney cancer is where anti-angiogenic drugs and immunotherapy came together, and where a Nobel-winning oxygen-sensing pathway yielded a drug, belzutifan.

## Summary

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.

## Fields

- Kind: Indication
- Last checked: 2026-09-07
- Also known as: RCC
- Tags: gu
- Group: genitourinary
- Burden: 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. ~180,000 deaths a year; registry five-year survival for metastatic disease is ~15% overall, higher with modern IO regimens.
- Subtypes: 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)
- Biomarkers: 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)

## Standard of care

- Localised: Partial/radical nephrectomy or ablation; adjuvant pembrolizumab ± belzutifan for high risk. ([Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/))
- Metastatic: IO-TKI or IO-IO doublet; belzutifan, cabozantinib, lenvatinib-everolimus later. ([Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/))
- 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.
- Localised T1b-T3: Partial or radical nephrectomy; no adjuvant therapy for low/intermediate risk.
- High-risk after nephrectomy (clear-cell): Adjuvant pembrolizumab for 1 year (KEYNOTE-564, OS benefit); pembrolizumab + belzutifan approved 2026 (LITESPARK-022); sunitinib adjuvant rarely used. ([Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/))
- Metastatic, intermediate/poor risk, first line: Nivolumab + ipilimumab, or an IO-TKI doublet (pembrolizumab + axitinib, nivolumab + cabozantinib, lenvatinib + pembrolizumab); cytoreductive nephrectomy deferred or omitted (CARMENA) except in selected cases. ([Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/), [Cabozantinib](https://nuclide.cc/drugs/cabozantinib/))
- Metastatic, favourable risk, first line: 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. ([Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/), [Cabozantinib](https://nuclide.cc/drugs/cabozantinib/), [Sunitinib](https://nuclide.cc/drugs/sunitinib/))
- Second line after IO-based therapy: 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). ([Cabozantinib](https://nuclide.cc/drugs/cabozantinib/), [Everolimus](https://nuclide.cc/drugs/everolimus/))
- Oligometastatic / oligoprogressive disease: Metastasectomy or SBRT to limited sites with continuation of systemic therapy or observation.
- Non-clear-cell RCC: Cabozantinib (PAPMET), lenvatinib + pembrolizumab (KEYNOTE-B61), or nivolumab + cabozantinib; MET inhibitors for MET-driven papillary; trials preferred. ([Cabozantinib](https://nuclide.cc/drugs/cabozantinib/), [Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/))
- VHL disease: Belzutifan for VHL-associated RCC, CNS haemangioblastoma, and pNET not requiring immediate surgery (LITESPARK-004).

## State of the art

- Adjuvant immunotherapy with OS benefit.
- HIF-2α inhibition.
- Four immunotherapy-based first-line regimens with survival benefit; durable remissions off treatment in ~20% with nivolumab-ipilimumab at 8 years.
- 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.

## Open problems

- 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.
- 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.
- Small renal mass overtreatment and the absence of a reliable non-invasive diagnostic (CAIX PET awaits approval).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Renal_cell_carcinoma
- NCI PDQ: renal cell cancer treatment: https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq
- CheckMate 214 8-year follow-up: https://www.annalsofoncology.org/article/S0923-7534(24)01516-3/fulltext

## Connected records

- collections: [UroToday](https://nuclide.cc/collections/src-urotoday/)
- technologies: [CAIX PET (89Zr-girentuximab)](https://nuclide.cc/technologies/caix-pet/), [Radio-antibody & radio-ADC](https://nuclide.cc/technologies/radioimmunotherapy/)
- companies: [Bristol Myers Squibb](https://nuclide.cc/companies/bms/), [Merck & Co. (MSD)](https://nuclide.cc/companies/merck/), [Novartis](https://nuclide.cc/companies/novartis/), [Pfizer (incl. Seagen)](https://nuclide.cc/companies/pfizer/), [Telix Pharmaceuticals](https://nuclide.cc/companies/telix/)
- institutions: [ANZUP Cancer Trials Group](https://nuclide.cc/institutions/anzup/), [Dana-Farber Brigham Cancer Center](https://nuclide.cc/institutions/dana-farber/), [MD Anderson Cancer Center](https://nuclide.cc/institutions/md-anderson/), [Memorial Sloan Kettering Cancer Center](https://nuclide.cc/institutions/mskcc/)
- pathways: [VHL / HIF oxygen sensing](https://nuclide.cc/pathways/hif-vhl/)
- terms: [Bone metastases and skeletal-related events](https://nuclide.cc/terms/bone-metastases/), [Oligometastatic disease](https://nuclide.cc/terms/oligometastatic/)
- trials: [89Zr-TLX250 for PET/CT Imaging of ccRCC - ZIRCON-CP Study](https://nuclide.cc/trials/nct06750419/), [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](https://nuclide.cc/trials/nct05706129/), [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](https://nuclide.cc/trials/nct03972657/), [Phase 3 Study to Assess Safety and Efficacy of 177Lu-TLX250 in Advanced Relapsed or Recurrent ccRCC](https://nuclide.cc/trials/nct07197580/), [ZIRCON](https://nuclide.cc/trials/zircon/)
- drugs: [Cabozantinib](https://nuclide.cc/drugs/cabozantinib/), [Everolimus](https://nuclide.cc/drugs/everolimus/), [Pembrolizumab](https://nuclide.cc/drugs/pembrolizumab/), [Sorafenib](https://nuclide.cc/drugs/sorafenib/), [Sunitinib](https://nuclide.cc/drugs/sunitinib/), [Zirconium-89 girentuximab](https://nuclide.cc/drugs/girentuximab-zr89/)
- ideas: [CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy](https://nuclide.cc/ideas/idea-caix-theranostics/)
- opportunities: [CAIX imaging of the indeterminate renal mass](https://nuclide.cc/opportunities/opp-caix-indeterminate-renal-mass/)
- fronts: [Bone-targeted radiopharmaceuticals](https://nuclide.cc/fronts/f-bone-targeted/), [Molecular imaging](https://nuclide.cc/fronts/f-molecular-imaging/)
- isotopes: [Zirconium-89](https://nuclide.cc/isotopes/zr-89/)
- key papers: [ZIRCON: [89Zr]Zr-girentuximab PET-CT for detecting clear-cell renal cell carcinoma](https://nuclide.cc/key-papers/paper-zircon-lancet-oncol-2024/)
- targets: [CAIX (carbonic anhydrase IX)](https://nuclide.cc/targets/caix/)

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