The association between smoking tobacco and RCC has been documented for many decades, as highlighted in Dr. Koop’s report from the Surgeon General in 1982. Modern studies have continued to document that exposure to tobacco smoke is associated with an increase in RCC. In a meta-analysis of 24 publications, the relative risk of RCC incidence was 1.31 higher in smokers compared with never-smokers, with the highest risk in heavy smokers. There appears to be a dose-dependent relationship between exposure to tobacco smoke and the risk of RCC, ^, with attenuation of risk after smoking cessation. Smoking is also associated with an increased risk of presenting with higher-grade RCC, as well as higher RCC-related mortality. ^,

Obesity and body weight have been associated with the risk of RCC in large national studies in Europe and systematic reviews. ^, Some studies suggest this effect is most prominent for women. ^, In China, metabolic syndrome was also associated with an increased risk of RCC. The association between obesity and RCC does appear to be dose dependent: The highest risk is among men and women with the highest body mass index (BMI). Obesity has also been associated with upstaging at the time of surgery and higher-grade RCC. However, there remains an “obesity paradox,” where patients with obesity are at higher risk of developing RCC but may have better clinical outcomes.

The association between high blood pressure (hypertension, HTN) and RCC was initially noted more than 30 years ago and appears to be stronger than for any other cancer type. Prospective studies in several countries confirmed that risk of RCC increased with presence of HTN in a dose-dependent manner, even when controlled for antihypertensive medications. Furthermore, a recent study favored a role of diastolic HTN rather than systolic HTN at the onset of RCC. However, any causal relation of HTN on RCC risk is difficult to disentangle from other conditions also associated with HTN and RCC (such as chronic kidney disease [CKD] and obesity) and has further complicated the evolving definition of HTN over the years. Nevertheless, large observational studies that adjusted for these factors found HTN to be independently associated with RCC.

The geographic distribution of RCC cases suggests that there may be local factors including various environmental exposures that contribute to the risk of developing RCC. A meta-analysis of multiple studies suggested a direct association between air pollution and the risk of RCC, with a 5 μg/m ³ increase in fine particulate matter pollution (PM _2.5 ) associated with a 9% increased risk of RCC. Serum measurements of perfluoroalkyl and polyfluoroalkyl substances (PFAS), which reflect environmental exposure to these pollutants, have also been associated with the development of RCC, particularly in White patients. ^, Exposure to the industrial solvent trichloroethylene, either through occupational exposure or through contaminated water supplies, has also been associated with RCC. In addition, various occupations have been associated with RCC including firefighters, agriculture workers, dry cleaners, and metal workers. ^{, ,} Occupational and environmental exposures are likely to increase with global urbanization, and knowledge of specific exposure risks can inform preventive measures in the future.

Renal cysts, ranging from simple to complex, are considered ubiquitous, with estimates that more than 50% of adults older than 50 years of age will have at least one renal cyst on abdominal imaging. The Bosniak Classification defines several characteristics, based on computed tomography (CT) and MRI, that can help estimate the risk that a cyst harbors some RCC and provides guidelines for surveillance of more complex cysts ^, ( Table 43.1 ). In general, thickened septations within cysts, thickened or nodular cyst walls, and evidence of enhancement within these structures suggest an increased risk of cystic RCC. Simple cysts (Bosniak 1) do not require any additional follow-up or surveillance, while the majority of Bosniak 4 cysts contain RCC. While treatment and surveillance options for solid renal masses are discussed later in this chapter, it is important to note that Bosniak 3 and 4 renal cystic masses, like small solid renal masses, may be appropriate for surveillance strategies since these lesions are often associated with more indolent forms of RCC.

The link between cystic diseases and RCC was described in 1880 by Brigidi and Severi. ^, CKD-related cystic diseases including acquired cystic kidney disease (ACKD) and polycystic kidney disease (PKD) have different characteristics from those of the general population and deserve further consideration.

The development of ACKD has been described among 7% to 22% of patients with CKD, with higher proportions among patients with dialysis-dependent end-stage kidney disease (ESKD) (10%−44% within 1−3 years) and increases further with prolonged duration of dialysis (>90% after 5−10 years). While patients with ACKD have historically been reported to have an elevated risk of malignant transformation to RCC, ^, the predominant renal mass histology identified in patients with ACKD is clear cell papillary renal tumor, which is no longer listed as a malignant RCC in the 2022 World Health Organization (WHO) classification due to its indolent nature and low metastatic potential. Although the presence of ACKD leading to RCC has also been described among kidney transplant recipients (23%), the proportion of kidney transplant recipients with ACKD is far less than that observed in patients receiving maintenance dialysis (80%). Acquired cysts seen in patients receiving maintenance dialysis have similar immunohistochemical profiles and histologic traits (epithelial cell−lined cysts with eosinophilic or foamy cytoplasm) when compared with tumors associated with ACKD, suggesting that acquired cysts are precursor lesions to renal tumors in this population. ^, Future studies will be required to understand the optimal evaluation of clear cell papillary renal tumors in patients with ACKD, to determine optimal surveillance regimens, and to determine when treatment may be required.

The prevalence of RCC in autosomal dominant polycystic kidney disease (ADPKD) does not appear to be greater than that in the general population, according to small case series and observational studies, ^{, ,} although there is some controversy in the literature on this subject. As in the general population, clear cell RCC tends to be the most common histologic diagnosis of RCC in ADPKD, although in one European series, tubulopapillary pathology was prominently observed as well (42%). ^{, ,} RCC in ADPKD presents at a younger mean age (50−60 years) than spontaneous RCC, but often with advanced disease, where one-third of patients have bilateral kidney involvement or metastatic disease. Presentation with advanced disease may be caused by delayed diagnosis, given the complexity of diagnostic images in the presence of multiple benign cysts in ADPKD. Symptomatic diagnosis rather than incidental discovery of RCC is more common in this select population. ^,

The causal relation between RCC and CKD is complex, with each pathology conferring risk to the other ( Fig. 43.1 ). The reported 100-fold increased risk of RCC among patients with ESKD may be due to the historical inclusion of clear cell papillary renal tumors in patients with ACKD, but this does not clearly explain the association of nondialysis-requiring CKD with RCC. The largest cohort study to date has examined the risk of RCC due to CKD stratified by estimated glomerular filtration rate (eGFR) among 1,190,538 subjects without known RCC. With decreasing eGFR ranges, RCC risk increased as follows: stage 3a CKD, hazard ratio (HR) 1.39 (confidence interval [CI], 1.22−1.58); stage 3b, HR 1.81 (CI, 1.51−2.17); and stages 4 and 5, HR 2.28 (CI, 1.78−2.92). The association was specifically with clear cell carcinoma and not with the other RCC subtypes. In contrast, the predominant RCC subtype seen in patients with ESKD is papillary RCC, suggesting pathology unrelated to ACKD. Moreover, findings of early or mild kidney pathology, such as albuminuria, have been related to cancer including RCC. The link between kidney function and localized RCC risk was abundantly apparent among 202,195 kidney transplant recipients. During periods of graft failure resulting in ESKD, the incidence of RCC rose and, during periods of graft function, RCC incidence fell. This pattern recurred during periods of kidney function loss (repeat graft failure). How loss of kidney function relates to RCC risk is largely unknown but may be related to increased use of imaging studies during evaluation of patients with impaired kidney function, or it may be attributed to inflammation, acidosis, or uremic factors often observed in advanced CKD.

Risk factors for chronic kidney disease (CKD).

Nephrectomy performed for renal cell carcinoma is associated with nephron loss due to tissue removal, as well as ischemic and vascular injury. This loss of nephrons is associated with either new-onset CKD or an increased risk of progression of CKD in patients who have various risk factors, as noted. ESKD, End-stage kidney disease; GS, glomerulosclerosis; IF, interstitial fibrosis; HTN, hypertension; VS, vascular sclerosis.

Clear cell RCC is the most common type of kidney cancer and originates in proximal tubular cells. Genetic abnormalities in ccRCC are roughly divided into those affecting the VHL gene, epigenetic regulators and chromatin remodeling genes, and disruption of PI3K-AKT-mTOR signaling. The VHL gene has three exons and is located on the short arm of chromosome 3 (3p25-26). Sporadic ccRCCs are characterized by loss of VHL function through loss of the short arm of chromosome 3, deletions, mutations, or epigenetic silencing of the VHL gene. ^,

The VHL gene plays a crucial role in a variety of cellular pathways. The key function of VHL protein (pVHL) is to serve as the substrate recognition unit in a protein complex responsible for polyubiquitination of a variety of proteins, including the HIF transcription factor complex. Polyubiquitination marks HIF for degradation in the presence of normal tissue oxygenation (normoxia). HIF protein subunits are encoded by HIF1A, EPAS1, HIF3A, ARNT, ARNT2, and ARNT3 genes. HIF1-alpha (HIF1a) or HIF2-alpha (HIF2a), which are the most important subunits in the pathogenesis of ccRCC, heterodimerize with HIF1-beta (HIF1b) to activate the transcription of hypoxia-inducible genes, such as vascular endothelial growth factor (VEGF), and to upregulate the VEGF receptor (VEGFR). The resulting clinical phenotype is characterized by florid vasculature, principally modulated by VEGF signaling pathways. In addition, HIF increases transcription of erythropoietin, platelet-derived growth factor-β (PDGF-β), transforming growth factor-α (TGF-α), and several glycolytic enzymes. Failure of pVHL to rein in the activity of HIF in normoxia has crucial implications for the clinical behavior and metabolic features of ccRCC. Among them are erythropoietin-dependent erythrocytosis, marked angiogenesis, and cell proliferation mediated by TGF-α and VEGF, ^, as well as aerobic glycolysis (Warburg effect) and the immunosuppressive effects of increased tryptophan catabolism.

Sporadic ccRCC commonly has additional mutations in epigenetic regulators, also localized to chromosome 3p25. These include polybromo 1 (PBRM1), BRCA-associated protein-1 ( BAP1 ), and SET domain–containing 2 (SETD2) genes involved in regulation of chromatin maintenance and remodeling. Generally, hypermethylation of promoter sites is associated with the tumors carrying these mutations (except for SETD2 ) and higher tumor grade. Loss of these genes further increases hypoxia signaling and genomic instability to fuel the RCC neoplastic phenotype. ^,

Genes encoding components of the mammalian target of rapamycin (mTOR) signaling pathway, such as PTEN, AKT, PIK3CA, and MTOR genes, are involved in cell growth, and cell proliferation signaling. Aberrations in these genes have been identified in up to 28% of RCC patients. PTEN deficiency in particular is associated with more aggressive tumors. Together with the abnormal expression of the focal adhesion kinase modulator of the mTOR pathway, these genetic defects are present in more than 50% of ccRCC patients.

The majority of ccRCC cases are sporadic; only 2% to 3% of ccRCC cases are linked to known hereditary diseases. Germline mutations in the VHL gene lead to VHL disease, an inherited syndrome with an estimated incidence of 1 in 36,000 live births, and a penetrance of more than 90% by age 65 years. ^, Most subjects affected by VHL disease inherit a germline mutation of the gene from the affected parent and a normal gene from the unaffected parent. All the cells of affected individuals who inherit the genetic trait will have germline mutations in VHL. However, tumors will develop only in those cells that undergo functional inactivation of the remaining wild-type allele (the second hit) and, in addition, are constituents of vulnerable target organs, with the formation of cysts, benign or malignant tumors in kidneys, the central nervous system, adrenal glands, pancreas, and reproductive adnexal organs. Germline BAP1 mutations can also be a cause of an autosomal dominant inherited predisposition for ccRCC. ^, When germline familial syndromes are present, careful monitoring for renal lesions starts at young ages, guided by expert genetics teams.

Papillary RCC (pRCC), also of proximal tubule origin, is the most common nccRCC. Previously, pRCC was divided into type 1 (typically characterized by MET mutations) and type 2 (which included RCCs that were fumarate hydratase [FH]-deficient or SMARCB1-deficient). In the latest 2022 WHO Classification, the type 1 and type 2 categories were removed because most pRCC tumors have both type 1 and type 2 histologic features and both types were determined to be composed of multiple molecular subtypes ^{, ,} ( Table 43.2 ). The current pRCC category still includes some patients who have a hereditary form (e.g., germline MET proto-oncogene−activating mutations). Therefore it is recommended that all new diagnoses of pRCC undergo genetic testing, especially if multifocal lesions are present. MET mutations can also occur in 10% to 20% of cases of somatic mutations in the sporadic form of pRCC. Additionally, trisomy 7 has been implicated in MET amplification in some cases of pRCC. Mutations in the epigenetic modifier genes PBRM1, BAP1, and SETD 2 have also been described with this tumor type but seem to be less prevalent compared with ccRCC. As additional molecular subtypes continue to be elucidated, it is possible that a subset of tumors currently classified as pRCC may, in turn, be renamed as distinct subtypes.

Comprising less than 5% of RCCs, this rare nccRCC originates from the renal collecting duct. ChRCC has a histologic appearance similar to benign oncocytomas, which can make diagnosis between these two distinct conditions challenging, especially when examining biopsy specimens. ChRCC is often linked with whole-chromosome losses and germline mutations in the folliculin gene (FLCN) found in the autosomal dominant Birt-Hogg-Dubé syndrome. The most frequent mutation in sporadic cases of chRCC involves downregulation of p53 tumor suppressor signaling and loss of function of PTEN leading to phosphatidylinositol-3 kinase (PI3K)-driven cell proliferation. ChRCC is more common in younger females and is typically the least aggressive of all RCC types, unless characterized by sarcomatoid transformation or metastasis.

Two rare nccRCCs are notable for their association with germline mutations and distinct clinical presentations and treatment options: FH-deficient RCC is one of the most aggressive RCCs. Loss of FH function can be a consequence of either germline or somatic alterations in the FH gene. Germline losses of FH lead to development of RCC at a very young age, thus screening for renal masses starts as early as age 8. FH loss can also be part of a genetic syndrome called hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC occurs predominantly in females and is associated with uterine fibroids. Another extremely rare RCC is SMARCB1-deficient RCC, associated with sickle cell trait and germline mutations in the SMARCB1 gene. Treatment of FH-deficient RCC and SMARCB1-deficient RCC differ from ccRCC, pRCC, and chRCC, as discussed in “ Systemic Therapy ” section later.

In addition to common considerations about surgical candidacy, guidelines suggest that patients with localized or locally advanced RCC considering surgery should also be assessed for their risk of significant CKD or ESKD following surgery. ^{, ,} This prognostic information can aid patients and clinicians in deciding between surveillance and treatment or choosing the type of surgical treatment to pursue. Identification of preexisting CKD (serum creatinine level and eGFR calculation) and proteinuria assessment (urine albumin-to-creatinine or urine protein-to-creatinine ratio) further allows for CKD staging using the Kidney Disease Improving Global Outcomes (KDIGO) classification criteria. Similarly, the risk of ESKD can be estimated by the Kidney Cancer Risk Equation, adapted from the Kidney Failure Risk Equation (KFRE). Further characterization of differential kidney function with renal nuclear scintigraphy before nephrectomy may help prognosticate the risk of CKD after treatment; however, these studies are limited because they tend to underestimate the postoperative function of the remaining kidney, which is often modestly augmented by compensatory hyperfiltration and hypertrophy. ^, Preservation of kidney function may be achieved by addressing CKD risk factors before RCC intervention. Optimization of comorbid diseases encompassing glycemic control among diabetics, blood pressure adjustment for those with HTN, prevention of acute kidney injury through medication review, and avoidance of hypotension and nephrotoxicity have been recommended.

For decades since the first nephrectomy in 1861, the primary treatment of kidney cancers had been radical nephrectomy, which involved total removal of the kidney and surrounding tissues, such as the adrenal glands or lymph nodes. Radical nephrectomy remains the primary treatment for locally advanced RCC and is increasingly supported by adjuvant systemic therapies for patients at a high risk of recurrence, with neoadjuvant treatment regimens on the horizon (discussed further later). Nephron-sparing surgery (i.e., partial nephrectomy) was originally reserved for imperative indications such as a renal mass in a solitary kidney. With the increase in appreciation for the importance of preservation of parenchymal mass and renal function, elective partial nephrectomy for eligible localized renal masses gained popularity. Partial nephrectomy has demonstrated equivalent oncologic outcomes for patients with small renal masses. The widespread adoption of technologies like robotic surgery has further encouraged the utilization of partial nephrectomy.

Partial nephrectomy has been associated with improved renal function preservation when compared with radical nephrectomy and, importantly, has also been associated with improved survival outcomes. A meta-analysis of 40,000 subjects during the early adoption of elective partial nephrectomy demonstrated improved all-cause and cancer-specific mortality for patients receiving partial nephrectomy. However, one randomized controlled trial, the European Organization for Research and Treatment of Cancer (EORTC) study, which assessed 541 patients with renal masses 5 cm or smaller, did not demonstrate improved survival with partial nephrectomy. This likely illustrates the selection bias that younger and healthier patients are more likely to receive a partial nephrectomy. With increasing access to experienced surgeons and minimally invasive techniques, the safety of both radical and partial nephrectomy has continued to improve. Currently, partial nephrectomy (when technically feasible) is a guideline-recommended treatment for patients with small renal tumors, Bosniak 3 or 4 renal cysts, baseline CKD, risk factors for progressive CKD following surgery, and multifocal tumors. ^,

The American Urological Association has recommended regular screening for tumor recurrence by imaging (abdominal CT, MRI, or ultrasound and chest radiography) initially after treatment. Imaging is performed on the basis of the risk of recurrence, with annual imaging recommended for low-risk tumors and imaging every 3 to 6 months for tumors at a high risk of recurrence. ^,

Interferon-α (IFN-α) and IL-2 were the initial immune therapies to be approved by the FDA. Cytokine therapy stimulates the immune system nonspecifically with the upregulation of T-cell and natural killer cell activity to recognize and destroy tumor cells, ^, but it can also have the undesired effect of suppressing the immune system and defeating natural immunosurveillance. ^, Response rates ranged from 10% to 25% and median OS from 11 to 13 months, with 5% sustained complete response for highly selected patients. Cytokine therapy, especially high-dose IL-2, is extremely limited by hypotension and “flulike” adverse events and could only be offered to patients with excellent heart, lung, and renal function. ^,

Immune checkpoint inhibitors (ICIs) have made immunotherapy far more accessible to patients and have nearly completely replaced cytokine therapy due to their higher tolerability and effectiveness. Immune checkpoint receptors sustain normal autoregulation of our immune system by downregulating T-cell and associated immune cell (macrophage, natural killer cell) activity. Tumors cells “hijack” this function to evade circulating immune cells. ICIs block the aberrant tumor-to–T-cell interaction, enabling T-cells to recognize the deviant cells and stimulate the natural immune mechanisms to eradicate them. Cytotoxic-T lymphocyte−associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are two receptor proteins regulating such adaptive immunity used in cancer treatment. Programmed cell death-ligand 1 (PD-L1) is the ligand for PD-1. Ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) have transformed the outlook of patients with RCC. ^, Single-agent nivolumab can shrink a minority of tumors but does increase OS, whereas single-agent ipilimumab has low activity. ^, However, a front-line combination regimen of ipilimumab with nivolumab is synergistic in patients with advanced ccRCC, yielding an overall response rate of 42% including 9% complete response rate and an excellent median OS of 53 months. Furthermore, for patients who have a response to this combination, the median duration of response is an impressive 75 months. Most strikingly, patients with sarcomatoid or rhabdoid histologies, historically with the worst outcomes, benefit the most from checkpoint inhibition. In most patients with metastatic ccRCC, it is standard of care to use combination ICI, typically in first-line therapy, or monotherapy in a later line of therapy, if not received in first line.

Toxicity related to checkpoint inhibitors tends to present with cutaneous, gastrointestinal, pulmonary, and hepatic involvement. Less commonly, renal complications can occur, with acute kidney injury due to acute tubulointerstitial nephritis (lymphocytic infiltration), which typically resolves with corticosteroid administration or cessation of treatment (as detailed in Chapter 57 ). ^,

Use of ICIs must be carefully considered in patients with preexisting autoimmune conditions or renal transplants, as immune tolerance can be broken. Retrospective studies demonstrate an approximately 40% graft rejection rate including a retrospective study of 69 patients by the Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium that demonstrated 42% of patients developed acute rejection and 28% experienced loss of allograft, at a median time of 24 days after first dose of ICI. However, in a prospective phase I study of 17 patients who remained on immunosuppression while receiving ICI for various cancers, rejection episodes attributed to the ICI occurred in only two patients (12%) and one had reversal of rejection through use of plasma exchange. Importantly, despite ongoing immunosuppression, 53% of patients had tumor responses to the ICI, including 24% who had a complete response. In patients with renal transplants, ICI treatment can be administered if the need for tumor control outweighs the risk of graft rejection. For patients on dialysis, because antibodies are cleared through the hepatic system, ICIs may be given and they result in excellent efficacy. ^,

Resistance to ICIs can be roughly grouped into tumor intrinsic and tumor extrinsic mechanisms. Tumor intrinsic mechanisms include decreased antigen presentation and decreased interferon gamma signaling. Beyond molecular characteristics found within tumor cells, extrinsic mechanisms such as host factors may also modify response to ICIs. For example, use of antibiotics can alter ICI efficacy and an individual’s microbiome may also confer sensitivity or resistance to ICIs. There appears to be cross-resistance among ICIs in RCC, which is borne out clinically: after progression with front-line ICI, there is limited value in either switching ICIs or including an ICI in a subsequent therapy doublet. Nevertheless, ICIs, used alone and in combination, provide durable responses and improve OS for advanced ccRCC. ICIs have transformed the therapeutic landscape of RCC.

The first VEGF inhibitor, the anti-VEGF antibody bevacizumab, prevents angiogenesis by inhibiting binding of VEGF ligand to VEGFR, thereby inhibiting the VEGF signaling pathway. VEGF inhibitors also impede tumor cell growth directly because VEGF is present in not only endothelial cells but also many other cell types including tumor cells. VEGF signaling can also be inhibited at the receptor level using VEGFR2 tyrosine kinase inhibitors (VEGFR2 TKIs, for simplicity here: TKIs) including axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, and most recently, tivozanib. ^, VEGFR2-targeted agents are only modestly effective as single agents and are often characterized by off-target effects and chronic toxicities, such as fatigue and rash. ^, Resistance can occur from the stimulation of alternative angiogenic pathways bypassing the VEGF blockage. ^, Interestingly, unlike for ICIs, there is not necessarily cross-resistance for TKIs: after progression on one, two, or three lines of TKIs, switching to yet another VEGFR2-targeted TKI can result in tumor shrinkage and stabilization. ^{, ,} Common, dose-dependent adverse effects of VEGF signaling inhibitors, which are important for the nephrologist to know and treat, are HTN (11%−43%) and proteinuria (41%−63%) related to the disruption of the role of VEGF in maintaining the integrity of the endothelium and slit diaphragm of the glomerular membrane. ^, Kidney biopsy most frequently shows thrombotic microangiopathy, but various glomerular diseases have been reported as well. ^, The drug toxicity is generally treated supportively with antihypertensive agents and protein-lowering medications (also see Chapter 57 ). TKIs, used as monotherapy or in combination with ICI, remain a mainstay of RCC treatment.

Pathways involving mTOR and its upstream kinase, PI3K, also promote tumor growth. mTOR is crucial for ribosomal activity in cell metabolism, growth, and proliferation through two separate complexes (mTORC1 and mTORC2). The PI3K pathway controls growth factor expression and tumor cell proliferation. The first-generation mTOR inhibitors (everolimus, temsirolimus) suppress mTORC1 activity alone; therefore mitogenic stimulation can occur alternately through mTORC2 and PI3K. These agents can generally stabilize RCC tumors (with a response rate of 7%–26%) but rarely reduce tumor size unless mTOR pathway mutations are present. ^, Newer MTOR inhibitors that additionally block the mTORC2 and PI3K pathway, have had disappointing clinical activity in RCC to date. ^, Everolimus was for many years a standard therapy for refractory disease and was used as the control arm in randomized trials of newer agents including nivolumab, cabozantinib, and belzutifan. In these trials, everolimus was consistently inferior. ^{, ,} Currently, with superior TKI monotherapy and combination therapies available, everolimus is rarely used as a single agent and has now been relegated to later lines of therapy. ^,

The HIF transcription factor complex is composed of HIF2a/HIF1b or HIF1a/HIF1b heterodimers and is the effector of a cellular oxygen-sensing pathway. When pVHL function is lost, HIF is stabilized and activates transcription of genes including VEGF, erythropoietin, and glycolytic enzymes critical for metabolic regulation. ^, Belzutifan is a first-in-class drug that targets HIF2a and is the newest targeted therapy for ccRCC. This small molecule binds the hydrophobic pocket of HIF2a, preventing heterodimerization with HIF1b and disrupting HIF’s ability to activate transcription of downstream hypoxia genes. In patients with VHL syndrome, treatment with belzutifan results in significant RCC control: With a median follow-up of 21.8 months, an unprecedented 0% of patients experienced tumor progression. Furthermore, hemangioblastomas in the central nervous system and pancreatic neuroendocrine tumors were also well controlled. In 2021, belzutifan was approved for adult patients with VHL syndrome for the treatment of their RCC and VHL-associated tumors.

In patients with sporadic advanced ccRCC, a randomized study compared belzutifan to everolimus in patients who had previously received two lines of therapy. At the first interim analysis, the HR for progression-free survival (PFS) significantly favored belzutifan (HR = 0.75, P < 0.001); OS data are still not mature. Nevertheless, due to its activity in later lines of therapy, in 2023, belzutifan was approved for patients with advanced RCC who had progressed on prior PD-1 or PD-L1 inhibitors and had also progressed on prior TKI. Adjuvant and first-line studies using belzutifan in conjunction with other agents (such as combined with ICI and/or TKI) are under way, as well as studies of additional small molecules targeting HIF2a.

Though both VEGF signaling and HIF inhibitors target the angiogenesis signaling pathway, side effect profiles are quite different. Treatment-emergent adverse events for belzutifan are related to the fact the fact that HIF-dependent transcription of erythropoietin is inhibited, resulting in anemia in 80% to 90% of patients, as well as fatigue in 30%, and hypoxia in 15%. ^, These toxicities can be mitigated by dose reduction and use of erythropoietin. Additional side effects in approximately 20% to 30% of patients include edema, increased serum creatinine, hypoglycemia, hypocalcemia, hyponatremia, hypokalemia, lymphopenia, myalgia, and transaminitis. Side effects are generally completely reversible by holding medication and reducing dose and are much easier to tolerate compared with side effects of TKIs or potential long-term side effects of ICIs. Due to its relatively mild side effect profile and clinical efficacy, the addition of belzutifan to the therapeutic armamentarium for RCC provides a gain for patients as an alternative to TKIs and opens the door for new combinations.

Each of the VEGF signaling/mTOR/HIF/ICIs discussed earlier has activity as a single agent. When combined in doublets, these agents can have synergistic clinical activity. Therefore combination therapies are now routinely used in first-line therapy for advanced disease. The combination with the longest median survival follow-up (> 8 years) is the combination of dual checkpoint inhibitors, ipilimumab + nivolumab, as discussed earlier. ^, Doublet combinations of TKI plus PD-1 or PD-L1 inhibitors, with reported median follow-up of 5 to 6 years, are also standard front-line therapies. The following combinations have been studied in randomized studies compared with single-agent sunitinib: axitinib/pembrolizumab, axitinib/avelumab, cabozantinib/nivolumab, ^, and lenvatinib/pembrolizumab. ^, OS HRs significantly favor TKI doublets compared with sunitinib, but the survival benefit does not yet seem to be as durable as for ipilimumab/nivolumab. Nevertheless, compared with ipilimumab plus nivolumab, doublets that include a TKI have a lower primary progression rate (as low as 10%), with a higher chance of tumor shrinkage and disease control. Therefore a doublet including a TKI is preferred over ipilimumab/nivolumab when patients have high tumor burden and/or require rapid tumor shrinkage. As TKI doublet studies mature, more information regarding therapy durability will emerge.

As an alternative combination regimen for patients who either cannot tolerate ICI or who have progressed on ICI, ^, there is an approved combination of VEGFR2 TKI lenvatinib and mTOR inhibitor everolimus. This combination has acceptable tolerability and high efficacy. To increase efficacy even higher, triplet combinations are being studied, with careful attention to the potential for greater toxicity and efficacy. One randomized study of triple therapy has been reported to date: Ipilimumab plus nivolumab plus cabozantinib demonstrated improved HR for PFS and higher overall response rates compared with ipilimumab plus nivolumab, as well as increased but tolerable adverse events. OS data are not yet mature. Additional studies of immune checkpoint inhibitors plus TKI plus HIF2a inhibitors are in progress (NCT06191796). The future of therapy for advanced RCC will continue to evolve as additional studies mature.

Much attention has been given to the selection of first-line therapy. However, optimal sequencing of therapies in second-line therapy and beyond have not yet been determined. In the absence of biomarkers to guide therapeutic decisions, the general approach is empiric use of any of the remaining approved agents, typically as single agents.

Non–clear cell RCC (nccRCC) subtypes are generally treated with the same single agent and combination regimens as ccRCC, with smaller studies that have demonstrated efficacy. Notably, a few specific nccRCC subtypes have different preferred therapies: 1. FH-deficient RCC has excellent disease control with EGFR inhibitor erlotinib + bevacizumab ; 2. collecting duct and renal medullary/SMARCB1-deficient subtypes are treated with standard cytotoxic chemotherapy regimens ^, ; and 3. ALK-rearranged RCCs respond to ALK inhibitors. Moving forward, as we better define molecular subtypes of RCC, therapies to target molecular vulnerabilities may offer improved outcomes.

The goal of neoadjuvant systemic therapy is either to reduce the size of the primary tumor to preserve renal function with a nephron-sparing approach or reduce size of advanced disease to improve feasibility of eradicating all tumors. Single-agent TKIs including axitinib, pazopanib, cabozantinib, sorafenib, and sunitinib were studied in small, mostly single-arm studies of 12 to 30 patients before nephrectomy. These agents were able to decrease tumor size in up to 46% of patients (axitinib). Axitinib was able to reduce the size of high-risk RCCs by an average of 1.3 cm, reduce nephrometry score by 1, and enable partial nephrectomy in 75% of patients. In a neoadjuvant study of 40 patients with axitinib plus avelumab, a 20% partial response rate has been reported. Prospective randomized trials specifically in the neoadjuvant setting are awaited to determine how long to treat before surgery and which regimen is most effective. So far, neoadjuvant treatment is an individualized and multidisciplinary decision, requiring close collaboration, reassessments, and discussion with medical oncologists and urologists.

Many patients are cured with nephrectomy alone. Patients at high risk of recurrence have been selected for many adjuvant studies including single agent VEGFR2 inhibitors (sunitinib, sorafenib, axitinib, pazopanib); mTOR inhibitor (everolimus); and ICIs (atezolizumab, pembrolizumab, nivolumab, and ipilimumab plus nivolumab). Sunitinib was the first adjuvant treatment approved for RCC, based on an improved disease-free survival (DFS) compared with surveillance alone. However, sunitinib has not demonstrated an OS benefit in the adjuvant setting, so it is seldom used for this indication. The Keynote-564 study ^, of adjuvant pembrolizumab is the first, and currently only, randomized study to demonstrate an OS benefit for patients with high-risk ccRCC (patients with pT2 grade 4, or any pT3 or pT4 or node-positive disease or fully resected metastatic disease). One year of adjuvant pembrolizumab treatment resulted in an OS HR of 0.62 (95% CI 0.44−0.87; P =.0024) and DFS HR of 0.72 (95% CI 0.59−0.87), both compared with placebo. Toxicities were common: The most common adverse events included fatigue and diarrhea. On the basis of efficacy and its safety profile, pembrolizumab has been approved by the FDA for adjuvant treatment of ccRCC. Notably, in contrast to the PD-1 inhibitor pembrolizumab, neither atezolizumab (PD-L1 inhibitor) nor nivolumab (PD-1 inhibitor) alone or in combination with ipilimumab have demonstrated DFS or OS benefits in their intention-to-treat cohorts. Furthermore, providers should consider that even in patients selected for high risk of recurrence, up to 40% of patients may be cured by nephrectomy alone. Thus development of biomarkers to select patients who benefit from treatment will be key to avoiding exposure of all patients to checkpoint inhibitor toxicity. With so many negative studies, newer adjuvant investigations focus on combinations, such as pembrolizumab plus belzutifan. It remains to be seen if combination therapies can affect OS in the adjuvant setting, as they have in the advanced setting.