{"entity":{"id":"rcc","kind":"indication","name":"Renal cell carcinoma","aka":["RCC"],"tldr":"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).\n\nFor 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.\n\nWhat 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.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Renal_cell_carcinoma","links":[{"label":"NCI PDQ: renal cell cancer treatment","url":"https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq"},{"label":"CheckMate 214 8-year follow-up","url":"https://www.annalsofoncology.org/article/S0923-7534(24)01516-3/fulltext"}],"tags":["gu"],"related":["src-urotoday"],"indications":[],"sections":[],"technologies":["caix-pet","radioimmunotherapy"],"targets":[],"drugs":[],"companies":["bms","merck","pfizer","novartis","telix"],"institutions":["mskcc","md-anderson","dana-farber"],"pathways":["hif-vhl"],"terms":["oligometastatic"],"trials":["nct07197580"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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)"],"standardOfCare":[{"setting":"Localised","approach":"Partial/radical nephrectomy or ablation; adjuvant pembrolizumab ± belzutifan for high risk.","refs":["pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Kidney Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440"}},{"setting":"Metastatic","approach":"IO-TKI or IO-IO doublet; belzutifan, cabozantinib, lenvatinib-everolimus later.","refs":["pembrolizumab"],"guideline":{"version":"NCCN Guidelines: Kidney Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440"}},{"setting":"Small renal mass (<4 cm)","approach":"Active surveillance, partial nephrectomy (usually robotic), or thermal ablation depending on growth, comorbidity, and biopsy; renal mass biopsy increasingly used.","refs":[],"guideline":{"nccn":"2A","version":"NCCN Kidney v3.2026"}},{"setting":"Localised T1b-T3","approach":"Partial or radical nephrectomy; no adjuvant therapy for low/intermediate risk.","refs":[],"guideline":{"nccn":"1 (surgery)"}},{"setting":"High-risk after nephrectomy (clear-cell)","approach":"Adjuvant pembrolizumab for 1 year (KEYNOTE-564, OS benefit); pembrolizumab + belzutifan approved 2026 (LITESPARK-022); sunitinib adjuvant rarely used.","refs":["pembrolizumab"],"guideline":{"nccn":"1 (pembrolizumab)","esmoMcbs":"A"}},{"setting":"Metastatic, intermediate/poor risk, first line","approach":"Nivolumab + ipilimumab, or an IO-TKI doublet (pembrolizumab + axitinib, nivolumab + cabozantinib, lenvatinib + pembrolizumab); cytoreductive nephrectomy deferred or omitted (CARMENA) except in selected cases.","refs":["pembrolizumab","cabozantinib"],"guideline":{"nccn":"1 (preferred: all four regimens)","esmoMcbs":"4"}},{"setting":"Metastatic, favourable risk, first line","approach":"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.","refs":["pembrolizumab","cabozantinib","sunitinib"],"guideline":{"nccn":"1 (IO-TKI); 2A (TKI alone)"}},{"setting":"Second line after IO-based therapy","approach":"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).","refs":["cabozantinib","everolimus"],"guideline":{"nccn":"1 (cabozantinib, belzutifan)"}},{"setting":"Oligometastatic / oligoprogressive disease","approach":"Metastasectomy or SBRT to limited sites with continuation of systemic therapy or observation.","refs":[],"guideline":{"nccn":"2A"}},{"setting":"Non-clear-cell RCC","approach":"Cabozantinib (PAPMET), lenvatinib + pembrolizumab (KEYNOTE-B61), or nivolumab + cabozantinib; MET inhibitors for MET-driven papillary; trials preferred.","refs":["cabozantinib","pembrolizumab"],"guideline":{"nccn":"2A"}},{"setting":"VHL disease","approach":"Belzutifan for VHL-associated RCC, CNS haemangioblastoma, and pNET not requiring immediate surgery (LITESPARK-004).","refs":[],"guideline":{"nccn":"1"}}],"stateOfArt":["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."],"history":[{"year":1992,"title":"High-dose IL-2 approved","refs":[]},{"year":1992,"title":"High-dose IL-2 approved: first immunotherapy for RCC, with rare cures","refs":[]},{"year":1993,"title":"VHL gene identified; the molecular basis of clear-cell RCC","refs":[]},{"year":2001,"title":"Cytoreductive nephrectomy improves survival with interferon (SWOG 8949)","refs":[]},{"year":2005,"title":"Sorafenib/sunitinib: VEGF era","refs":[]},{"year":2005,"title":"Sorafenib approved: first VEGF-pathway TKI in RCC","refs":[]},{"year":2006,"title":"Sunitinib approved; replaces interferon","refs":["sunitinib"]},{"year":2009,"title":"Everolimus approved second line (RECORD-1)","refs":["everolimus"]},{"year":2012,"title":"Axitinib approved (AXIS)","refs":[]},{"year":2015,"title":"Nivolumab beats everolimus (CheckMate 025): immunotherapy returns to RCC","refs":[]},{"year":2016,"title":"Cabozantinib approved (METEOR)","refs":["cabozantinib"]},{"year":2018,"title":"Nivolumab-ipilimumab first line","refs":[]},{"year":2018,"title":"Nivolumab-ipilimumab first line (CheckMate 214); CARMENA questions cytoreductive nephrectomy","refs":[]},{"year":2019,"title":"Pembrolizumab-axitinib and avelumab-axitinib: IO-TKI era begins","refs":[]},{"year":2021,"title":"Belzutifan approved","refs":[]},{"year":2021,"title":"Nivolumab-cabozantinib, lenvatinib-pembrolizumab, adjuvant pembrolizumab, belzutifan (VHL), tivozanib approved","refs":[]},{"year":2023,"title":"COSMIC-313 triplet fails on OS; CONTACT-03 closes IO rechallenge; belzutifan approved after IO/TKI (LITESPARK-005); ZIRCON validates CAIX PET","refs":["caix-pet"]},{"year":2024,"title":"KEYNOTE-564 shows OS benefit; CheckMate 214 8-year data; TiNivo-2 negative","refs":[]},{"year":2026,"title":"LITESPARK-022 positive and approved (adjuvant belzutifan + pembrolizumab); LITESPARK-012 first-line triplet falls short","refs":[]}],"pipeline":["caix-pet","idea-caix-theranostics","radioimmunotherapy"],"openProblems":["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)."],"prognosis":{"text":"In the United States, 79.2% of people diagnosed with kidney or renal pelvis cancer in 2016-2022 were alive five years later, relative to people of the same age without the disease. Two thirds (66%) are found while confined to the kidney, often incidentally on a scan for something else, with five-year relative survival of 93.6%; it is 77.6% for regional disease (17% of cases) and 20.3% for distant disease (15% of cases). The distant-stage figure only partly reflects the immunotherapy combinations that became first-line treatment during this period.","sources":[{"label":"SEER Cancer Stat Facts: Kidney and Renal Pelvis Cancer","url":"https://seer.cancer.gov/statfacts/html/kidrp.html"}]}},"route":"/indications/rcc/","neighbours":{"collection":[{"id":"src-urotoday","kind":"collection","name":"UroToday","route":"/collections/src-urotoday/"}],"technology":[{"id":"caix-pet","kind":"technology","name":"CAIX PET (89Zr-girentuximab)","route":"/technologies/caix-pet/"},{"id":"radioimmunotherapy","kind":"technology","name":"Radio-antibody & radio-ADC","route":"/technologies/radioimmunotherapy/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"},{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/"},{"id":"telix","kind":"company","name":"Telix Pharmaceuticals","route":"/companies/telix/"}],"institution":[{"id":"anzup","kind":"institution","name":"ANZUP Cancer Trials Group","route":"/institutions/anzup/"},{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"term":[{"id":"bone-metastases","kind":"term","name":"Bone metastases and skeletal-related events","route":"/terms/bone-metastases/"},{"id":"oligometastatic","kind":"term","name":"Oligometastatic disease","route":"/terms/oligometastatic/"}],"trial":[{"id":"nct06750419","kind":"trial","name":"89Zr-TLX250 for PET/CT Imaging of ccRCC - ZIRCON-CP Study","route":"/trials/nct06750419/"},{"id":"nct05706129","kind":"trial","name":"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","route":"/trials/nct05706129/"},{"id":"nct03972657","kind":"trial","name":"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","route":"/trials/nct03972657/"},{"id":"nct07197580","kind":"trial","name":"Phase 3 Study to Assess Safety and Efficacy of 177Lu-TLX250 in Advanced Relapsed or Recurrent ccRCC","route":"/trials/nct07197580/"},{"id":"zircon","kind":"trial","name":"ZIRCON","route":"/trials/zircon/"}],"drug":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"sorafenib","kind":"drug","name":"Sorafenib","route":"/drugs/sorafenib/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"},{"id":"girentuximab-zr89","kind":"drug","name":"Zirconium-89 girentuximab","route":"/drugs/girentuximab-zr89/"}],"idea":[{"id":"idea-caix-theranostics","kind":"idea","name":"CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy","route":"/ideas/idea-caix-theranostics/"}],"opportunity":[{"id":"opp-caix-indeterminate-renal-mass","kind":"opportunity","name":"CAIX imaging of the indeterminate renal mass","route":"/opportunities/opp-caix-indeterminate-renal-mass/"}],"section":[{"id":"f-bone-targeted","kind":"section","name":"Bone-targeted radiopharmaceuticals","route":"/fronts/f-bone-targeted/"},{"id":"f-molecular-imaging","kind":"section","name":"Molecular imaging","route":"/fronts/f-molecular-imaging/"}],"isotope":[{"id":"zr-89","kind":"isotope","name":"Zirconium-89","route":"/isotopes/zr-89/"}],"paper":[{"id":"paper-zircon-lancet-oncol-2024","kind":"paper","name":"ZIRCON: [89Zr]Zr-girentuximab PET-CT for detecting clear-cell renal cell carcinoma","route":"/key-papers/paper-zircon-lancet-oncol-2024/"}],"target":[{"id":"caix","kind":"target","name":"CAIX (carbonic anhydrase IX)","route":"/targets/caix/"}]}}