Key points
- The most common type of kidney cancer is renal cell carcinoma (RCC), particularly the clear-cell type [3]; smoking, obesity and high blood pressure are the most important preventable risk factors [2, 3].
- Most kidney tumors today are discovered incidentally, on an ultrasound or CT scan done for another reason [3].
- For small tumors (T1), partial nephrectomy (removing the tumor while preserving the rest of the kidney) is the preferred approach; in older people or those in poor health, active surveillance, ablation or stereotactic radiation therapy is an option [3, 7].
- After surgery in high-risk patients, one year of adjuvant pembrolizumab reduced the risk of recurrence and death; in the 5-year report, 5-year overall survival was 87.7% versus 82.3% (HR 0.66) [18].
- In advanced disease, the standard first-line treatment is an immunotherapy-based combination: lenvatinib + pembrolizumab, nivolumab + cabozantinib or pembrolizumab + axitinib, or the combination of two immunotherapy drugs, nivolumab + ipilimumab [3, 4]. For patients who cannot receive immunotherapy, sunitinib or pazopanib is used [3].
- After the disease progresses on immunotherapy, another oral anti-angiogenic drug such as cabozantinib or the combination lenvatinib + everolimus is recommended [3, 21, 22]; belzutifan, a newer oral HIF-2α inhibitor, alone or with lenvatinib, is another option in later lines [14, 19].
What is kidney cancer?
The kidneys are two bean-shaped organs at the back of the abdomen that filter the blood and make urine. Most malignant kidney tumors are renal cell carcinomas (RCC), and about 70% of them have clear-cell histology. Less common (non-clear-cell) types include papillary (the second most common type), chromophobe, translocation RCC and collecting duct carcinoma; renal medullary carcinoma is a very rare (less than 0.5%) and aggressive type, seen mostly in young people with sickle cell disease or sickle cell trait [3].
According to GLOBOCAN estimates, there were about 434,840 new cases of kidney cancer and 155,953 deaths from the disease worldwide in 2022 [1]. The incidence is about twice as high in men as in women (age-standardized rate 13.7 versus 6.4 per 100,000) and the disease is seen more often at older ages [3]. While the incidence of kidney cancer has risen worldwide, its mortality trend has stabilized [2].
Most of the new treatments on this page have been studied in the clear-cell type; the treatment of non-clear-cell subtypes differs in some respects (see “treatment of advanced disease”) and should be discussed with the treatment team [3, 4].
Symptoms and incidental detection
Many kidney masses remain asymptomatic until late stages. Today, most cases of RCC are discovered incidentally on ultrasound, CT or MRI performed for other abdominal problems; in one study, 60% of all patients and 87% of patients with stage T1a tumors were diagnosed incidentally [3].
The classic triad of “flank pain, blood in the urine and an abdominal mass” is very rare today, and the presence of symptoms is usually associated with more advanced disease and a worse prognosis. Paraneoplastic syndromes (symptoms such as fever, weight loss or laboratory abnormalities caused by substances secreted by the tumor) are seen in about one third of symptomatic patients [3].
Warning signs
If you have any of these symptoms, see a doctor to get checked [3]:
- Visible blood in the urine
- Pain in the side (flank)
- A lump in the abdomen that you can feel
- Symptoms caused by metastases, such as bone pain or a persistent cough
If you are having treatment (especially immunotherapy), tell your treatment team right away about any new symptom, such as diarrhea, cough, a skin rash or severe fatigue; details are in the guide to immunotherapy side effects (Persian).
Risk factors and prevention
The most important known risk factors for kidney cancer are [2, 3]:
- Smoking: 50.2% of patients with RCC are current or former smokers [3].
- Obesity: a body mass index above 35, compared with below 25, is associated with increased risk (hazard ratio 1.71) [3].
- High blood pressure: (hazard ratio 1.70) [3].
- Chronic kidney disease and kidney failure requiring dialysis [2].
- Family history and inherited syndromes: having an affected first-degree relative roughly doubles the risk [3]. The most common inherited form is von Hippel–Lindau (VHL) disease, which is caused by an inherited mutation in the VHL gene and predisposes affected people to clear-cell RCC and to other tumors and cysts (in the adrenal glands, nervous system, retina and pancreas) [3]. Hereditary kidney cancer accounts for about 5% to 8% of cases (probably an underestimate) [3].
The EAU guideline recommends genetic assessment in patients aged 46 years or younger and in patients with bilateral or multifocal tumors (strong recommendation) [3].
According to the European Association of Urology guideline, the most effective preventive steps are stopping smoking completely, losing weight if you have obesity and being more physically active [3]. Controlling your blood pressure also matters, because high blood pressure is one of the three main risk factors [2].
Diagnosis, staging and risk stratification
The usual diagnostic pathway for a kidney mass
- 1
Imaging
Contrast-enhanced CT or MRI defines the features of the mass (solid or cystic, size, extension into blood vessels). In metastatic disease, when systemic therapy or cytoreductive nephrectomy is being considered, brain imaging is recommended [3].
- 2
- 3
TNM staging
The size and extent of the tumor (T), lymph node involvement (N) and distant metastasis (M) are determined. The most important prognostic factors are stage, grade, local extent, lymph node involvement and metastasis at diagnosis [3].
- 4
For physicians
| Risk group | Number of adverse factors | Median overall survival | 2-year survival |
|---|---|---|---|
| Favorable | 0 | Not reached | 75% |
| Intermediate | 1 or 2 | 27 months | 53% |
| Poor | 3 to 6 | 8.8 months | 7% |
Six adverse factors: hemoglobin below the lower limit of normal, corrected calcium above the upper limit of normal, Karnofsky performance status below 80%, less than 1 year from diagnosis to start of treatment, neutrophils above the upper limit of normal and platelets above the upper limit of normal. The survival figures come from patients treated with anti-VEGF agents in the pre-immunotherapy era (645 patients) and have improved with current treatments [6].
Small kidney masses and active surveillance
With the wider use of imaging, small kidney masses (usually up to 4 cm) are being discovered more often. Not all of these masses are cancer, and many small cancers grow slowly. In older people with other medical conditions who have a small, incidentally found mass, the risk of dying from RCC is low and the risk of dying from other causes is substantial [3].
Active surveillance means regularly monitoring the size of the tumor with imaging (ultrasound, CT or MRI) and intervening only if it progresses; it differs from “watchful waiting,” which is used for very frail patients with a short life expectancy and does not involve regular imaging follow-up [3]. The EAU guideline suggests active surveillance for cT1a masses that do not need immediate treatment, and tumor ablation or stereotactic radiation therapy for patients with a cT1 lesion who need treatment but are not suitable for surgery (weak recommendation), and stresses that the limitations of the evidence on cancer outcomes and complications should be discussed with the patient (strong recommendation) [3]. The AUA guideline likewise emphasizes individualized counseling based on overall health, cancer-related considerations and the implications for kidney function [7].
Treatment of localized disease: surgery and alternatives
Partial nephrectomy
Radical nephrectomy
Removal of the entire kidney; for larger or complex tumors in which preserving the kidney is not possible or not safe. Removing the adrenal gland on the same side is not recommended without evidence that it is involved [3].
Ablation or stereotactic radiation therapy
Destruction of the tumor with heat or cold through the skin, or precise high-dose radiation therapy; an option for patients with a small tumor who are not suitable for surgery. A biopsy is required before ablation; radiofrequency ablation for tumors larger than 3 cm and cryoablation for tumors larger than 4 cm are not routinely recommended [3]. Ablation is effective for tumors up to 3 cm [7].
Active surveillance
For older people or those with other medical conditions who have a small mass; regular imaging follow-up, with treatment only if the mass grows [3].
Partial or radical nephrectomy?
In the only randomized trial that compared the two procedures, cancer outcomes were excellent with both [8]; based on the totality of the evidence, current guidelines prefer partial nephrectomy for T1 tumors in order to preserve kidney function [3, 7].
Adjuvant therapy after surgery
In patients at high risk of the cancer coming back, about one year of immunotherapy with pembrolizumab after surgery reduced both recurrence and death [9, 18]. Adding belzutifan tablets to pembrolizumab reduced recurrence further, but caused more severe side effects, and an overall survival benefit has not yet been shown [10].
Adjuvant pembrolizumab has been studied only in patients whose tumors have a clear-cell component and a high risk of recurrence (based on tumor stage and grade, or complete removal of metastases) [9, 18]. Grade 3 or higher adverse events from any cause were more frequent with pembrolizumab (32.4% versus 17.7%) [9]. Some immune-related side effects (such as an underactive thyroid) may be permanent, and some patients are treated without truly needing it; the decision should be made after a thorough discussion with an oncologist [3].
Treatment of advanced and metastatic disease
The treatment of advanced kidney cancer has been transformed over the past decade. Today, first-line treatment of advanced clear-cell RCC is usually an immunotherapy-based combination: an immunotherapy drug plus an oral anti-angiogenic drug (a VEGF receptor tyrosine kinase inhibitor), or two immunotherapy drugs together [3, 4]. Four combinations — lenvatinib + pembrolizumab, nivolumab + cabozantinib, pembrolizumab + axitinib and nivolumab + ipilimumab — have improved overall survival compared with sunitinib in phase 3 trials, and in the absence of head-to-head comparisons, each of them is recommended; the IMDC risk group and tumor characteristics play a role in the choice [3, 4]. For patients who cannot receive or do not tolerate immunotherapy, sunitinib or pazopanib (in any risk group) and, in intermediate and poor risk, cabozantinib are recommended [3].
If the disease progresses
Continuing or repeating immunotherapy after progression on it has shown no benefit [3, 4]. Usually an oral anti-angiogenic drug that has not been used before, especially cabozantinib, or the combination lenvatinib + everolimus is used [3, 4, 21, 22]. Belzutifan, a tablet that blocks the HIF-2α protein, alone or with lenvatinib, is a newer option in later lines [3, 14, 19]. The choice of drug depends on previous treatments and the patient’s general condition.
Non-clear-cell subtypes
The evidence for non-clear-cell subtypes is more limited and their treatment differs in some respects; participation in a clinical trial is recommended for these patients [3, 4].
What should I do after diagnosis?
Frequently asked questions
My kidney mass was found by chance; is it definitely cancer?
Can you live a normal life with one kidney?
Most people with one healthy kidney live a normal life, but preserving as much kidney tissue as possible is valuable; that is why partial nephrectomy is preferred for small tumors [3, 7].
Is chemotherapy used for kidney cancer?
Do I need immunotherapy after surgery?
My cancer had already spread when it was diagnosed; will they still remove the kidney?
Is kidney cancer hereditary?
Evidence and recent advances (for physicians)
For physicians
Surgery for localized disease
The only randomized trial in this setting (EORTC 30904) assigned 541 patients with a solitary tumor of 5 cm or smaller to nephron-sparing surgery or radical nephrectomy. After a median follow-up of 9.3 years, oncologic outcomes were excellent with both procedures: only 12 of the 117 deaths were due to kidney cancer. In the intention-to-treat analysis, 10-year overall survival was slightly higher in the radical nephrectomy arm (81.1% vs 75.7%), but in patients who actually had RCC the difference was not significant [8]. The study closed early because of slow accrual and did not assess renal function or quality of life [8]; based on the totality of the evidence, current guidelines prefer partial nephrectomy for T1 tumors [3, 7].
Adjuvant therapy
In KEYNOTE-564, 994 patients with ccRCC at intermediate-high risk (pT2 grade 4 or sarcomatoid, or pT3), high risk (pT4 or N+) or M1 NED after complete metastasectomy received pembrolizumab (every 3 weeks for up to 17 cycles, approximately 1 year) or placebo. Pembrolizumab improved disease-free survival (24-month DFS 77.3% vs 68.1%; HR 0.68) [9]. In the 5-year report (median follow-up 70 months), the benefit was sustained and consistent across key subgroups: 5-year DFS 60.9% vs 52.2% (HR 0.71; 95% CI 0.59–0.86) and 5-year OS 87.7% vs 82.3% (HR 0.66; 0.48–0.90) [18]. The EAU guideline recommends adjuvant pembrolizumab for patients at trial-defined risk of recurrence (strong recommendation); for recurrence during or shortly after adjuvant pembrolizumab, immunotherapy rechallenge (monotherapy or combination) is not recommended [3], and there is no level 1 evidence for subsequent therapy [4].
In LITESPARK-022 (1,841 patients), pembrolizumab 400 mg every 6 weeks (up to 9 doses) plus belzutifan 120 mg daily was compared with pembrolizumab + placebo. The combination further improved DFS (HR 0.72; 24-month DFS 80.7% vs 73.7%), but OS did not differ significantly at the interim analysis, which is immature with 29% of the final events (HR 0.78; 95% CI 0.51–1.19); grade ≥3 adverse events were more frequent (52.1% vs 30.2%) [10].
First-line treatment of advanced disease (clear cell)
Key results of the four first-line combinations versus sunitinib (latest report of each trial). ICI + TKI combinations provide higher objective response rates and faster disease control.
- Lenvatinib + pembrolizumab (CLEAR): the longest median PFS reported in these trials (23.9 vs 9.2 months) [12]. In the final analysis, with 23 months of additional follow-up, the OS HR was 0.79 (95% CI 0.63–0.99) and median OS was similar in the two arms (53.7 vs 54.3 months), while 36-month OS was 66.4% vs 60.2% [13].
- Nivolumab + cabozantinib (CheckMate 9ER): in the final analysis, with 5.6 years of follow-up, median OS was 46.5 vs 35.5 months (HR 0.79) and median PFS 16.4 vs 8.3 months; the probability of maintaining a response through 60 months was 22.0% vs 10.0%, and grade 3–4 treatment-related adverse events occurred in 67.8% vs 55.0% [17].
- Pembrolizumab + axitinib (KEYNOTE-426): at 5-year follow-up, the OS benefit (HR 0.84) and PFS benefit (HR 0.69) were sustained; the PD-L1 combined positive score was associated with OS only in the sunitinib arm [16].
- Nivolumab + ipilimumab (CheckMate 214): the primary endpoints were assessed only in IMDC intermediate/poor-risk patients, and in the primary report PFS did not reach the prespecified significance threshold (HR 0.82) [11]. In the final analysis, with 9.3 years of follow-up, the risk of death was reduced in intermediate/poor risk (HR 0.69; 108-month OS 30.2% vs 18.7%); the OS HR was 0.71 in all patients and 0.80 in favorable risk (95% CI 0.59–1.09), the probability of an ongoing response at 96 months was 48.0% vs 19.0%, and grade 3–4 treatment-related adverse events occurred in 48.6% vs 64.1% [15]. For tumors with sarcomatoid features, the SITC guideline considers this combination the preferred option [4].
The EAU guideline recommends these four combinations for patients with IMDC intermediate and poor risk (strong recommendation). In favorable risk, where immunotherapy + anti-angiogenic combinations have improved PFS and response but have not shown an OS benefit with long follow-up, monotherapy with sunitinib or pazopanib is also an acceptable option [3]. According to the EAU, patients who discontinue an ICI + TKI combination because of immune-related adverse events may continue the TKI, and rechallenge with a checkpoint inhibitor after discontinuation for toxicity should be undertaken with the support of an experienced multidisciplinary team [3]. Adding cabozantinib to nivolumab + ipilimumab (COSMIC-313) did not improve OS and is not recommended [4].
| Combination (trial) | Number of patients | Median PFS | Overall survival | Objective response |
|---|---|---|---|---|
| Lenvatinib + pembrolizumab (CLEAR) [12, 13] | 1,069 (355 vs 357 in this comparison) | 23.9 vs 9.2 months; HR 0.39 (primary report) | Final analysis: HR 0.79; 36-month OS 66.4% vs 60.2% | 71.3% vs 36.7% |
| Nivolumab + cabozantinib (CheckMate 9ER) [17] | 651 | 16.4 vs 8.3 months; HR 0.58 | Median 46.5 vs 35.5 months; HR 0.79; 60-month OS 40.9% vs 35.4% | 55.7% vs 27.4% (complete response 13.9% vs 4.6%) |
| Pembrolizumab + axitinib (KEYNOTE-426) [16] | 861 | HR 0.69 | HR 0.84 | 60.6% vs 39.6% |
| Nivolumab + ipilimumab (CheckMate 214) [11, 15] | 1,096 (847 intermediate/poor risk) | 96-month PFS 25.4% vs 8.5% | HR 0.69; 108-month OS 30.2% vs 18.7% | 42% vs 27% (primary report) |
CheckMate 214 figures refer to intermediate- and poor-risk patients (the primary endpoint population). Figures are from the latest report of each trial (final analyses of CLEAR, CheckMate 9ER and CheckMate 214, and the 5-year report of KEYNOTE-426), except where “primary report” is stated. The trials differ in population, follow-up duration and assessment methods, so direct comparison of figures across them is not valid.
Cytoreductive nephrectomy
In CARMENA (450 patients), sunitinib alone was non-inferior to nephrectomy followed by sunitinib for overall survival; in the updated analysis, median OS was 19.8 vs 15.6 months (HR 0.97) [20]. On this basis, the EAU does not recommend cytoreductive nephrectomy in poor-risk patients and, in intermediate-risk patients with an asymptomatic primary tumor who require systemic therapy, suggests starting systemic therapy without immediate nephrectomy [3]. Nevertheless, nephrectomy in selected patients (e.g., those with good performance status who do not need immediate systemic therapy, or with limited metastases amenable to complete local treatment) and deferred nephrectomy in patients who benefit from systemic therapy still have a role [3].
Later lines
If the disease progresses after immunotherapy-based first-line treatment, an oral anti-angiogenic drug (VEGF-TKI) not previously used is recommended (EAU strong recommendation), and cabozantinib has the strongest evidence in this setting [3, 4]; if the patient has already received an ICI + TKI combination, a different TKI should be chosen [4]. In CONTACT-03, adding atezolizumab to cabozantinib after progression on immunotherapy provided no benefit and increased toxicity, and in TiNivo-2, adding nivolumab to tivozanib did not improve PFS [4]. In the phase 3 METEOR trial in patients previously treated with an anti-VEGF agent, cabozantinib improved overall survival compared with everolimus (median 21.4 vs 16.5 months; HR 0.66) [21]. The combination lenvatinib + everolimus is another option; in a randomized phase 2 trial after one prior anti-VEGF therapy, it improved PFS compared with everolimus alone (median 14.6 vs 5.5 months; HR 0.40) [3, 22]. In patients who received only an anti-angiogenic drug in the first line, nivolumab or cabozantinib is recommended [3].
Belzutifan inhibits the HIF-2α protein, part of a pathway that is overactive in clear-cell RCC because of loss of VHL gene function. In the phase 3 LITESPARK-005 trial, 746 patients who had progressed after immunotherapy and anti-angiogenic therapy received belzutifan or everolimus. Median PFS was 5.6 months in both arms and the curves were non-proportional, but at 18 months 24.0% of patients in the belzutifan arm vs 8.3% in the everolimus arm were alive and progression-free, and the objective response rate was 21.9% vs 3.5%. At the second interim analysis, overall survival did not differ significantly (21.4 vs 18.1 months; HR 0.88), and discontinuation due to adverse events was less frequent with belzutifan (5.9% vs 14.7%) [14]. The EAU considers belzutifan an alternative to everolimus in later lines (weak recommendation) [3].
In the phase 3 LITESPARK-011 trial (747 patients after immunotherapy), belzutifan + lenvatinib improved PFS compared with cabozantinib (median 14.8 vs 10.7 months; HR 0.70), but overall survival did not differ significantly (HR 0.85), and grade ≥3 adverse events were common in both arms (84% vs 83%); the most common grade ≥3 adverse event in both arms was hypertension (31% vs 29%) [19].
Non-clear-cell subtypes
For non-clear-cell subtypes, the EAU guideline suggests lenvatinib + pembrolizumab; in the papillary subtype, cabozantinib (based on one randomized trial) and nivolumab + cabozantinib, and in other subtypes sunitinib, are also options (all weak recommendations) [3]. In the randomized SUNNIFORECAST trial, nivolumab + ipilimumab improved 12-month overall survival compared with standard of care (86.9% vs 76.8%) [4].
Adjuvant pembrolizumab and the four first-line combinations on this page are FDA-approved in the United States [4]; belzutifan was approved for advanced disease in December 2023 on the basis of LITESPARK-005. Details are given in each study card. Adjuvant belzutifan + pembrolizumab (LITESPARK-022) and belzutifan + lenvatinib (LITESPARK-011) are the newest data, and an overall survival benefit has not yet been shown for either [10, 19]; check their place in up-to-date guidelines before use (most recent published guidelines: ESMO 2024 [5], EAU 2025 [3] and SITC 2026 [4]). Therapies being studied only in clinical trials (such as neoantigen vaccines) are not approved and can be used only within a trial.
Treatment regimens and dosing (for physicians)
Treatment regimens and doses: index13 regimens
- Pembrolizumab and nivolumab (all regimens containing a checkpoint inhibitor): dose reduction is not recommended; withhold for severe (grade 3) immune-mediated adverse reactions, and permanently discontinue for life-threatening (grade 4) reactions, recurrent grade 3 reactions requiring immunosuppression, or inability to taper prednisone to 10 mg/day or less within 12 weeks. Check liver enzymes, creatinine and thyroid function at baseline and periodically [23, 25]. Ipilimumab rules are given under the nivolumab + ipilimumab regimen.
- Oral anti-angiogenic drugs (lenvatinib, cabozantinib, axitinib, sunitinib, pazopanib): monitor and control blood pressure before starting and regularly during treatment [24, 26, 27, 29, 30]; the monitoring schedule for liver function, thyroid function and urine protein, the interruption interval before surgery and the dose-reduction steps for each drug are given in the notes of the respective regimen.
- Belzutifan (all regimens): monitor hemoglobin and oxygen saturation before starting and periodically (withholding thresholds in the notes of each regimen); dose reductions: 80 mg, then 40 mg. It causes embryo-fetal toxicity and may render some hormonal contraceptives ineffective; before starting, exclude pregnancy and advise non-hormonal contraception [31].
For physicians
Adjuvant therapy regimens after nephrectomy
Adjuvant pembrolizumab (KEYNOTE-564)
RCC with a clear-cell component after nephrectomy at intermediate-high risk (pT2 grade 4 or sarcomatoid, or pT3) or high risk (pT4 or N+), or M1 NED after nephrectomy and complete resection of metastases
RCC with a clear-cell component after nephrectomy at intermediate-high risk (pT2 grade 4 or sarcomatoid, or pT3) or high risk (pT4 or N+), or M1 NED after nephrectomy and complete resection of metastases
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg (or 400 mg) | IV, 30-minute infusion | Day 1 every 3 weeks (400 mg dose: every 6 weeks) |
Dose and duration per the FDA label [23] and the trial [9]. The EAU recommends starting treatment preferably within 12 to 16 weeks after nephrectomy, after repeat imaging [3].
Evidence: KEYNOTE-564 (2026), KEYNOTE-564 (2024), KEYNOTE-564 (2021)
Adjuvant pembrolizumab + belzutifan (LITESPARK-022)
Same criteria as KEYNOTE-564 (RCC with a clear-cell component at intermediate-high or high risk, or M1 NED); a newer combination whose overall survival benefit has not yet been shownEach drug’s schedule in the table
Same criteria as KEYNOTE-564 (RCC with a clear-cell component at intermediate-high or high risk, or M1 NED); a newer combination whose overall survival benefit has not yet been shown
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 400 mg (or 200 mg every 3 weeks) | IV, 30-minute infusion | Day 1 every 6 weeks |
| Belzutifan | 120 mg once daily | Oral, with or without food | Daily, continuously |
Doses per the FDA labels [23, 31] and the trial [10]. Belzutifan as adjuvant therapy: withhold for hemoglobin <9 g/dL or if a blood transfusion is needed; oxygen saturation <88%: withhold [31].
Evidence: LITESPARK-022 (2026)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
First-line regimens for advanced RCC
Lenvatinib + pembrolizumab (CLEAR)
Advanced RCC, first line, all IMDC risk groups; also an EAU-recommended option for non-clear-cell subtypesEach drug’s schedule in the table
Advanced RCC, first line, all IMDC risk groups; also an EAU-recommended option for non-clear-cell subtypes
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Lenvatinib | 20 mg once daily | Oral, with or without food | Daily, continuously |
| Pembrolizumab | 200 mg (or 400 mg) | IV, 30-minute infusion | Day 1 every 3 weeks (400 mg dose: every 6 weeks) |
Per the FDA labels [23, 24] and the trial [12]. Lenvatinib dose reductions in RCC: 14 mg, then 10 mg, then 8 mg; in severe renal impairment (CrCl <30 mL/min) or severe hepatic impairment (Child-Pugh C), 10 mg. Control blood pressure before starting, and monitor it after 1 week, then every 2 weeks for 2 months, then at least monthly; liver tests every 2 weeks for 2 months, then monthly; thyroid function and calcium at least monthly; urine protein (if dipstick ≥2+, obtain a 24-hour urine collection; withhold for ≥2 g/24 h). Withhold lenvatinib at least 1 week before elective surgery and do not start it until 2 weeks after major surgery [24].
Evidence: CLEAR (2024), CLEAR (2021)
Nivolumab + cabozantinib (CheckMate 9ER)
Advanced RCC, first line, all IMDC risk groups; also an option in the papillary subtype (EAU)Each drug’s schedule in the table
Advanced RCC, first line, all IMDC risk groups; also an option in the papillary subtype (EAU)
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Nivolumab | 240 mg (or 480 mg) | IV, 30-minute infusion | Every 2 weeks (480 mg dose: every 4 weeks) |
| Cabozantinib | 40 mg once daily | Oral, on an empty stomach (1 hour before or 2 hours after a meal) | Daily, continuously |
Per the FDA labels [25, 26] and the trial [17]. Cabozantinib dose reductions in this combination: 20 mg daily, then 20 mg every other day. ALT or AST >3 to 10 × ULN with bilirubin <2 × ULN: withhold both drugs until recovery to grade 0–1 (consider corticosteroids); >10 × ULN, or >3 × ULN with bilirubin ≥2 × ULN: permanently discontinue both. Liver enzymes should be monitored more frequently with this combination than with monotherapy. Stop cabozantinib 3 weeks before surgery (including dental surgery) and do not restart it for at least 2 weeks after major surgery; with strong CYP3A4 inhibitors, reduce the dose by 20 mg [26].
Evidence: CheckMate 9ER (2026), CheckMate 9ER (2021)
Pembrolizumab + axitinib (KEYNOTE-426)
Advanced RCC, first line, all IMDC risk groupsEach drug’s schedule in the table
Advanced RCC, first line, all IMDC risk groups
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg (or 400 mg) | IV, 30-minute infusion | Day 1 every 3 weeks (400 mg dose: every 6 weeks) |
| Axitinib | 5 mg twice daily (12 hours apart) | Oral, with or without food | Daily, continuously |
Per the FDA labels [23, 27] and the trial [16]. If the patient has had no adverse reaction above grade 2 for at least 2 consecutive weeks, is normotensive and is not taking antihypertensive medication, the axitinib dose in this combination may be increased at intervals of 6 weeks or longer to 7 mg and then 10 mg twice daily; dose reductions: 3 mg, then 2 mg twice daily. In moderate hepatic impairment (Child-Pugh B), reduce the starting dose by about half. ALT or AST increase to 3 to <10 × ULN without bilirubin ≥2 × ULN: withhold both drugs until grade 0–1 (consider corticosteroids); ≥10 × ULN, or >3 × ULN with bilirubin ≥2 × ULN: permanently discontinue both [23, 27]. Monitor thyroid function and urine protein before starting and periodically [27].
Evidence: KEYNOTE-426 (2025), KEYNOTE-426 (2019)
Nivolumab + ipilimumab (CheckMate 214)
Advanced RCC, first line, IMDC intermediate or poor risk; SITC-preferred option for tumors with sarcomatoid features
Advanced RCC, first line, IMDC intermediate or poor risk; SITC-preferred option for tumors with sarcomatoid features
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Induction | |||
| Nivolumab | 3 mg/kg | IV, 30-minute infusion (nivolumab first, then ipilimumab on the same day) | Day 1 every 3 weeks, 4 doses |
| Ipilimumab | 1 mg/kg | IV, 30-minute infusion | Day 1 every 3 weeks, 4 doses |
| Maintenance | |||
| Nivolumab | 240 mg (or 480 mg) | IV, 30-minute infusion | Every 2 weeks (480 mg dose: every 4 weeks) |
Per the FDA labels [25, 28] and the trial [11]. Dose reduction of ipilimumab is not recommended; for toxicity, both drugs are withheld or permanently discontinued together [28]. This combination should be given in experienced centers with the support of a multidisciplinary team [3].
Evidence: CheckMate 214 (2026), CheckMate 214 (2018)
Sunitinib
Patients who cannot receive or do not tolerate immunotherapy (all risk groups); an acceptable option in IMDC favorable risk; also an option in non-clear-cell subtypes
Patients who cannot receive or do not tolerate immunotherapy (all risk groups); an acceptable option in IMDC favorable risk; also an option in non-clear-cell subtypes
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Sunitinib | 50 mg once daily | Oral, with or without food | 4 weeks on, 2 weeks off |
Per the FDA label [29]; place in therapy per the EAU [3]. Dose reductions: 37.5 mg, then 25 mg. Boxed warning for hepatotoxicity (sometimes fatal): monitor liver tests (ALT, AST, bilirubin) at baseline and during each cycle. Thyroid function and urinalysis at baseline and periodically; in patients at high risk of QT prolongation, monitor ECGs and electrolytes [29].
Pazopanib
Patients who cannot receive or do not tolerate immunotherapy (all risk groups); an acceptable option in IMDC favorable riskCycle length: Continuous
Patients who cannot receive or do not tolerate immunotherapy (all risk groups); an acceptable option in IMDC favorable risk
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pazopanib | 800 mg once daily | Oral, without food (1 hour before or 2 hours after a meal); do not crush tablets | Daily, continuously |
Per the FDA label [30]; place in therapy per the EAU [3]. Dose reductions in RCC: 400 mg, then 200 mg. Boxed warning for hepatotoxicity: liver tests at baseline, at weeks 3, 5, 7 and 9, at months 3 and 4, and periodically thereafter; ALT >3 × ULN with bilirubin >2 × ULN: permanently discontinue. In moderate hepatic impairment, consider an alternative drug or use 200 mg. Monitor thyroid function [30].
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Regimens for later lines and immunotherapy-free treatment
Cabozantinib monotherapy (METEOR)
After progression on immunotherapy or an anti-VEGF agent (strongest evidence in this setting); also first line in intermediate and poor risk for patients not receiving immunotherapy, and in the papillary subtype (EAU)Cycle length: Continuous
After progression on immunotherapy or an anti-VEGF agent (strongest evidence in this setting); also first line in intermediate and poor risk for patients not receiving immunotherapy, and in the papillary subtype (EAU)
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cabozantinib | 60 mg once daily | Oral, on an empty stomach (1 hour before or 2 hours after a meal); do not crush tablets | Daily, continuously |
Per the FDA label [26]; place in therapy per the EAU [3] and the trial [21]. Cabozantinib tablets (CABOMETYX) are not interchangeable with cabozantinib capsules. Dose reductions: 40 mg, then 20 mg; in moderate hepatic impairment (Child-Pugh B), start at 40 mg; with a strong CYP3A4 inhibitor, reduce by 20 mg, and with a strong or moderate CYP3A4 inducer, increase by 20 mg (maximum 80 mg). Stop 3 weeks before surgery (including dental surgery). Do not start in uncontrolled hypertension; monitor urine protein, diarrhea and hand-foot syndrome [26].
Lenvatinib + everolimus
Advanced RCC after one prior anti-angiogenic therapyCycle length: Continuous
Advanced RCC after one prior anti-angiogenic therapy
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Lenvatinib | 18 mg once daily | Oral, with or without food | Daily, continuously |
| Everolimus | 5 mg once daily | Oral | Daily, continuously |
Per the FDA label [24] and the trial [22]. For overlapping toxicities, interrupt or reduce lenvatinib first, then everolimus; lenvatinib dose reductions in RCC: 14 mg, 10 mg, then 8 mg; for CrCl <30 mL/min or Child-Pugh C, 10 mg. Monitor blood pressure, liver tests, urine protein and thyroid function as for the lenvatinib + pembrolizumab regimen [24].
Nivolumab monotherapy
Advanced RCC after anti-angiogenic therapy, in patients who did not receive immunotherapy in the first lineCycle length: Every 14 or 28 days
Advanced RCC after anti-angiogenic therapy, in patients who did not receive immunotherapy in the first line
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Nivolumab | 240 mg (or 480 mg) | IV, 30-minute infusion | Every 2 weeks (480 mg dose: every 4 weeks) |
Belzutifan monotherapy (LITESPARK-005)
Advanced RCC with a clear-cell component after a PD-1 or PD-L1 inhibitor and a VEGF-TKICycle length: Continuous
Advanced RCC with a clear-cell component after a PD-1 or PD-L1 inhibitor and a VEGF-TKI
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Belzutifan | 120 mg once daily | Oral, with or without food; do not crush tablets | Daily, continuously |
Per the FDA label [31] and the trial [14]. Anemia is very common: hemoglobin <8 g/dL or transfusion needed: withhold. Oxygen saturation <88% at rest: withhold, then resume at a reduced dose or discontinue [31].
Evidence: LITESPARK-005 (2024)
Belzutifan + lenvatinib (LITESPARK-011)
Advanced RCC with a clear-cell component after a PD-1 or PD-L1 inhibitor; better progression-free survival than cabozantinib, with no significant difference in overall survivalCycle length: Continuous
Advanced RCC with a clear-cell component after a PD-1 or PD-L1 inhibitor; better progression-free survival than cabozantinib, with no significant difference in overall survival
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Belzutifan | 120 mg once daily | Oral | Daily, continuously |
| Lenvatinib | 20 mg once daily | Oral | Daily, continuously |
Per the FDA labels [24, 31] and the trial [19]. Grade 3 cardiac dysfunction: withhold both drugs until LVEF recovers to baseline or grade 1; grade 4: permanently discontinue both [31]. Monitoring for lenvatinib (blood pressure, liver, urine protein, thyroid) [24] and belzutifan (hemoglobin, oxygen saturation) [31] as in the regimens above.
Evidence: LITESPARK-011 (2026)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Scientific evidence
Key studies
12 itemsAdjuvant pembrolizumab for the treatment of clear cell renal cell carcinoma: five-year results from the phase III KEYNOTE-564 study
Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study
Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial
Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial
Sunitinib Alone or After Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Is There Still a Role for Cytoreductive Nephrectomy?
Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial
Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial
Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma
Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma
Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: final analysis of efficacy and safety from the phase III CheckMate 214 trial
Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
Clinical guidelines
3 itemsEuropean Association of Urology Guidelines on Renal Cell Carcinoma: The 2025 Update
Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of renal cell carcinoma, version 3.0
References
31 referencesShow all references, 21 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
- 1Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
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- 3European Association of Urology Guidelines on Renal Cell Carcinoma: The 2025 Update
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- 5Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
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- 13Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study
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- 15Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: final analysis of efficacy and safety from the phase III CheckMate 214 trial
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- 20Sunitinib Alone or After Nephrectomy for Patients with Metastatic Renal Cell Carcinoma: Is There Still a Role for Cytoreductive Nephrectomy?
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This page is based on reputable scientific sources and was last updated on 21 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.