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Kidney (urinary system)

Kidney cancer (renal cell carcinoma)

How the VHL gene, targeted therapy, checkpoint immunotherapy and HIF-2α inhibition shaped care for kidney cancer.

Kidney and renal pelvis cancer · 5-year relative survival · United States, SEER 8 registries

54.61%→81.47%

1975 (observed value; first year in the table) to 2018 (observed value; last observed year in the table). Read these with the caveats under “Then and now”.Source

24 milestones, by decade

  • The von Hippel-Lindau (VHL) disease tumour suppressor gene was reported in Science in 1993: the abstract describes rearrangements in 28 of 221 VHL kindreds and intragenic mutations in cell lines derived from VHL patients and from sporadic renal cell carcinomas. A 1994 Nature Genetics paper analysed tumours from 110 patients with sporadic renal carcinoma and reported VHL mutations in 57% of the clear cell renal carcinomas analysed, with loss of heterozygosity in 98% of those samples. A 1999 Nature paper reported that the VHL protein is needed for oxygen-dependent degradation of the alpha subunits of hypoxia-inducible factor, which are constitutively stabilised in VHL-defective cells. The 2019 Nobel Prize in Physiology or Medicine was shared by Kaelin, Ratcliffe and Semenza, per the Nobel record, "for their discoveries of how cells sense and adapt to oxygen availability". A 2021 phase 2 trial in VHL disease describes belzutifan as an HIF-2α inhibitor, and the FDA approved belzutifan on 13 August 2021 for adults with VHL disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors. Each statement comes from an abstract, the Nobel record or the approval letter; none of these sources itself states a causal chain from the gene to the drug.
  • On the SEER Cancer Stat Facts page for kidney and renal pelvis cancer, the SEER 8 table shows observed 5-year relative survival of 54.61% in 1975 and 81.47% in 2018, age-adjusted incidence of 6.83 and 16.46 per 100,000 in the same two years, and a US age-adjusted death rate that was 3.61 per 100,000 in 1975, 4.34 in 1995 (the highest value in the table) and 3.41 in 2024. These are different series (a limited set of registries, and US mortality data), the category includes renal pelvis cancer and Wilms tumor as well as renal cell carcinoma, and the page assigns the changes to no cause. Survival measured from diagnosis can be affected by earlier detection and case mix, so rising survival beside rising incidence does not by itself show the effect of any treatment.
  • FDA letters read for advanced renal cell carcinoma include sorafenib on 20 December 2005 and sunitinib on 26 January 2006. The sunitinib letter says the advanced renal cell carcinoma approval was accelerated, based on partial response rates and duration of response, and that no randomised trial then showed a clinical benefit such as longer survival or improved symptoms; a supplement letter signed 2 February 2007 states that approval of one of its supplements fulfils commitments made under the accelerated approval regulations (21 CFR 314.510). The same set of letters includes nivolumab after prior anti-angiogenic therapy on 23 November 2015, nivolumab with ipilimumab for previously untreated intermediate or poor risk disease on 16 April 2018, pembrolizumab with axitinib on 19 April 2019, and belzutifan with lenvatinib after a PD-1 or PD-L1 inhibitor on 24 September 2026. These are regulatory actions, not comparisons of the regimens.

Evidence current to October 2026 · Checked against primary sources to the extent possible

A guided tour of 12 milestones. You can pause or step through it yourself.

Filter milestonesshowing all 24
Treatment type
Setting

Chemotherapy

  1. 1963 · Treatment · Surgery⚑ needs reviewRobson and radical nephrectomy for renal cell carcinoma (1963, 1969)Two papers on radical nephrectomy, an operation that removes the kidney, for kidney cancer were published in the Journal of Urology in 1963 and 1969, with C. J. Robson as first author. They are cited here by title only, so their methods and results are not summarised.Robson CJ, J Urol 1963: 'Radical nephrectomy for renal cell carcinoma'; Robson CJ, Churchill BM, Anderson W, J Urol 1969: 'The results of radical nephrectomy for renal cell carcinoma'. Neither PubMed record has an abstract and the text was not available, so no technique, staging or outcome data are reported. PubMed indexes a 2002 reprint of the 1969 paper as a Seminal Article and Historical Article.

Molecular origins

  1. 1992 · Treatment · ImmunotherapyCytokine therapy: high-dose interleukin-2 and interferon alfaBefore targeted drugs, advanced kidney cancer was treated with immune-signalling proteins. High-dose interleukin-2 made tumours shrink in a minority of people, some for a long time, but caused severe side effects and some deaths. In a randomised trial, interferon alfa helped people live somewhat longer than a hormone tablet.High-dose IL-2, seven phase 2 trials (255 assessable patients): ORR 14% (90% CI 10-19%), 12 CRs (5%), 24 PRs (9%); 4% died of possibly or probably treatment-related adverse events. MRC randomised trial (interferon-alpha vs medroxyprogesterone acetate, intention to treat, early results): OS HR 0.72 (95% CI 0.55-0.94; P=0.017); median OS 8.5 vs 6 months; 1-year survival 43% vs 31%.
  2. 1993 · Understanding · UnderstandingThe von Hippel-Lindau tumour suppressor gene is identified (1993)In 1993 researchers reported finding the gene behind von Hippel-Lindau disease, an inherited condition in which people can develop kidney tumours. A year later, a study of 110 people with non-inherited kidney cancer found changes in this gene in more than half of the clear cell tumours examined.Latif 1993 (Science): positional cloning identified the VHL disease tumour suppressor gene; restriction-fragment rearrangements in 28 of 221 VHL kindreds, 18 of them deletions within the candidate gene; intragenic mutations in cell lines from VHL patients and sporadic renal cell carcinomas. Gnarra 1994 (Nat Genet): 110 patients with sporadic renal carcinoma; VHL mutations in 57% of clear cell carcinomas analysed, LOH in 98% of those samples.

Targeted therapy

  1. 1999 · Understanding · UnderstandingpVHL and HIF: oxygen-dependent degradation (1999)In 1999 researchers showed in cell experiments that the protein made by the VHL tumour suppressor gene is needed to break down hypoxia-inducible factor when oxygen is available. In 2019 the Nobel Prize in Physiology or Medicine recognised discoveries on how cells sense oxygen.Maxwell et al., Nature 1999: in VHL-defective cells HIF alpha-subunits were constitutively stabilised and HIF-1 was active; re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitated; the interaction was iron dependent and necessary for oxygen-dependent degradation. Laboratory study; no patient outcomes. Nobel Prize in Physiology or Medicine 2019 to Kaelin, Ratcliffe and Semenza for discoveries on cellular oxygen sensing.
  2. 2001 · Treatment · SurgeryNephrectomy before interferon alfa: two randomised trials (2001)Two randomised trials in the interferon era tested removing the kidney before interferon alfa in people whose kidney cancer had already spread. Both reported longer survival with surgery plus interferon: a median of 11.1 against 8.1 months in one, and 17 against 7 in the other. Both enrolled fewer people than the later CARMENA trial, which revisited the question.Flanigan et al. (NEJM): metastatic RCC, nephrectomy then interferon alfa-2b vs interferon alone; median survival 11.1 months (120 eligible) vs 8.1 months (121 eligible), P=0.05. Mickisch et al. (EORTC Genitourinary Group, ITT): 85 patients, nephrectomy plus interferon-alfa-based immunotherapy vs interferon alone; median time to progression 5 vs 3 months (HR 0.60; 95% CI 0.36-0.97); median survival 17 vs 7 months (HR 0.54; 95% CI 0.31-0.94).
  3. 2005 · Treatment · TargetedSorafenib in previously treated RCC: TARGET and FDA approvalSorafenib, a pill that blocks signals tumours use to grow, was tested against placebo in 903 people whose kidney cancer had stopped responding to standard treatment. The cancer stayed controlled for a median of 5.5 months with sorafenib and 2.8 months with placebo. Diarrhoea, rash and hand-foot skin reactions were common. The FDA approved it in December 2005.TARGET (double-blind phase 3, N=903, RCC resistant to standard therapy): sorafenib 400 mg twice daily vs placebo. At the January 2005 cutoff median PFS was 5.5 vs 2.8 months, HR 0.44 (95% CI 0.35-0.55; P<0.01). First interim OS (May 2005): HR 0.72 (95% CI 0.54-0.94; P=0.02), not significant by the O'Brien-Fleming threshold; crossover from placebo was permitted from May 2005.
  4. 2006 · Treatment · TargetedSunitinib versus interferon alfa as first-line therapy (2006-2007)Sunitinib, a pill that blocks signals tumours use to grow, was compared with the older injected drug interferon alfa in 750 people with untreated, spread kidney cancer. The cancer stayed controlled for a median of about eleven months with sunitinib and five months with interferon, and tumours shrank far more often. The FDA approved sunitinib in January 2006.Randomised phase 3 (N=750), previously untreated metastatic RCC: sunitinib 50 mg (4 weeks on, 2 off) vs interferon alfa 9 MU three times weekly. Primary report: median PFS 11 vs 5 months, HR 0.42 (95% CI 0.32-0.54; P<0.001); ORR 31% vs 6%. Final analysis: median OS 26.4 vs 21.8 months, HR 0.821 (95% CI 0.673-1.001; P=0.051); 33% of the interferon group later received sunitinib.
  5. 2007 · Treatment · TargetedmTOR inhibitors: temsirolimus (ARCC) and everolimus (RECORD-1)Two drugs that block the mTOR growth pathway were tested in kidney cancer. In 626 people with untreated, poor-prognosis disease, weekly temsirolimus was linked to longer survival than interferon alfa (about eleven months against seven). In people whose cancer had progressed on earlier targeted pills, everolimus delayed progression compared with placebo (four months against two).Global ARCC (phase 3, N=626, untreated poor-prognosis): temsirolimus vs interferon alfa, median OS 10.9 vs 7.3 months, HR 0.73 (95% CI 0.58-0.92; P=0.008); temsirolimus plus interferon vs interferon HR 0.96 (95% CI 0.76-1.20; P=0.70). RECORD-1 (double-blind phase 3, ITT, progression on sunitinib and/or sorafenib): everolimus (n=272) vs placebo (n=138), median PFS 4.0 vs 1.9 months, HR 0.30 (95% CI 0.22-0.40; P<0.0001).
  6. 2009 · Treatment · TargetedPazopanib approved (2009); COMPARZ compares it with sunitinibPazopanib, a daily pill, delayed progression compared with placebo in people with advanced kidney cancer (median 9.2 months against 4.2). In a later head-to-head trial of 1,110 people it held the cancer back about as well as sunitinib; side effects and quality-of-life results differed between the two drugs.Placebo-controlled phase 3 (2:1; 435 patients, 54% treatment-naive): median PFS 9.2 vs 4.2 months, HR 0.46 (95% CI 0.34-0.62; P<0.0001); ORR 30% vs 3%. COMPARZ (N=1110, clear-cell, first line, non-inferiority): independently reviewed PFS HR 1.05 (95% CI 0.90-1.22), meeting the margin (upper bound below 1.25); OS HR 0.91 (95% CI 0.76-1.08).
  7. 2010 · Treatment · SurgeryEORTC 30904: nephron-sparing surgery versus radical nephrectomyResearchers randomly assigned 541 people with small kidney tumours to surgery that spares part of the kidney or to removal of the whole kidney. After about nine years, survival was lower with the kidney-sparing operation in the main analysis, though few deaths came from kidney cancer. The trial closed early and did not show non-inferiority for survival.EORTC-GU 30904, randomised noninferiority phase 3, closed early for poor accrual: 541 patients with solitary T1-T2 N0 M0 tumours of 5 cm or less and a normal contralateral kidney; nephron-sparing surgery (n=268) vs radical nephrectomy (n=273). Median follow-up 9.3 years; ITT 10-year OS 75.7% vs 81.1% (HR 1.50; 95% CI 1.03-2.16); noninferiority not shown (p=0.77). 12 of 117 deaths were from renal cancer.

Immunotherapy

  1. 2015 · Treatment · ImmunotherapyCheckMate 025: nivolumab versus everolimus in treated RCC (2015)In people whose kidney cancer had progressed after one or two antiangiogenic treatments, nivolumab was compared with everolimus. Median survival was about five months longer with nivolumab, and more tumours shrank. Progression-free survival was similar. The FDA approved nivolumab for this use in November 2015.CheckMate 025 (phase 3, n=821, clear-cell RCC after 1-2 antiangiogenic regimens): nivolumab 3 mg/kg every 2 weeks vs everolimus 10 mg daily. Median OS 25.0 vs 19.6 months, HR 0.73 (98.5% CI 0.57-0.93), P=0.002; ORR 25% vs 5%; median PFS 4.6 vs 4.4 months, HR 0.88 (0.75-1.03). At median follow-up 72 months: OS HR 0.73 (0.62-0.85), 5-year OS 26% vs 18%. FDA approval 23 November 2015.
  2. 2015 · Treatment · TargetedCabozantinib: METEOR (after VEGF therapy) and CABOSUN (first line)Cabozantinib, a pill that blocks several growth signals including MET and AXL, was tested twice. After earlier VEGF-targeted therapy it delayed progression compared with everolimus (median 7.4 months against 3.8), and later survival data also favoured it. In a smaller randomised phase 2 trial of first-line treatment it was compared with sunitinib.METEOR (open-label phase 3, N=658, progression after VEGFR-targeted therapy): cabozantinib vs everolimus, median PFS 7.4 vs 3.8 months (first 375 patients), HR 0.58 (95% CI 0.45-0.75; P<0.001); final OS 21.4 vs 16.5 months, HR 0.66 (95% CI 0.53-0.83; P=0.00026). CABOSUN (randomised phase 2, N=157, IMDC intermediate/poor risk, first line): cabozantinib vs sunitinib, median PFS 8.2 vs 5.6 months, adjusted HR 0.66 (95% CI 0.46-0.95; one-sided P=0.012).
  3. 2016 · Treatment · TargetedAdjuvant VEGF-TKIs: ASSURE, S-TRAC, PROTECT and SORCESeveral trials tested one to three years of VEGF-blocking tablets after kidney cancer surgery. Sunitinib delayed recurrence in one trial but not in a larger one, and pazopanib and sorafenib showed no clear benefit. Many people stopped treatment early because of side effects. The US approved sunitinib for this use in 2017.Adjuvant VEGF-TKI vs placebo after nephrectomy. S-TRAC (n=615, clear cell, central-review DFS): median 6.8 vs 5.6 years, HR 0.76 (95% CI 0.59-0.98; P=0.03). ASSURE (n=1943): sunitinib HR 1.02, sorafenib HR 0.97 (97.5% CI); no DFS benefit. PROTECT (pazopanib 600 mg): HR 0.86 (95% CI 0.70-1.06); final OS HR 1.0. SORCE (sorafenib 3 years): HR 1.01 (95% CI 0.83-1.23).
  4. 2018 · Treatment · ImmunotherapyCheckMate 214: nivolumab plus ipilimumab versus sunitinib (2018)In people with previously untreated advanced clear cell kidney cancer, nivolumab plus ipilimumab was compared with sunitinib. In the intermediate- and poor-risk group, survival and response rates were higher with the combination. Follow-up now exceeds nine years. The FDA approved the combination for that risk group in April 2018.CheckMate 214 (phase 3, n=1096; intermediate/poor risk 425 vs 422): OS HR 0.63 (99.8% CI 0.44-0.89), 18-month OS 75% vs 60%; ORR 42% vs 27%; median PFS 11.6 vs 8.4 months, HR 0.82, P=0.03 (not significant at the 0.009 threshold). At 9.3 years' median follow-up, OS HR 0.69 (0.59-0.81); 108-month OS 30.2% vs 18.7%. FDA approval 16 April 2018, intermediate/poor risk.
  5. 2018 · Reversal · SurgeryCARMENA and SURTIME question upfront cytoreductive nephrectomyFor about twenty years, removing the kidney was standard for people whose kidney cancer had already spread. In CARMENA, sunitinib alone was found not inferior to surgery first for survival (a median of about eighteen months against fourteen). A smaller trial, SURTIME, found no difference in early progression between operating first or after sunitinib.CARMENA (phase 3, 450 patients, clear cell, MSKCC intermediate/poor risk): sunitinib alone was noninferior to nephrectomy then sunitinib for OS at a planned interim analysis, stratified HR 0.89 (95% CI 0.71-1.10; non-inferiority bound 1.20 or less); median OS 18.4 vs 13.9 months. SURTIME (99 patients): 28-week progression-free rate 42% vs 43% (immediate vs deferred nephrectomy), P=0.61; OS HR 0.57 (95% CI 0.34-0.95), a secondary end point.
  6. 2019 · Treatment · ImmunotherapyKEYNOTE-426: pembrolizumab plus axitinib versus sunitinib (2019)In untreated advanced clear cell kidney cancer, pembrolizumab plus axitinib was compared with sunitinib. At the first planned analysis, more people were alive at 12 months, the cancer took longer to progress and more tumours shrank. Follow-up has continued beyond five years. The FDA approved the combination in April 2019.KEYNOTE-426 (phase 3, n=861, ITT): pembrolizumab plus axitinib vs sunitinib. First interim analysis (median follow-up 12.8 months): 12-month OS 89.9% vs 78.3%, HR 0.53 (95% CI 0.38-0.74); median PFS 15.1 vs 11.1 months, HR 0.69 (0.57-0.84); ORR 59.3% vs 35.7%. At 30.6 months: OS HR 0.68 (0.55-0.85). With at least 5 years of follow-up: OS HR 0.84 (0.71-0.99). FDA approval 19 April 2019.

Precision & engineered

  1. 2021 · Treatment · ImmunotherapyKEYNOTE-564: adjuvant pembrolizumab after nephrectomy (2021)After kidney cancer surgery, people at high risk of recurrence received the immunotherapy pembrolizumab or a placebo for about a year. About 77 in 100 on pembrolizumab and 68 in 100 on placebo were free of recurrence at two years. A later report found longer overall survival with pembrolizumab. Side effects were more frequent.Phase 3, double-blind; clear-cell RCC at high recurrence risk after nephrectomy with or without metastasectomy; pembrolizumab 200 mg every 3 weeks for up to 17 cycles (n=496) vs placebo (n=498). Investigator-assessed DFS at 24 months 77.3% vs 68.1% (HR 0.68; 95% CI 0.53-0.87; P=0.002). Update, median follow-up 57.2 months: OS HR 0.62 (95% CI 0.44-0.87; P=0.005); 48-month OS 91.2% vs 86.0%.
  2. 2021 · Treatment · TargetedBelzutifan for VHL disease-associated tumours (LITESPARK-004)Belzutifan, a tablet that blocks a protein called HIF-2 alpha, was tested in people with von Hippel-Lindau disease, an inherited condition with a high risk of kidney cancer. About half of the participants had a measurable kidney tumour response in the first report, and about two thirds at roughly four years of follow-up. The FDA approved it in August 2021.LITESPARK-004 (single-arm phase 2, 61 patients with VHL disease-associated RCC): belzutifan 120 mg daily; ORR 49% (95% CI 36-62) at median follow-up 21.8 months by independent review. At 49.9 months, ORR 67% (95% CI 54-79), complete responses 11%; grade 3 treatment-related events 18%, none grade 4-5. FDA approval 13 August 2021 for VHL disease needing therapy for RCC, CNS haemangioblastomas or pNET.
  3. 2021 · Treatment · ImmunotherapyCheckMate 9ER: nivolumab plus cabozantinib versus sunitinib (2021)In untreated advanced clear cell kidney cancer, nivolumab plus cabozantinib was compared with sunitinib. Cancer took about twice as long to progress (16.6 versus 8.3 months), more tumours shrank, and survival was longer in the first report and in the final analysis. The FDA approved the combination in January 2021.CheckMate 9ER (phase 3, open-label, 651 randomised, ITT): nivolumab 240 mg every 2 weeks plus cabozantinib 40 mg daily vs sunitinib. Median PFS 16.6 vs 8.3 months, HR 0.51 (95% CI 0.41-0.64); 12-month OS 85.7% vs 75.6%, HR 0.60 (98.89% CI 0.40-0.89); ORR 55.7% vs 27.1%. Final OS (median follow-up 32.9 months): median 37.7 vs 34.3 months, HR 0.70 (0.55-0.90). FDA approval 22 January 2021.
  4. 2021 · Treatment · ImmunotherapyCLEAR: lenvatinib plus pembrolizumab versus sunitinib (2021)In untreated advanced kidney cancer, lenvatinib plus pembrolizumab and lenvatinib plus everolimus were each compared with sunitinib. The cancer took about 15 months longer to progress with lenvatinib plus pembrolizumab, and the risk of death was lower in the first report and in the final survival analysis. The FDA approved this combination in August 2021.CLEAR (phase 3, n=1069): lenvatinib plus pembrolizumab vs sunitinib: median PFS 23.9 vs 9.2 months, HR 0.39 (95% CI 0.32-0.49); OS HR 0.66 (0.49-0.88). Lenvatinib plus everolimus: median PFS 14.7 months, HR 0.65 (0.53-0.80); OS HR 1.15 (0.88-1.50). Final OS (cutoff 31 July 2022): HR 0.79 (0.63-0.99); medians 53.7 vs 54.3 months. FDA approval of the pembrolizumab combination 10 August 2021.
  5. 2022 · Reversal · Immunotherapy⚑ needs reviewAdjuvant checkpoint trials: IMmotion010, CheckMate 914, PROSPERThree trials tested immunotherapy around kidney cancer surgery: atezolizumab, nivolumab with ipilimumab, and perioperative nivolumab. None lengthened the time free of recurrence compared with placebo or surgery alone, and the nivolumab trial stopped early for futility. Side effects were more frequent with immunotherapy.Three phase 3 trials, none showing a primary-endpoint benefit. IMmotion010 (atezolizumab vs placebo, n=778): investigator-assessed DFS HR 0.93 (95% CI 0.75-1.15; P=0.50). CheckMate 914 part A (nivolumab plus ipilimumab vs placebo, n=816): central-review DFS HR 0.92 (95% CI 0.71-1.19; P=0.53). PROSPER EA8143 (perioperative nivolumab vs surgery only, n=819, open-label): RFS HR 0.94 (95% CI 0.74-1.21; one-sided P=0.32); stopped for futility.
  6. 2023 · Treatment · Targeted⚑ needs reviewLITESPARK-005: belzutifan versus everolimus after ICI and TKI (2023)Belzutifan was compared with everolimus in people whose kidney cancer had progressed after both an immunotherapy and an antiangiogenic drug. Median time without progression was the same (5.6 months), but more people were progression-free at 18 months and more tumours shrank. Survival did not differ significantly. The FDA approved belzutifan in December 2023.LITESPARK-005 (phase 3, open-label, n=746) after checkpoint-inhibitor and antiangiogenic therapy: belzutifan 120 mg vs everolimus 10 mg daily. First interim analysis (median follow-up 18.4 months): median PFS 5.6 months in both arms; 18-month PFS 24.0% vs 8.3%; ORR 21.9% vs 3.5%. FDA page: PFS HR 0.75 (95% CI 0.63-0.90). OS at second interim: 21.4 vs 18.1 months, HR 0.88 (0.73-1.07), not significant. FDA approval 14 December 2023.
  7. 2026 · Treatment · Targeted⚑ needs reviewLITESPARK-011: belzutifan plus lenvatinib versus cabozantinib (2026)After immunotherapy, people with advanced clear cell kidney cancer received belzutifan plus lenvatinib or cabozantinib. Median time without progression was 14.8 versus 10.7 months in the published analysis. Survival was not significantly different. The FDA approved the combination in September 2026.LITESPARK-011 (phase 3, open-label, n=747) after anti-PD-1/PD-L1 therapy: belzutifan 120 mg plus lenvatinib 20 mg vs cabozantinib 60 mg daily. Second interim analysis (median follow-up 29.0 months): median PFS 14.8 vs 10.7 months, HR 0.70 (95% CI 0.59-0.84); OS 34.9 vs 27.6 months, HR 0.85 (0.68-1.05), not significant. FDA page: ORR 53% vs 40%; final OS HR 0.85 (0.70-1.03), not significant. FDA approval 24 September 2026.
  8. 2026 · Treatment · TargetedLITESPARK-022: adjuvant belzutifan added to pembrolizumab (2026)After kidney cancer surgery, everyone received pembrolizumab, and half also took belzutifan tablets for up to a year. At two years, about 81 in 100 on the combination and 74 in 100 on pembrolizumab alone were free of recurrence. Serious side effects were more common with belzutifan. Survival data were still too early to compare.Phase 3, double-blind; clear-cell RCC at increased recurrence risk after nephrectomy; pembrolizumab 400 mg every 6 weeks plus belzutifan 120 mg daily (n=921) vs pembrolizumab plus placebo (n=920), up to 1 year. Interim analysis, median 28.4 months: investigator-assessed DFS HR 0.72 (95% CI 0.59-0.87; P<0.001); 24-month DFS 80.7% vs 73.7%. OS HR 0.78 (95% CI 0.51-1.19) with 29% of events; grade 3 or higher adverse events 52.1% vs 30.2%.

Then and now

  • 5-year relative survival · United States, SEER 8 registries

    • 54.61%

      1975 (observed value; first year in the table)

    All races, both sexes; SEER Cancer Stat Facts category 'kidney and renal pelvis cancer', all stages together; the SEER 8 five-year relative survival series (1975-2018). The page defines the category as renal cell carcinoma, renal pelvis carcinoma (urine-collecting system) and Wilms tumor, so the series is not renal cell carcinoma alone; age range, histology mix and the stage mix over time are not stated for this series.

    Modeled trend value for 1975: 49.24%. The observed series moves from year to year (lowest 48.28% in 1977, highest 81.47% in 2018). Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only 'SEER 8 5-Year Relative Survival Percent from 1975-2018'; the page does not say the year is the year of diagnosis. SEER 8 covers a limited set of registries. Survival measured from diagnosis can change through earlier detection (lead time) and through changes in case mix as well as through treatment, and the page does not apportion the change between such factors; read it beside the incidence and mortality values. Compare only with other values from this same SEER 8 series, not with the SEER 21 values. SEER 8 age-adjusted incidence per 100,000 was 6.83 in 1975 and 16.46 in 2018 (observed).

    Source

  • 5-year relative survival · United States, SEER 8 registries

    • 81.47%

      2018 (observed value; last observed year in the table)

    All races, both sexes; SEER Cancer Stat Facts category 'kidney and renal pelvis cancer', all stages together; the SEER 8 five-year relative survival series (1975-2018). The page defines the category as renal cell carcinoma, renal pelvis carcinoma (urine-collecting system) and Wilms tumor, so the series is not renal cell carcinoma alone; age range, histology mix and the stage mix over time are not stated for this series.

    Modeled trend value for 2018: 80.49%; the table shows no observed five-year value for 2019 onward (modeled trend values are listed to 2023: 82.79%). Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only 'SEER 8 5-Year Relative Survival Percent from 1975-2018'; the page does not say the year is the year of diagnosis. SEER 8 covers a limited set of registries. Survival measured from diagnosis can change through earlier detection (lead time) and through changes in case mix as well as through treatment, and the page does not apportion the change between such factors; read it beside the incidence and mortality values. Compare only with other values from this same SEER 8 series, not with the SEER 21 values.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 79.2%

      2016-2022

    All races, both sexes; kidney and renal pelvis cancer, all stages combined (SEER 21 excluding IL, 2016-2022, as shown in the page headline). The category includes renal pelvis carcinoma and Wilms tumor as well as renal cell carcinoma.

    A different registry set and period from the SEER 8 series above; do not chain or subtract them. Relative survival excludes deaths from other causes.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 93.6%

      2016-2022; localized stage at diagnosis (66% of cases)

    All races, both sexes; kidney and renal pelvis cancer, SEER Combined Summary Stage 'localized' (confined to the primary site).

    SEER summary stage, not AJCC TNM or histology. Same SEER 21 series as the all-stages value; the page text gives 65.6% of cases as localized and shows 66% in its stage table.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 77.6%

      2016-2022; regional stage at diagnosis (17% of cases)

    All races, both sexes; kidney and renal pelvis cancer, SEER Combined Summary Stage 'regional' (spread to regional lymph nodes).

    SEER summary stage, not AJCC TNM or histology. Same SEER 21 series as the all-stages value.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 20.3%

      2016-2022; distant stage at diagnosis (15% of cases)

    All races, both sexes; kidney and renal pelvis cancer, SEER Combined Summary Stage 'distant' (cancer has metastasized).

    SEER summary stage, not AJCC TNM or histology. Same SEER 21 series as the all-stages value; unknown stage (3% of cases) is shown by the page as 55.2%. The page does not say whether 2016-2022 refers to years of diagnosis; if it does, follow-up for the later years is short. The page gives no breakdown by treatment, so the figure cannot be read against any single regimen.

    Source

  • Age-standardised mortality · United States (U.S. Mortality data shown on the SEER page; not a SEER registry series)

    • 3.61per 100,000

      1975 (observed value; first year in the table)

    All races, both sexes; kidney and renal pelvis cancer deaths; age-adjusted rate per 100,000 (the page text read does not name the standard population).

    Death-rate series 1975-2024, observed; modeled trend value for 1975: 3.54. Mortality depends on incidence as well as survival: SEER 8 incidence per 100,000 was 6.83 in 1975 and 16.46 in 2018 (observed), and the page states that new diagnoses are rising while deaths have remained steady. Shown beside the survival series.

    Source

  • Age-standardised mortality · United States (U.S. Mortality data shown on the SEER page; not a SEER registry series)

    • 4.34per 100,000

      1995 (observed value; highest value in the 1975-2024 table)

    All races, both sexes; kidney and renal pelvis cancer deaths; age-adjusted rate per 100,000 (the page text read does not name the standard population).

    Modeled trend value for 1995: 4.24. Other observed values include 4.30 in 1991, 4.22 in 2000, 4.02 in 2007 and 3.99 in 2008. Deaths by site depend on cause-of-death coding, which the page does not discuss.

    Source

  • Age-standardised mortality · United States (U.S. Mortality data shown on the SEER page; not a SEER registry series)

    • 3.41per 100,000

      2024 (observed value; last year in the table)

    All races, both sexes; kidney and renal pelvis cancer deaths; age-adjusted rate per 100,000 (the page text read does not name the standard population).

    Modeled trend value for 2024: 3.37; the lowest observed value in the table is 3.39 (2023). The page text reports that age-adjusted death rates have been falling on average 1.1% each year over 2015-2024 and new cases rising on average 0.7% each year over 2014-2023, and gives 3.4 per 100,000 for 2020-2024 deaths and 18.0 per 100,000 for new cases (2019-2023, a different registry basis from the SEER 8 table). The page attributes the pattern to no cause.

    Source

Survival figures are affected by earlier detection (lead time) and overdiagnosis, and by changes in who is diagnosed. For screened cancers, read them alongside mortality.

Evidence chains

A lane follows one defined population and setting, where each new trial tests against what was then standard. Compare only within a lane, and read every comparison as illustrative.

Metastatic clear cell, first line

Adults with previously untreated advanced or metastatic renal cell carcinoma (clear cell in most of these trials) · Metastatic · endpoint: PFS

Results are not comparable across trials.

Eras, comparators and populations differ. The 2006 trial used interferon alfa as the control; the later trials used sunitinib. CheckMate 214's figure is for the intermediate- and poor-risk group, and CABOSUN (a randomised phase 2 trial) enrolled only intermediate- and poor-risk patients, while the other figures are for all randomised patients. The figures are median PFS from each trial's reported analysis (interim for KEYNOTE-426, primary for the others), and review methods and follow-up differ. COMPARZ (pazopanib versus sunitinib, a non-inferiority trial) reported a hazard ratio without medians, so it is listed but not drawn; the placebo-controlled pazopanib trial mixed untreated and cytokine-pretreated patients and is not part of this lane. Compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

051015202530PFS, median (months)200620152018201920212021sunitinib-vs-interferon-rccCABOSUNCheckMate 214KEYNOTE-426CLEARCheckMate 9ER
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 6 trials in this lane. sunitinib-vs-interferon-rcc (2006): experimental 11 months vs control 5 months; CABOSUN (2015): experimental 8.2 months vs control 5.6 months; CheckMate 214 (2018): experimental 11.6 months vs control 8.4 months; KEYNOTE-426 (2019): experimental 15.1 months vs control 11.1 months; CLEAR (2021): experimental 23.9 months vs control 9.2 months; CheckMate 9ER (2021): experimental 16.6 months vs control 8.3 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
sunitinib-vs-interferon-rcc2006PFS5 months11 months
CABOSUN2015PFS5.6 months8.2 months
CheckMate 2142018PFS8.4 months11.6 months
KEYNOTE-4262019PFS11.1 months15.1 months
CLEAR2021PFS9.2 months23.9 months
CheckMate 9ER2021PFS8.3 months16.6 months

Metastatic clear cell, after earlier systemic therapy

Adults with advanced renal cell carcinoma whose disease progressed after VEGF-targeted therapy (RECORD-1, METEOR, CheckMate 025) or after both a checkpoint inhibitor and a VEGF-targeted drug (LITESPARK-005) · Metastatic · endpoint: PFS

Results are not comparable across trials.

Earlier treatment differs: RECORD-1 enrolled people whose disease progressed on sunitinib, sorafenib or both; METEOR and CheckMate 025 enrolled people after VEGF-targeted therapy (CheckMate 025 after one or two antiangiogenic regimens); LITESPARK-005 enrolled people after a checkpoint inhibitor and a VEGF-targeted drug. The control was placebo in RECORD-1 and everolimus in the other three trials. METEOR's figure is for its first 375 randomised patients; RECORD-1 and LITESPARK-005 figures are from interim analyses; LITESPARK-005 is marked for clinical review because the paper was not available in full. Review methods and follow-up differ, so compare only each trial's own two arms. The ARCC temsirolimus trial (untreated, poor-prognosis disease against interferon alfa, with overall survival as its endpoint) and the first-line CABOSUN trial are not part of this lane.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

0246810PFS, median (months)2007201520152023RECORD-1CheckMate 025METEORLITESPARK-005
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 4 trials in this lane. RECORD-1 (2007): experimental 4 months vs control 1.9 months; CheckMate 025 (2015): experimental 4.6 months vs control 4.4 months; METEOR (2015): experimental 7.4 months vs control 3.8 months; LITESPARK-005 (2023): experimental 5.6 months vs control 5.6 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
RECORD-12007PFS1.9 months4 months
CheckMate 0252015PFS4.4 months4.6 months
METEOR2015PFS3.8 months7.4 months
LITESPARK-0052023PFS5.6 months5.6 months

Metastatic clear cell, after anti-PD-1/PD-L1 therapy, cabozantinib as comparator

Adults with advanced clear cell renal cell carcinoma whose disease progressed after anti-PD-1 or anti-PD-L1 therapy · Metastatic · endpoint: PFS

Results are not comparable across trials.

This lane holds one trial, whose control arm was cabozantinib, so its figures are not comparable with the everolimus-controlled trials in the other later-line lane, which had different earlier treatment, eras and comparators. The figure is the median PFS from the published second interim analysis (not the FDA page figures); the paper was not available in full and the record is marked for clinical review. Compare only the trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

05101520PFS, median (months)2026LITESPARK-011
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 1 trial in this lane. LITESPARK-011 (2026): experimental 14.8 months vs control 10.7 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
LITESPARK-0112026PFS10.7 months14.8 months

Metastatic, surgery to remove the kidney with the primary tumour in place

Adults with metastatic renal cell carcinoma and the primary tumour still in place, considered candidates for nephrectomy · Metastatic · endpoint: OS

Results are not comparable across trials.

The questions are mirror images. In the 2001 interferon-era trial, nephrectomy plus interferon alfa was the experimental arm against interferon alone. In CARMENA, nephrectomy followed by sunitinib was the control and sunitinib alone was the experimental arm, tested for non-inferiority, at a planned interim analysis. Systemic drugs, eras and risk groups differ (CARMENA enrolled MSKCC intermediate- and poor-risk patients). The chart draws one result per milestone: the Flanigan trial for the interferon-era milestone (a second trial, the EORTC one, is described in the milestone) and CARMENA for the second. SURTIME's primary endpoint was a 28-week progression-free rate, a different measure, so it is not plotted; its overall survival result was exploratory in an underpowered trial. Compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

0510152025OS, median (months)20012018nephrectomy-ifn-flanigan-2001CARMENA
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
OS, median, across 2 trials in this lane. nephrectomy-ifn-flanigan-2001 (2001): experimental 11.1 months vs control 8.1 months; CARMENA (2018): experimental 18.4 months vs control 13.9 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
nephrectomy-ifn-flanigan-20012001OS8.1 months11.1 months
CARMENA2018OS13.9 months18.4 months

Adjuvant therapy after nephrectomy

Adults at increased risk of recurrence after nephrectomy for renal cell carcinoma (clear cell in most of these trials) · Adjuvant · endpoint: DFS

Results are not comparable across trials.

Populations, DFS definitions and assessors differ (for example investigator versus central review), and ASSURE also enrolled non-clear-cell tumours. ASSURE and IMmotion010 report median DFS; KEYNOTE-564 and LITESPARK-022 report the percentage disease-free at 24 months, a different measure that the chart lists but does not place on the same axis. LITESPARK-022's control arm received pembrolizumab with placebo, so it asks what belzutifan adds to pembrolizumab and is not comparable with the placebo-controlled trials. The chart draws one result per milestone: ASSURE (sunitinib against placebo) for the VEGF-TKI milestone, and IMmotion010 for the checkpoint-negative milestone. S-TRAC, PROTECT, SORCE, CheckMate 914 (no median for the nivolumab arm) and PROSPER (relapse-free survival, record marked for clinical review) are described in the milestones but not drawn. Compare only each trial's own two arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080DFS, median (months)20162022ASSUREIMmotion010
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
DFS, median, across 2 trials in this lane. ASSURE (2016): experimental 69.6 months vs control 79.19999999999999 months; IMmotion010 (2022): experimental 57.2 months vs control 49.5 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
ASSURE2016DFS79.19999999999999 months69.6 months
IMmotion0102022DFS49.5 months57.2 months
KEYNOTE-5642021DFS (not plotted: different measure or time point)68.1 %77.3 %
LITESPARK-0222026DFS (not plotted: different measure or time point)73.7 %80.7 %

Standard of care, then and now

How the usual sequence of treatment changed for one setting. Choose a point in time; each step links to the milestone behind it.

Metastatic kidney cancer: lines of treatment

Adults with advanced or metastatic renal cell carcinoma (clear cell in most of the cited trials) · Metastatic

  1. Immunotherapy11st line: nivolumab + ipilimumabCheckMate 214: nivolumab plus ipilimumab versus sunitinib (2018) (2018)
  2. Immunotherapy21st line: pembrolizumab + axitinibKEYNOTE-426: pembrolizumab plus axitinib versus sunitinib (2019) (2019)
  3. Immunotherapy31st line: lenvatinib + pembrolizumabCLEAR: lenvatinib plus pembrolizumab versus sunitinib (2021) (2021)
  4. Immunotherapy41st line: nivolumab + cabozantinibCheckMate 9ER: nivolumab plus cabozantinib versus sunitinib (2021) (2021)
  5. Targeted5After ICI and TKI: belzutifanLITESPARK-005: belzutifan versus everolimus after ICI and TKI (2023) (2023)
  6. Targeted6After anti-PD-1: belzutifan + lenvatinibLITESPARK-011: belzutifan plus lenvatinib versus cabozantinib (2026) (2026)
  7. Surgery7Upfront nephrectomy tested vs sunitinibCARMENA and SURTIME question upfront cytoreductive nephrectomy (2018)
Today. Based only on the trials cited in each step. Combination regimens were tested in untreated disease, and belzutifan-based treatment after immunotherapy; the FDA actions are listed in the milestones.
Text version
  • 2002: Interferon alfa or high-dose IL-2 → Nephrectomy plus interferon alfa
  • 2010: Nephrectomy plus interferon alfa → 1st line: sunitinib → 1st line: pazopanib → After cytokines: sorafenib → After a VEGF-targeted drug: everolimus
  • 2019: Upfront nephrectomy tested vs sunitinib → 1st line: sunitinib → 1st line: pazopanib → 1st line: nivolumab + ipilimumab → 1st line: pembrolizumab + axitinib → After a VEGF-targeted drug: cabozantinib → After a VEGF-targeted drug: nivolumab
  • Today: 1st line: nivolumab + ipilimumab → 1st line: pembrolizumab + axitinib → 1st line: lenvatinib + pembrolizumab → 1st line: nivolumab + cabozantinib → After ICI and TKI: belzutifan → After anti-PD-1: belzutifan + lenvatinib → Upfront nephrectomy tested vs sunitinib

Adjuvant treatment after nephrectomy

Adults at increased risk of recurrence after nephrectomy for renal cell carcinoma · Adjuvant

  1. Immunotherapy1Adjuvant pembrolizumabKEYNOTE-564: adjuvant pembrolizumab after nephrectomy (2021) (2021)
  2. Targeted2Pembrolizumab + belzutifanLITESPARK-022: adjuvant belzutifan added to pembrolizumab (2026) (2026)
Today. Based only on the trials cited in each step. Belzutifan added to pembrolizumab was compared with pembrolizumab plus placebo; the FDA action is listed in the milestone.
Text version
  • 2016: VEGF-TKIs after surgery: mixed results
  • 2022: VEGF-TKIs after surgery: mixed results → Adjuvant pembrolizumab → Other adjuvant ICI trials: negative
  • Today: Adjuvant pembrolizumab → Pembrolizumab + belzutifan

Reversals and dead ends

Approaches that were abandoned or withdrawn, and trials whose results were later questioned, are part of the story.

  • 2018

    CARMENA and SURTIME question upfront cytoreductive nephrectomy

    For about twenty years, removing the kidney was standard for people whose kidney cancer had already spread. In CARMENA, sunitinib alone was found not inferior to surgery first for survival (a median of about eighteen months against fourteen). A smaller trial, SURTIME, found no difference in early progression between operating first or after sunitinib.

    CARMENA (phase 3, 450 patients, clear cell, MSKCC intermediate/poor risk): sunitinib alone was noninferior to nephrectomy then sunitinib for OS at a planned interim analysis, stratified HR 0.89 (95% CI 0.71-1.10; non-inferiority bound 1.20 or less); median OS 18.4 vs 13.9 months. SURTIME (99 patients): 28-week progression-free rate 42% vs 43% (immediate vs deferred nephrectomy), P=0.61; OS HR 0.57 (95% CI 0.34-0.95), a secondary end point.

  • 2022

    Adjuvant checkpoint trials: IMmotion010, CheckMate 914, PROSPER

    Three trials tested immunotherapy around kidney cancer surgery: atezolizumab, nivolumab with ipilimumab, and perioperative nivolumab. None lengthened the time free of recurrence compared with placebo or surgery alone, and the nivolumab trial stopped early for futility. Side effects were more frequent with immunotherapy.

    Three phase 3 trials, none showing a primary-endpoint benefit. IMmotion010 (atezolizumab vs placebo, n=778): investigator-assessed DFS HR 0.93 (95% CI 0.75-1.15; P=0.50). CheckMate 914 part A (nivolumab plus ipilimumab vs placebo, n=816): central-review DFS HR 0.92 (95% CI 0.71-1.19; P=0.53). PROSPER EA8143 (perioperative nivolumab vs surgery only, n=819, open-label): RFS HR 0.94 (95% CI 0.74-1.21; one-sided P=0.32); stopped for futility.

Today and tomorrow

Standard of care today

Localised

Randomised evidence read for surgery in small tumours:

  • EORTC 30904 randomised 541 patients with small (5 cm or less), solitary tumours suspicious for renal cell carcinoma and a normal contralateral kidney, between March 1992 and January 2003, to nephron-sparing surgery (268) or radical nephrectomy (273)
  • the trial closed early because of poor accrual. In the abstract's intention-to-treat analysis, 10-year overall survival was 81.1% with radical nephrectomy and 75.7% with nephron-sparing surgery (hazard ratio 1.50, 95% CI 1.03 to 2.16)
  • the noninferiority test was not significant (p=0.77) and the superiority test was significant (p=0.03). In patients with renal cell carcinoma the hazard ratio was 1.43 and in clinically and pathologically eligible patients 1.34, with superiority tests no longer significant (p=0.07 and p=0.17)
  • only 12 of 117 deaths were from renal cancer, and the authors note that quality of life and renal function were not addressed. No FDA or EMA action is cited for this setting. EAU 2025 (PMID 40118739), ESMO 2024 (PMID 38788900) and the NCCN Guidelines Insights, Kidney Cancer, version 2.2024 (PMID 38394781) are guideline papers. Guideline texts were not opened
  • the papers are cited by identifier only and no recommendation is attributed to them (whether these are the current editions was not checked)
Van Poppel H, Da Pozzo L, Albrecht W, Matveev V, Bono A, Borkowski A, et al 2011Guideline: Bex A, Ghanem YA, Albiges L, Bonn S, Campi R, Capitanio U, et al 2025Guideline: Powles T, Albiges L, Bex A, Comperat E, Grünwald V, Kanesvaran R, et al 2024Guideline: Motzer RJ, Jonasch E, Agarwal N, Alva A, Bagshaw H, Baine M, et al 2024
Adjuvant

Renal cell carcinoma after nephrectomy. FDA letters read:

  • sunitinib on 16 November 2017 (adjuvant treatment of adults at high risk of recurrent renal cell carcinoma following nephrectomy)
  • pembrolizumab on 17 November 2021 (adjuvant treatment of patients with renal cell carcinoma at intermediate high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions)
  • and belzutifan in combination with pembrolizumab or with pembrolizumab and berahyaluronidase alfa on 12 June 2026 (adjuvant treatment of adults with clear cell renal cell carcinoma at intermediate-high or high risk of recurrence, based on Interim Analysis 1 of LITESPARK-022 according to the letter). The subcutaneous product Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) was approved on 19 September 2025 with renal cell carcinoma indications that include adjuvant treatment of adults at intermediate-high or high risk of recurrence following nephrectomy or nephrectomy and resection of metastatic lesions, and a Keytruda Qlex supplement letter of 12 June 2026 adds adjuvant use in combination with belzutifan. EMA: the Keytruda product page (read 21 October 2026) lists pembrolizumab monotherapy for adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy or nephrectomy and resection of metastatic lesions
  • the Welireg page read the same day lists no adjuvant indication. Three further adjuvant trials (atezolizumab, nivolumab with ipilimumab, and perioperative nivolumab) appear in the milestone timeline
  • no regulatory document for them was opened. ESMO 2024 (PMID 38788900), EAU 2025 (PMID 40118739) and SITC version 3.0 (J Immunother Cancer 2026, PMID 41871874) are guideline papers. Guideline texts were not opened
  • the papers are cited by identifier only and no recommendation is attributed to them (whether these are the current editions was not checked)
FDA 2017FDA 2021FDA 2026FDA 2025FDA 2026European Medicines Agency 2026European Medicines Agency 2026Guideline: Powles T, Albiges L, Bex A, Comperat E, Grünwald V, Kanesvaran R, et al 2024Guideline: Bex A, Ghanem YA, Albiges L, Bonn S, Campi R, Capitanio U, et al 2025Guideline: McKay RR, Ajmera A, Atkins MB, Barata PC, Bergerot C, Bukavina L, et al 2026
Metastatic

First-line treatment of advanced renal cell carcinoma. FDA letters read:

  • nivolumab with ipilimumab on 16 April 2018 (intermediate or poor risk, previously untreated advanced disease)
  • pembrolizumab with axitinib on 19 April 2019
  • nivolumab with cabozantinib on 22 January 2021 (separate letters for Opdivo and Cabometyx)
  • and pembrolizumab with lenvatinib on 10 August 2021 (separate letters for Keytruda and Lenvima). Single-agent labels for advanced renal cell carcinoma read in letters: sorafenib (20 December 2005), sunitinib (26 January 2006, accelerated approval
  • a supplement letter signed 2 February 2007 states that approval of one of its supplements fulfils commitments made under 21 CFR 314.510), temsirolimus (30 May 2007), pazopanib (19 October 2009) and cabozantinib (supplement of 19 December 2017 for patients with advanced renal cell carcinoma). EMA product pages read on 21 October 2026 list: Opdivo with ipilimumab for intermediate or poor risk advanced disease and with cabozantinib for advanced disease
  • Keytruda with axitinib or with lenvatinib
  • Cabometyx as monotherapy (first-line, intermediate or poor risk, or after prior VEGF-targeted therapy) and with nivolumab
  • Kisplyx with pembrolizumab
  • and Fotivda for first-line treatment of advanced disease. The dates of those EU extensions were not read. ASCO 2022 (metastatic clear cell renal cell carcinoma, PMID 35728020), ESMO 2024 (PMID 38788900), EAU 2025 (PMID 40118739) and SITC version 3.0 (PMID 41871874) are guideline papers. Guideline texts were not opened
  • the papers are cited by identifier only and no recommendation is attributed to them (whether these are the current editions was not checked)
U 2018U 2019U 2021U 2021U 2021U 2021U 2005U 2006U 2007U 2007U 2009U 2017European Medicines Agency 2026European Medicines Agency 2026European Medicines Agency 2026European Medicines Agency 2026European Medicines Agency 2026Guideline: Rathmell WK, Rumble RB, Van Veldhuizen PJ, Al-Ahmadie H, Emamekhoo H, Hauke RJ, et al 2022Guideline: Powles T, Albiges L, Bex A, Comperat E, Grünwald V, Kanesvaran R, et al 2024Guideline: Bex A, Ghanem YA, Albiges L, Bonn S, Campi R, Capitanio U, et al 2025Guideline: McKay RR, Ajmera A, Atkins MB, Barata PC, Bergerot C, Bukavina L, et al 2026
Relapsed / refractory

Advanced renal cell carcinoma after prior therapy. FDA documents read:

  • everolimus (30 March 2009
  • after failure of treatment with sunitinib or sorafenib)
  • nivolumab on 23 November 2015 (patients who have received prior antiangiogenic therapy)
  • cabozantinib on 25 April 2016 (prior anti-angiogenic therapy)
  • tivozanib on 10 March 2021 (adults with relapsed or refractory advanced disease following two or more prior systemic therapies, per the FDA notification page)
  • belzutifan on 14 December 2023 (advanced disease following a PD-1 or PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor)
  • and belzutifan in combination with lenvatinib on 24 September 2026 (advanced disease with a clear cell component following a PD-1 or PD-L1 inhibitor
  • the letter cites LITESPARK-011). EMA: the Welireg page (read 21 October 2026) shows a conditional marketing authorisation issued on 12 February 2025 (opinion adopted 12 December 2024) for monotherapy in advanced clear cell renal cell carcinoma that progressed after two or more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF-targeted therapies
  • the Kisplyx page lists lenvatinib with everolimus following one prior VEGF-targeted therapy, and the Opdivo page lists nivolumab monotherapy after prior therapy. ASCO 2022 (PMID 35728020) and ESMO 2024 (PMID 38788900) are guideline papers. Guideline texts were not opened
  • the papers are cited by identifier only and no recommendation is attributed to them (whether these are the current editions was not checked)
U 2009U 2015U 2016FDA 2023U 2023U 2026European Medicines Agency 2026European Medicines Agency 2026European Medicines Agency 2026Guideline: Rathmell WK, Rumble RB, Van Veldhuizen PJ, Al-Ahmadie H, Emamekhoo H, Hauke RJ, et al 2022Guideline: Powles T, Albiges L, Bex A, Comperat E, Grünwald V, Kanesvaran R, et al 2024
Metastatic
Cytoreductive nephrectomy in synchronous metastatic disease. CARMENA enrolled 450 patients with metastatic clear cell renal cell carcinoma at presentation, intermediate or poor risk by the Memorial Sloan Kettering model and suitable for nephrectomy, between September 2009 and September 2017. At a planned interim analysis (median follow-up 50.9 months, 326 deaths), the abstract reports sunitinib alone as noninferior to nephrectomy followed by sunitinib for overall survival (stratified hazard ratio for death 0.89, 95% CI 0.71 to 1.10; noninferiority boundary 1.20), with median overall survival of 18.4 months with sunitinib alone and 13.9 months with nephrectomy and sunitinib. The trial enrolled before the checkpoint-inhibitor combinations were labelled; whether surgery adds benefit alongside immunotherapy-based combinations is being tested in randomised trials (see the horizon list). No regulatory document applies to this question. EAU 2025 (PMID 40118739) is a guideline paper. Guideline texts were not opened; the papers are cited by identifier only and no recommendation is attributed to them (whether these are the current editions was not checked).
Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al 2018Guideline: Bex A, Ghanem YA, Albiges L, Bonn S, Campi R, Capitanio U, et al 2025
Metastatic

Subcutaneous PD-1 formulations. FDA corrected approval letter for Opdivo Qvantig (nivolumab and hyaluronidase-nvhy; BLA 761381; effective action date 27 December 2024, letter e-signed 2 January 2025) lists renal cell carcinoma indications:

  • adults with intermediate or poor risk advanced disease as first-line treatment following combination treatment with intravenous nivolumab and ipilimumab
  • adults with advanced disease as first-line treatment in combination with cabozantinib
  • and adults with advanced disease who have received prior anti-angiogenic therapy. The letter states a limitation of use that Opdivo Qvantig is not indicated in combination with ipilimumab for renal cell carcinoma. The FDA letter for Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph
  • BLA 761467/Original 1, e-signed 19 September 2025) lists, for renal cell carcinoma, first-line treatment of adults with advanced disease in combination with axitinib and in combination with lenvatinib, and adjuvant treatment (see the adjuvant entry). The Opdivo Qvantig letter describes only its colorectal and hepatocellular indications as accelerated approvals, and the Keytruda Qlex Original 1 letter is headed BLA approval, so no accelerated wording applies to the renal cell carcinoma indications in these letters. No trial data for the subcutaneous formulations in renal cell carcinoma were read
FDA 2024FDA 2025FDA 2026
Any setting
von Hippel-Lindau disease. The FDA approved belzutifan on 13 August 2021 for adults with VHL disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors, not requiring immediate surgery. The EMA Welireg page (read 21 October 2026) shows a conditional marketing authorisation issued on 12 February 2025 for monotherapy in adults with VHL disease who require therapy for associated, localised renal cell carcinoma, central nervous system haemangioblastomas or pancreatic neuroendocrine tumours when localised procedures are unsuitable. In the phase 2, single-group trial reported in 2021, the objective response among patients with renal cell carcinoma was 49% (95% CI 36 to 62) after median follow-up of 21.8 months; anaemia occurred in 90% of patients. No guideline text was opened for this setting.
U 2021European Medicines Agency 2026Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al 2021
Any setting
Check of the FDA notifications for kidney cancer. The FDA oncology approval notifications page (read 21 October 2026; the table starts in January 2023) names renal cell carcinoma announcements on 14 December 2023 (belzutifan), 12 June 2026 (belzutifan with pembrolizumab, adjuvant) and 24 September 2026 (belzutifan with lenvatinib), and an announcement of 27 December 2024 for subcutaneous nivolumab across approved nivolumab indications; the page states that FDA does not issue announcements for every approval or label update. An Internet Archive capture of the same page from 21 January 2023 lists oncology notifications dated 25 January to 23 December 2022 with no renal cell carcinoma entry; its renal cell carcinoma entries are from 2021. The FDA supplement approval letters dated 2022 for Opdivo, Yervoy, Keytruda, Cabometyx, Lenvima, Inlyta, Bavencio and Afinitor (all those listed with a letter on openFDA Drugs@FDA) added no renal cell carcinoma indication; two dated 14 July 2022 (Opdivo and Cabometyx) updated overall survival information from CheckMate 9ER in the labels. One Keytruda supplement dated 4 February 2022 (S-095) has no letter listed.
FDA 2026FDA 2023FDA 2022FDA 2022

Trials to watch

  • LITESPARK-012 NCT04736706

    In previously untreated advanced clear cell renal cell carcinoma, how do pembrolizumab plus belzutifan plus lenvatinib, and pembrolizumab with quavonlimab (coformulated as MK-1308A) plus lenvatinib, compare with pembrolizumab plus lenvatinib? Registry record: open-label, randomised phase 3 with three arms; Merck Sharp & Dohme; 1,688 enrolled (actual); status active, not recruiting; primary outcomes are progression-free survival by blinded independent central review (RECIST 1.1) and overall survival; primary completion listed as 2026-02-04 (actual); the registry record was last updated 2026-10-02 and has no results posted. This entry gives registry information only.

  • PDIGREE NCT03793166

    In previously untreated metastatic renal cell carcinoma with a clear cell component and IMDC intermediate or poor risk, after induction with nivolumab and ipilimumab, does continuing nivolumab with the addition of cabozantinib differ from nivolumab alone in overall survival (the registry's primary outcome)? Registry record: randomised phase 3 (Alliance study, sponsor National Cancer Institute); 1,175 estimated; status active, not recruiting; primary completion listed as 2028-03 (estimated); no results posted.

  • STELLAR-304 NCT05678673

    In previously untreated unresectable, locally advanced or metastatic non-clear cell renal cell carcinoma, how does XL092 (zanzalintinib) plus nivolumab compare with sunitinib for progression-free survival by blinded independent radiology committee and objective response rate (the registry's two primary outcomes)? Registry record: randomised, open-label phase 3 (2:1); Exelixis; 317 enrolled (actual); status active, not recruiting; primary completion listed as 2026-12-15 (estimated); no results posted. A design paper was published in Future Oncology in 2025 (PMID 40008409; abstract read).

  • PROBE NCT04510597

    In metastatic clear cell or non-clear cell renal cell carcinoma with the primary tumour in place, does adding nephrectomy to continued systemic immunotherapy-based combination therapy (nivolumab with ipilimumab, pembrolizumab with axitinib, or avelumab with axitinib, per the registry's detailed description; the arm description lists nivolumab, pembrolizumab with axitinib and avelumab with axitinib) differ from continued systemic therapy alone in overall survival (the registry's primary outcome)? Registry record: randomised phase 3 (SWOG S1931); 364 estimated; status recruiting; primary completion listed as 2033-07 (estimated); no results posted.

  • RAMPART NCT03288532

    After nephrectomy for renal cell carcinoma at intermediate or high risk of relapse, does adjuvant durvalumab, or durvalumab with tremelimumab, differ from active monitoring in disease-free survival or overall survival (the registry's primary outcomes)? Registry record: randomised, multi-arm multi-stage phase 3 platform trial; University College London; 1,750 estimated; status recruiting; primary completion listed as 2024-07 (estimated); no results posted. The record was last updated on 2020-09-07, so its status and dates may be out of date; two 2021 Contemporary Clinical Trials papers describe the trial (PMID 34538401 and 34538402; abstracts read).

  • PEAK-1 NCT07011719

    In advanced clear cell renal cell carcinoma, does casdatifan added to cabozantinib differ from placebo plus cabozantinib in progression-free survival by blinded independent central review (the registry's primary outcome)? Registry record (organisation study ID PEAK-1): randomised, double-blind, placebo-controlled phase 3; Arcus Biosciences; 720 estimated; status recruiting; primary completion listed as 2028-04 (estimated); no results posted. The registry brief summary describes patients who have had progression on or after prior anti-PD-1 or anti-PD-L1 immunotherapy.

References

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2021TreatmentTargeted

landmarkAny setting

Belzutifan for VHL disease-associated tumours (LITESPARK-004)

Belzutifan, a tablet that blocks a protein called HIF-2 alpha, was tested in people with von Hippel-Lindau disease, an inherited condition with a high risk of kidney cancer. About half of the participants had a measurable kidney tumour response in the first report, and about two thirds at roughly four years of follow-up. The FDA approved it in August 2021.

LITESPARK-004 (single-arm phase 2, 61 patients with VHL disease-associated RCC): belzutifan 120 mg daily; ORR 49% (95% CI 36-62) at median follow-up 21.8 months by independent review. At 49.9 months, ORR 67% (95% CI 54-79), complete responses 11%; grade 3 treatment-related events 18%, none grade 4-5. FDA approval 13 August 2021 for VHL disease needing therapy for RCC, CNS haemangioblastomas or pNET.

Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma, which the trial authors link to inactivation of the VHL gene and constitutive activation of the transcription factor HIF-2α. [1]

LITESPARK-004 was a phase 2, open-label, single-group trial of the oral HIF-2α inhibitor belzutifan, 120 mg daily, in patients with VHL disease-associated renal cell carcinoma. The primary end point was objective response by an independent central radiology review committee. [1]

In the first report, after a median follow-up of 21.8 months, 49% of patients with renal cell carcinoma had an objective response (95% CI 36 to 62). Responses were also seen in pancreatic lesions (47 of 61 patients) and in central nervous system hemangioblastomas (15 of 50 patients). [1]

The FDA approved belzutifan on 13 August 2021 for adults with VHL disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors, not requiring immediate surgery. [2]

An update at a median follow-up of 49.9 months reported an objective response in 41 of 61 participants (67%; 95% CI 54 to 79), with seven complete responses and no grade 4 or 5 treatment-related adverse event. [3]

In the EU, Welireg received a conditional marketing authorisation on 12 February 2025 that covers VHL disease-associated tumours only where localised procedures are unsuitable. [4]

What changed

FDA approved belzutifan on 13 August 2021 for adults with VHL disease who require therapy for associated RCC, CNS haemangioblastomas or pancreatic neuroendocrine tumours, not requiring immediate surgery. In the EU, a conditional authorisation dated 12 February 2025 covers VHL disease-associated tumours for patients in whom localised procedures are unsuitable.

Why it mattered

It reported objective responses to an oral HIF-2α inhibitor in people defined by germline VHL alterations, the genetic setting in which HIF-2α is constitutively active, and led to the FDA approval for VHL disease.

Caveats

  • This is a single-arm phase 2 trial with no control group; the response rates cannot be compared with those of other treatments or trials.
  • The primary end point was objective response. In the first report the most common adverse events were anaemia (90% of patients) and fatigue (66%).
  • The EU conditional authorisation (12 February 2025) is narrower than the FDA wording: tumours must be localised and localised procedures unsuitable. The authorisation was renewed (CHMP opinion 13 November 2025, Commission decision 8 January 2026).