{"entity":{"id":"clear-cell-rcc","kind":"cancer","name":"Clear cell renal cell carcinoma","aka":["ccRCC","Conventional renal cell carcinoma"],"tldr":"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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Clear-cell_renal_cell_carcinoma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Clear-cell_renal_cell_carcinoma"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"notes":[],"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"],"standardOfCare":[{"setting":"Small renal mass","approach":"Partial nephrectomy, thermal ablation or active surveillance by size, growth and patient fitness.","refs":["thermal-ablation","cryoablation","active-surveillance"]},{"setting":"Localised, higher risk","approach":"Radical or partial nephrectomy followed by one year of adjuvant pembrolizumab (KEYNOTE-564, overall survival benefit).","refs":["pembrolizumab","keynote-564"]},{"setting":"Metastatic, first line","approach":"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.","refs":["pembrolizumab","axitinib","lenvatinib","nivolumab","cabozantinib","ipilimumab","keynote-426","checkmate-214"]},{"setting":"Later lines","approach":"Cabozantinib, axitinib, belzutifan (LITESPARK-005), lenvatinib plus everolimus, tivozanib.","refs":["cabozantinib","belzutifan","everolimus","hif2a"]},{"setting":"VHL disease","approach":"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.","refs":["belzutifan"]}],"stateOfArt":["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."],"history":[{"year":1993,"title":"VHL gene identified","refs":[]},{"year":2005,"title":"Sorafenib and sunitinib open the anti-angiogenic era","refs":["sunitinib"]},{"year":2015,"title":"Nivolumab beats everolimus after anti-angiogenic therapy (CheckMate 025)","refs":["nivolumab"]},{"year":2018,"title":"Nivolumab plus ipilimumab first line (CheckMate 214)","refs":["checkmate-214"]},{"year":2019,"title":"Pembrolizumab plus axitinib first line (KEYNOTE-426)","refs":["keynote-426"]},{"year":2021,"title":"Belzutifan approved for VHL disease; adjuvant pembrolizumab (KEYNOTE-564)","refs":["belzutifan","keynote-564"]}],"pipeline":["belzutifan","hif2a"],"openProblems":["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."],"parent":"rcc"},"route":"/cancers/clear-cell-rcc/","neighbours":{"drug":[{"id":"axitinib","kind":"drug","name":"Axitinib","route":"/drugs/axitinib/"},{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}],"trial":[{"id":"checkmate-214","kind":"trial","name":"CheckMate 214","route":"/trials/checkmate-214/"},{"id":"keynote-426","kind":"trial","name":"KEYNOTE-426","route":"/trials/keynote-426/"},{"id":"keynote-564","kind":"trial","name":"KEYNOTE-564","route":"/trials/keynote-564/"}],"target":[{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"}],"technology":[{"id":"active-surveillance","kind":"technology","name":"Active surveillance","route":"/technologies/active-surveillance/"},{"id":"thermal-ablation","kind":"technology","name":"Thermal ablation (RFA, microwave, cryo)","route":"/technologies/thermal-ablation/"}],"term":[{"id":"cryoablation","kind":"term","name":"Cryoablation","route":"/terms/cryoablation/"}],"cancer":[{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"}]}}