Systemic therapy of advanced clear cell renal carcinoma

INTRODUCTION — Surgical resection of stage I to III renal cell carcinoma (RCC) can be curative, but up to one-third of patients eventually recur. In addition, approximately 15 percent of patients with RCC present with locally advanced or metastatic RCC, for which surgery is noncurative. The natural history of disease for patients with advanced or metastatic RCC can vary widely from a few months to many years depending on the clinical, pathologic, laboratory, and radiographic features of the disease.

Immunotherapy with checkpoint inhibitors has become a major modality for the treatment of clear cell RCC. This topic will discuss initial systemic therapy for advanced clear cell RCC, with a particular focus on immunotherapy-based combinations. An overview of the treatment approach to clear and non-clear cell RCC, prognostic factors in RCC, and the use of antiangiogenic and molecularly targeted therapy are discussed separately. (See "Overview of the treatment of renal cell carcinoma" and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma" and "The treatment of advanced non-clear cell renal carcinoma".)

RATIONALE FOR IMMUNOTHERAPY — Immunotherapy with monoclonal antibodies directed against programmed cell death 1 protein (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has become an integral part of the management of RCC.

The fields of immunology and oncology have been linked since the late 19^th century, when the surgeon William Coley reported that injection of killed bacteria into sites of sarcoma could lead to tumor shrinkage. Since that time, exponential advances in the understanding of the intersection between immune surveillance and tumor growth and development have led to broad therapeutic advances that are now being studied in all cancer types. (See "Principles of cancer immunotherapy".)

Removal of primary RCCs can evoke an immune response that occasionally results in spontaneous and dramatic remissions in metastases, particularly in the lungs [1,2]. These observations were followed by the clinical demonstration of antitumor activity with the cytokine interleukin 2 (IL-2) and interferon alfa (IFNa), although only a minority of patients derived major clinical benefit.

SELECTION OF INITIAL THERAPY — Systemic therapy is usually given as a combination of agents from the following classes [3]:

●Programmed cell death 1 protein (PD-1) checkpoint inhibitors (nivolumab and pembrolizumab)

●Programmed cell death ligand 1 (PD-L1) checkpoint inhibitors (avelumab and atezolizumab)

●Anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies (ipilimumab)

●Inhibitors of the vascular endothelial growth factor (VEGF) pathway (ie, antiangiogenic agents; axitinib, sunitinib, pazopanib, cabozantinib, lenvatinib, and bevacizumab)

●Mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (everolimus)

Interleukin 2 (IL-2) is used less frequently, and interferon alfa (IFNa) has effectively been replaced by other agents. (See 'Less preferred treatment options' below.)

Systemic therapy for patients with previously untreated RCC without brain metastases is discussed below (algorithm 1). Treatment options for those with brain metastases are discussed separately. (See "Overview of the treatment of renal cell carcinoma" and "Overview of the treatment of renal cell carcinoma", section on 'Brain metastases, treatment naïve'.)

Importantly, the patterns of response to treatment with immunotherapy agents differ from those with molecularly targeted agents or cytotoxic chemotherapy. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

Risk stratification — The choice of treatment for patients with advanced disease has been based on prognostic risk factors historically developed in the era of frontline vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (ie, antiangiogenic agents). The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model integrates six adverse factors (table 1) [4]:

●Karnofsky performance status (KPS) <80 percent

●Time from diagnosis to treatment <1 year

●Hemoglobin concentration less than the lower limit of normal

●Serum calcium greater than the upper limit of normal

●Neutrophil count greater than the upper limit of normal

●Platelet count greater than the upper limit of normal

Patients with none of these risk factors are considered favorable risk, those with one or two are considered intermediate risk, and those with three or more are considered poor risk.

In the absence of alternative immunotherapy-based prognostic criteria, the IMDC prognostic criteria continue to be used in the era of immunotherapy, both by clinical trials to risk-stratify patients and by providers and clinical guidelines to direct therapy [5,6].

Favorable-risk disease — The decision to treat patients with favorable-risk disease takes into account multiple factors, including rate of growth, location of tumor (eg, proximity to vital organs with potential for damage), and symptoms (algorithm 1).

Limited disease burden — For patients with treatment-naïve, favorable-risk disease with limited disease burden who are asymptomatic, we suggest close active surveillance, with initiation of systemic therapy at onset of new lesions, accelerated growth of existing lesions, or symptomatic disease. (See 'Risk stratification' above and 'Active surveillance' below.)

For those with limited burden, favorable-risk disease who desire a more aggressive management approach, options include:

●Single-agent antiangiogenic therapy – Single-agent antiangiogenic therapy may be an appropriate treatment option for those who wish to avoid the potential toxicities of immunotherapy-based regimens and/or prefer the convenience of orally administered treatments. Preferred agents include sunitinib or pazopanib. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Inhibitors of the VEGF pathway'.)

●Single-agent immunotherapy – Single-agent immunotherapy with pembrolizumab (table 2) or nivolumab (table 3) may be an appropriate treatment option for patients with favorable-risk tumors and limited disease burden who are eligible for immunotherapy, but are not good candidates for ipilimumab-based regimens or antiangiogenic agents. Data on single-agent immunotherapy have demonstrated good clinical response rates and the opportunity for durable responses in this population. However, single-agent immunotherapy does not have regulatory approval as initial therapy in this population. (See 'Pembrolizumab' below and 'Nivolumab' below.)

Substantial disease burden — Treatment is indicated for those with favorable-risk disease who have more substantial disease burden, are symptomatic, and/or have more rapidly progressive disease. Immunotherapy-based combinations with either pembrolizumab plus axitinib, nivolumab plus cabozantinib, or lenvatinib plus pembrolizumab are generally preferred. Although these regimens improve response rates and progression-free survival (PFS), which are important clinical endpoints that translate into a better quality of life, none have shown superior overall survival (OS) compared with sunitinib in this patient population.

●Pembrolizumab plus axitinib – Pembrolizumab plus axitinib is one preferred option for patients who are candidates for combined immunotherapy and antiangiogenic therapy. (See 'Pembrolizumab plus axitinib' below.)

In a phase III trial that included patients with favorable-risk disease, pembrolizumab plus axitinib conferred an OS benefit and improved objective response rates (ORRs) and complete response (CR) rates over antiangiogenic therapy alone in the overall population [7-9]. Among the favorable-risk patients, the combination had higher ORRs, but similar PFS and OS compared with antiangiogenic therapy alone.

●Nivolumab plus cabozantinib – In patients who are candidates for combined immunotherapy plus antiangiogenic therapy, nivolumab plus cabozantinib is a reasonable alternative to pembrolizumab plus axitinib. This combination is well tolerated [10] and may be preferred in patients who require a rapid treatment response due to substantial, symptomatic disease burden (eg, bony metastases). In a phase III trial that included patients with favorable-risk disease, nivolumab plus cabozantinib improved OS and PFS over antiangiogenic therapy in the overall population and demonstrated clinical efficacy across all IMDC risk subgroups, including longer PFS and ORR in those with favorable-risk disease [11,12]. (See 'Nivolumab plus cabozantinib' below.)

●Lenvatinib plus pembrolizumab – In patients with favorable-risk disease, lenvatinib plus pembrolizumab is another acceptable treatment option. This combination demonstrated higher ORR compared with sunitinib, with higher PFS and similar OS benefits. However, this regimen has higher toxicity due to lenvatinib (eg, hypertension, proteinuria) and may not be tolerated as well as the above regimens. (See 'Lenvatinib plus pembrolizumab' below.)

●Other strategies – Alternative strategies include combination therapy with nivolumab plus ipilimumab; avelumab plus axitinib; or antiangiogenic monotherapy [13].

•Nivolumab plus ipilimumab – Nivolumab plus ipilimumab (table 4) is a reasonable option for patients who are willing to tolerate the potential toxicities of combination immunotherapy to achieve treatment-free survival. This combination results in sustained CR rates in 13 percent of patients with favorable-risk disease. Among those with favorable-risk disease, nivolumab plus ipilimumab improved treatment-free survival relative to sunitinib [14] despite having similar OS and lower PFS and ORRs [15]. (See 'Nivolumab plus ipilimumab' below.)

•Avelumab plus axitinib – In a phase III trial, axitinib plus avelumab, relative to antiangiogenic therapy alone, improved PFS and ORRs in those with favorable-risk disease, although an OS benefit has not been established with this approach [16]. Data on CRs and treatment-free survival for the combination are also immature. (See 'Avelumab plus axitinib' below.)

Ineligible for immunotherapy (favorable-risk) — Antiangiogenic therapy that incorporates a VEGFR inhibitor may be preferred in those who are ineligible for or who decline immunotherapy. Preferred options include sunitinib, pazopanib, and lenvatinib plus everolimus. An alternative option is cabozantinib, which is more effective than sunitinib in patients with intermediate- and poor-risk disease but has not been formally evaluated in those with favorable-risk disease. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma" and 'Lenvatinib plus everolimus' below.)

Intermediate- and poor-risk disease — For patients with treatment-naïve intermediate- or poor-risk disease, we recommend checkpoint inhibitor immunotherapy-based regimens over antiangiogenic therapy alone. Our choice of therapy is primarily determined by the presence of symptomatic or life-threatening disease burden and patient clinical characteristics, as follows:

Patients with symptomatic or life-threatening disease burden — For patients with symptomatic or life-threatening disease burden, we suggest either lenvatinib plus pembrolizumab or nivolumab plus cabozantinib rather than other available agents. Patients with symptomatic tumor involvement of organs such as the liver or bones often require a rapid treatment response, which has been demonstrated by the high ORRs of lenvatinib plus pembrolizumab (71 percent) and nivolumab plus cabozantinib (57 percent), compared with other regimens. Lenvatinib plus pembrolizumab also results in a high CR rate (18 percent) [17-19]. (See 'Lenvatinib plus pembrolizumab' below and 'Nivolumab plus cabozantinib' below.)

Patients without symptomatic, life-threatening disease burden — For those without symptomatic, life-threatening disease burden, we suggest nivolumab plus ipilimumab (table 4) rather than combination immunotherapy and antiangiogenic therapy. Nivolumab plus ipilimumab offers the opportunity for curative intent therapy by providing durable responses, preserving OS benefit in extended follow-up, and improving treatment-free survival relative to single-agent sunitinib. By indirect comparison of randomized trials, nivolumab plus ipilimumab confers these treatment benefits to a greater degree than combination immunotherapy plus antiangiogenic therapy, despite having a relatively lower ORR. (See 'Nivolumab plus ipilimumab' below.)

For patients who are not anticipated to tolerate the toxicities of nivolumab plus ipilimumab (eg, those with active autoimmune conditions or limited mobility), the combination of immunotherapy plus antiangiogenic therapy is an appropriate alternative. These regimens have high ORRs and improve OS, but treatment responses are less durable relative to nivolumab plus ipilimumab. Options include lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, or pembrolizumab plus axitinib. (See 'Lenvatinib plus pembrolizumab' below and 'Nivolumab plus cabozantinib' below and 'Pembrolizumab plus axitinib' below.)

Regimens that combine immunotherapy using PD-1 inhibitors and antiangiogenic therapy have high objective response rates and improve OS compared with single-agent sunitinib. However, the OS benefit initially seen (eg, with pembrolizumab plus axitinib and lenvatinib plus pembrolizumab) diminishes over time (ie, the tails on the OS curves for these combinations versus sunitinib converge). Furthermore, treatment responses are not as durable as those seen with nivolumab plus ipilimumab. It is likely that the benefits of combining immunotherapy and antiangiogenic therapy are not additive for immunotherapy-specific endpoints (eg, cure, treatment-free interval, tails on the OS curve). Rather, similar or better results could possibly be achieved by giving immunotherapy alone, followed by antiangiogenic therapy in individuals who do not experience a durable response to the immunotherapy. Patients treated with an initial combination therapy also continue to receive an antiangiogenic agent until disease progression or unacceptable toxicity. In contrast, patients whose disease responds to nivolumab plus ipilimumab have the opportunity for a treatment-free remission after stopping therapy either due to toxicity, CR, or completing planned nivolumab maintenance therapy. (See 'Nivolumab plus ipilimumab' below.)

While avelumab plus axitinib has been evaluated as initial therapy, it is not one of our preferred regimens since it has not demonstrated an OS benefit in randomized trials (algorithm 1) [16]. (See 'Avelumab plus axitinib' below.)

Ineligible for immunotherapy (intermediate- and poor-risk) — For those who are ineligible for or choose to forego initial treatment with immunotherapy combinations, regardless of risk category, we offer therapy that incorporates an antiangiogenic agent. While we prefer the combination of lenvatinib plus everolimus, an mTOR inhibitor, as this combination improved PFS over single-agent sunitinib in a randomized trial [11,12], another reasonable alternative includes cabozantinib (algorithm 1). (See 'Lenvatinib plus everolimus' below and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Preferred VEGFR inhibitors'.)

ACTIVE SURVEILLANCE — For patients with treatment-naïve, favorable-risk disease who are asymptomatic or minimally symptomatic with limited disease burden, we suggest close active surveillance to determine the pace of disease. Surveillance allows the deferral of therapy and its associated toxicity until more compelling disease progression is documented (algorithm 1).

Our approach to surveillance is to use computed tomography (CT) imaging of the chest, abdomen, and pelvis every three months for the first year, every four months for the second year, and every six months thereafter. Systemic therapy is initiated at the onset of accelerated disease progression, new lesions, and/or symptomatic disease. (See 'Initial treatment options' below.)

Both observational and trial data support the use of active surveillance [20,21]. As an example, in a prospective phase II trial, 52 patients with treatment-naïve metastatic RCC underwent radiographic surveillance [20]. Median time on surveillance until initiation of systemic therapy was longer for those with favorable-risk disease relative to those with intermediate- or poor-risk disease (22 versus 9 months). There was no impact on rates of depression or anxiety, or on quality of life, based on patient-reported questionnaires.

INITIAL TREATMENT OPTIONS

Nivolumab plus ipilimumab — For patients with advanced RCC without prior exposure to systemic therapy, the combination of nivolumab plus ipilimumab (table 4) improves overall survival (OS) compared with sunitinib and preserves this OS benefit in extended follow-up [15,22-25]. Furthermore, nivolumab plus ipilimumab offers the opportunity for curative intent therapy by improving complete response (CR) rates across all patient subgroups; providing durable responses; and improving treatment-free survival relative to sunitinib [14]. By indirect comparison of randomized trials, nivolumab plus ipilimumab confers these treatment benefits to a greater degree than combination immunotherapy plus an antiangiogenic agent, despite having a lower ORR.

Nivolumab plus ipilimumab is approved by the US Food and Drug Administration (FDA) for treatment-naïve patients with intermediate- or poor-risk advanced RCC. We also use nivolumab plus ipilimumab off label as initial therapy in those with favorable-risk disease who are symptomatic and/or experience interval disease progression while on surveillance. (See 'Selection of initial therapy' above.)

Subsequent maintenance therapy with two years of nivolumab is also well tolerated, and those who stop therapy for reasons other than disease progression have the opportunity for a prolonged treatment-free interval. The initial use of nivolumab plus ipilimumab also avoids potential cardiovascular adverse events (eg, hypertension, thrombotic events, wound healing issues) commonly associated with antiangiogenic agents and allows for a wider range of available antiangiogenic therapies upon disease progression. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and 'Subsequent therapy' below.)

In an open-label phase III trial (CheckMate 214), 1096 patients with treatment-naïve advanced or metastatic clear cell RCC were randomly assigned to nivolumab plus ipilimumab versus sunitinib [15,22-24,26]. Patients with brain metastases were excluded. The combination of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) was given every three weeks for four doses, followed by single-agent nivolumab (3 mg/kg or a flat dose of 240 mg (table 3)) every two weeks for up to two years. Sunitinib was given at 50 mg/day for four out of every six weeks.

At a median follow-up of 68 months, nivolumab plus ipilimumab, relative to sunitinib, had the following results [15]:

●Entire study population – Improved OS (five-year OS 48 versus 37 percent; hazard ratio [HR] 0.72, 95% CI 0.62-0.85). Progression-free survival (PFS) was higher for the combination, although the results did not meet statistical significance (five-year PFS 30 versus 14 percent; HR 0.86, 95% CI 0.73-1.01). Objective response rates (ORRs; 39 versus 32 percent) and CR rates (12 versus 3 percent) were both higher for the combination. Duration of response (DOR) was also longer for the combination (median not reached versus 20 months, five-year DOR 56 versus 25 percent; HR 0.46, 95% CI 0.31-0.66).

●Intermediate- or poor-risk disease – Improved OS and PFS (five-year OS 43 versus 31 percent; HR 0.68, 95% CI 0.58-0.81; five-year PFS 31 versus 11 percent; HR 0.73, 95% CI 0.61-0.87). ORRs (42 versus 27 percent) and CR rates (11 versus 2 percent) were both superior for the combination. Treatment-free survival is also twice as long for the combination (seven versus three months) [14].

●Favorable-risk disease – Similar OS (five-year OS 63 versus 55 percent; HR 0.94, 95% CI 0.65-1.37) but lower PFS (five-year PFS 26 versus 21 percent, median 12 versus 29 months; HR 1.60, 95% CI 1.13-2.26). Lower ORRs (30 versus 52 percent) but higher CR rates (13 versus 6 percent) were seen for the combination. Despite these outcomes, treatment-free survival is almost three times as long for the combination (11 versus 4 months) [14].

Nivolumab plus ipilimumab offers the opportunity for curative intent therapy by providing more durable treatment responses than those seen in separate studies of immunotherapy plus antiangiogenic agents (ie, pembrolizumab plus axitinib [9] and lenvatinib plus pembrolizumab [19]). Most patients with a complete and/or ongoing treatment response can discontinue all therapy, and many experience prolonged treatment-free survival [14]. (See 'Pembrolizumab plus axitinib' below and 'Lenvatinib plus pembrolizumab' below.)

In extended four-year follow-up of CheckMate-214, among those with a CR to nivolumab plus ipilimumab, 86 percent (51 of 59 patients) demonstrated ongoing disease response, and approximately half of those with durable responses (27 of 51 patients) discontinued therapy and did not require further treatment at long-term follow-up. Among those with a partial response (PR), 61 percent (95 of 156 patients) also demonstrated ongoing disease response [22].

Side effects and quality of life data (which is associated with improved OS [27]) also favored the combination of nivolumab plus ipilimumab over sunitinib [28]. The toxicity of this combination was consistent with that observed with its use for other indications. (See "Toxicities associated with immune checkpoint inhibitors" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Toxicity'.)

Pembrolizumab plus axitinib — For patients with advanced RCC without prior exposure to systemic therapy, the combination of pembrolizumab plus axitinib improves OS and PFS compared with sunitinib. This combination is approved by the FDA as initial therapy for patients with advanced RCC, regardless of risk stratification. This combination has not been directly compared with other immunotherapy-based combinations.

For pembrolizumab plus axitinib, treatment-related toxicities may be easier to manage due to the dosing flexibility and short half-life of axitinib. In patients who experience treatment-related toxicities on this combination, such as diarrhea or transaminitis, interrupting therapy may allow the clinician to distinguish more easily immunotherapy-related adverse events (which may persist despite stopping treatment) from vascular endothelial growth factor receptor (VEGFR) inhibitor-related toxicities (which may quickly resolve once axitinib is discontinued). (See "Immune checkpoint inhibitor colitis", section on 'Differential diagnosis' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

In a phase III trial (KEYNOTE-426), 861 patients with previously untreated advanced clear cell RCC were randomly assigned to pembrolizumab plus axitinib versus sunitinib alone [7-9]. Pembrolizumab was administered at 200 mg intravenously every three weeks for up to 35 cycles (approximately two years), whereas axitinib or sunitinib was continued until disease progression or unacceptable toxicity. Patient subgroups included those with favorable-, intermediate-, or poor-risk disease (based on the International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk classification) and sarcomatoid features.

In preliminary results, after a median follow-up of 67 months, relative to sunitinib, pembrolizumab plus axitinib had the following results [7-9]:

●Entire study population – Improved OS, although the benefit diminished over time (median 47 versus 41 months, three-year OS 63 versus 54 percent; four-year OS 49 versus 45 percent; five-year OS 42 versus 37 percent; HR 0.84, 95% CI 0.71-0.99), longer PFS (five-year PFS 18 versus 7 percent; HR 0.69, 95% CI 0.59-0.81), higher objective response rates (ORR) (61 versus 36 percent), and higher CR rate (12 versus 4 percent). The median duration of response (DOR) for the combination versus sunitinib was 24 and 15 months, respectively.

●Intermediate- or poor-risk disease – Improved OS (five-year OS 38 versus 30 percent; HR 0.76, 95% CI 0.62-0.93), longer PFS (five-year PFS 18 versus 7 percent; HR 0.68, 95% CI 0.56-0.82), and higher ORRs (46 versus 32 percent).

●Favorable-risk disease – Similar OS (five-year OS 50 versus 52 percent; HR 1.10, 95% CI 0.79-1.54) and PFS (five-year PFS 19 versus 8 percent; HR 0.76, 95% CI 0.57-1.02). ORRs were higher for the combination (69 versus 44 percent).

The combination of pembrolizumab plus axitinib had slightly higher rates of grade ≥3 adverse events compared with sunitinib (67 versus 62 percent), but the rate of any grade treatment-related toxicities were lower with the combination than with sunitinib, when adjusted for exposure time (63 versus 97 events per 100 person-months) [8]. In both groups, the most common grade ≥3 adverse events were diarrhea (10 versus 5 percent) and hypertension (22 versus 20 percent). Pembrolizumab plus axitinib demonstrated similar health-related quality of life outcomes compared with sunitinib [29].

The efficacy of pembrolizumab plus axitinib and other immunotherapy-based regimens for those with RCCs containing sarcomatoid features is discussed separately. (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Non-clear cell RCC with sarcomatoid features'.)

Nivolumab plus cabozantinib — For patients with advanced RCC without prior exposure to systemic therapy, the combination of nivolumab and cabozantinib improves OS and PFS compared with sunitinib. This combination is approved by the US FDA as initial therapy for patients with advanced RCC, regardless of risk stratification [30]. This combination has not been directly compared with other immunotherapy-based combination regimens.

In a phase III trial (CheckMate 9ER), 651 patients with treatment-naïve advanced RCC were randomly assigned to either nivolumab plus cabozantinib or sunitinib [11,12]. Patient subgroups included those with favorable-, intermediate-, or poor-risk disease (based on the IMDC risk classification).

At median follow-up of 33 months, compared with sunitinib, nivolumab plus cabozantinib had the following results [11,12]:

●Entire study population – Improved OS (two-year OS 70 versus 60 percent, median 38 versus 34 months; HR 0.70, 95% CI 0.55-0.90) and PFS (two-year PFS 40 versus 21 percent, median 17 versus 8 months; HR 0.56, 95% CI 0.46-0.68). The combination also demonstrated higher ORR (56 versus 28 percent) and CR rate (12 versus 5 percent). Median time to response was faster with the combination compared with sunitinib (2.8 versus 4.2 months).

●Intermediate- or poor-risk disease – Higher OS (median 38 versus 34 months; HR 0.74, 95% CI 0.54-1.01 for intermediate-risk disease, which was not statistically significant; median 32 versus 11 months, 0.49, 95% CI 0.31-0.79 for poor-risk disease), improved PFS (median 18 versus 9 months; HR 0.54, 95% CI 0.46-0.76 for intermediate-risk disease; median 10 versus 4 months; HR 0.35, 95% CI 0.23-0.55 for poor-risk disease), and higher ORR (57 versus 29 percent for intermediate-risk disease; 38 versus 10 percent for poor-risk disease).

●Favorable-risk disease – Similar OS (HR 1.03, 95% CI 0.55-1.92), longer PFS (median 21 versus 14 months; HR 0.73, 95% CI 0.48-1.11, which is not statistically significant), and higher ORR (66 versus 44 percent).

Additionally, PFS benefit results were consistent across all subgroups, including those with positive or negative PD-L1 expression, with or without prior nephrectomy, and with or without bone metastases.

Grade ≥3 treatment-related adverse events occurred in 65 percent receiving nivolumab plus cabozantinib versus 54 percent receiving sunitinib. For nivolumab plus cabozantinib, grade ≥3 toxicities included hypertension (13 percent), hyponatremia (9 percent), palmar-plantar erythrodysesthesia (8 percent), diarrhea (7 percent), increased ALT level (5 percent), hypophosphatemia (6 percent), increased AST and proteinuria (4 percent each), and fatigue (3 percent) [10-12].

Lenvatinib combinations

Lenvatinib plus pembrolizumab — For patients with treatment-naïve advanced RCC, the combination of lenvatinib plus pembrolizumab improved both OS and PFS in a randomized phase III trial [17,18]. Additionally, this combination demonstrated high CR rates. This combination is approved by the US FDA as initial therapy for patients with advanced RCC, regardless of risk stratification [31,32].

For patients treated with lenvatinib plus pembrolizumab, we initiate treatment with full-dose lenvatinib upfront, as reduced doses of VEGFR tyrosine kinase inhibitors, including lenvatinib, have been associated with decreased efficacy. However, we encourage proactive dose adjustment for treatment-related toxicities to maintain quality of life [33-38].

Based on data from early phase trials [39,40], the combination of lenvatinib plus pembrolizumab was evaluated in an open-label phase III clinical trial (CLEAR) [17,18]. In this study, 1069 patients with treatment-naïve advanced RCC were randomly assigned to either lenvatinib plus pembrolizumab; lenvatinib plus everolimus; or sunitinib. For patients treated with lenvatinib plus pembrolizumab, lenvatinib was given at 20 mg daily and pembrolizumab was given at 200 mg on day 1 of a 21-day cycle for up to 35 cycles (approximately two years). In those treated with lenvatinib plus everolimus, lenvatinib was given at 18 mg daily, and everolimus was given at 5 mg daily on a 21-day cycle.

At a median follow-up of approximately four years relative to sunitinib, the combination of lenvatinib plus pembrolizumab demonstrated the following results [18,19]:

●Entire study population – Improved OS, although the benefit diminished over time (median 54 months each; two-year OS 80 versus 70 percent; three-year OS 66 versus 60 percent; HR 0.79, 95% CI 0.63-0.99); improved PFS (median 24 versus 9 months; three-year PFS 37 versus 18 percent; HR 0.47, 95% CI 0.38-0.57); and longer DOR (median 27 versus 15 months; HR 0.57, 95% CI 0.43-0.76). ORR was also higher for the combination (71 versus 37 percent), including CR rates (18 versus 4 percent).

●Intermediate- and poor-risk disease – Improved PFS (median 22 versus 6 months; HR 0.43, 95% CI 0.34-0.55) and improved OS (median 48 versus 34 months; HR 0.74, 95% CI 0.57-0.96) that was mainly driven by those with poor-risk disease (HR 0.47).

●Favorable risk disease – Improved PFS (median 29 versus 13 months; HR 0.50, 95% CI 0.35-0.71) and similar OS (median not reached versus 60 months; HR 0.94, 95% CI 0.58-1.52).

Grade ≥3 adverse events of any cause were higher for the combination compared with sunitinib (82 versus 72 percent), and no new toxicity profiles were reported [17]. For lenvatinib plus pembrolizumab, grade ≥3 toxicities included hypertension (28 percent), diarrhea (10 percent), weight decrease or proteinuria (8 percent each), and palmar-plantar erythrodysesthesia syndrome (4 percent).

Lenvatinib plus pembrolizumab also demonstrated similar or more favorable health-related quality of life outcomes compared with sunitinib [41]. However, the similar quality of life outcomes between the two treatment arms suggest an increase in treatment-related toxicity from lenvatinib plus pembrolizumab, despite its increased clinical efficacy and reduction of tumor-related symptoms.

Lenvatinib plus everolimus — In the randomized phase III trial (CLEAR), among patients with treatment-naïve RCC, the combination of lenvatinib plus everolimus improved PFS (median 15 versus 9 months; HR 0.65, 95% CI 0.53-0.8) over sunitinib, which was consistent across all IMDC subgroup [17]. ORR was also higher for the combination (54 versus 36 percent), including CR rates (10 versus 4 percent). However, OS was not higher for the combination (medians not reached; HR 1.15, 95% CI 0.88-1.5). Grade ≥3 adverse events of any cause were higher for the combination compared with sunitinib (83 versus 72 percent).

Data for lenvatinib plus everolimus as subsequent therapy in patients with advanced RCC who have progressed on antiangiogenic therapy are discussed separately. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Lenvatinib plus everolimus'.)

Other strategies — While some other combinations have suggested activity, they have yet to show an OS benefit. Initial data regarding these combinations are presented below.

Avelumab plus axitinib — Axitinib has also been shown to combine safely and effectively with the checkpoint inhibitor avelumab, and this is an option for first-line therapy. However, we prefer other immunotherapy combinations over axitinib plus avelumab for patients without a contraindication to immunotherapy. In separate randomized trials, axitinib plus avelumab improved PFS, but not OS, in all patient subgroups relative to sunitinib, whereas both survival outcomes were improved and simultaneously evident for the other two combination regimens. These three regimens have not been directly compared in a single randomized trial. (See 'Nivolumab plus ipilimumab' above and 'Pembrolizumab plus axitinib' above.)

Based on data from early phase clinical trials [42,43], avelumab plus axitinib was evaluated in a phase III trial (JAVELIN Renal 101). In this study, 886 treatment-naïve patients with advanced clear cell RCC were randomly assigned to the combination of avelumab plus axitinib versus sunitinib [16,44].

At a median follow-up of approximately 19 months, compared with sunitinib, avelumab plus axitinib demonstrated the following results by population:

●Entire study population – Improved PFS (median 13.3 versus 8 months; HR 0.69, 95% CI 0.57-0.83) and higher ORRs (53 versus 27 percent). CR rates were similar for the two treatment arms (4 versus 2 percent). Although OS data are immature, the combination did not demonstrate an improvement in OS at data cutoff for the overall population (HR 0.80, 95% CI 0.62-1.03) or for any other patient subgroup.

●PD-L1-positive tumors – Improved PFS (median 13.8 versus 7 months; HR 0.62, 95% CI 0.49-0.78) and higher ORRs (56 versus 27 percent) and CR rates (6 versus 2 percent).

●Favorable-risk disease – Improved PFS (HR 0.63, 95% CI 0.4-0.99) and higher ORRs (67 versus 40 percent).

●Intermediate- or poor-risk disease – Improved PFS (HR 0.76, 95% CI 0.6-0.95, for intermediate-risk disease; HR 0.51, 95% CI 0.34-0.77, for poor-risk disease) and higher ORRs (53 versus 27 percent for intermediate-risk disease; 32 versus 13 percent for poor-risk disease).

Rates of grade ≥3 toxicities were similar between the two groups (71 percent each), with the most common toxicities including hypertension (26 versus 17 percent), diarrhea (7 versus 3 percent), fatigue (4 percent each), and palmar-plantar erythrodysesthesia (6 versus 4 percent). The most frequent immune-mediated adverse event in those treated with avelumab plus axitinib was immune-related thyroid disorders (25 percent). Major cardiovascular toxicities occurred more frequently in those treated with the combination of avelumab plus axitinib compared with sunitinib (7 versus 4 percent) [45] and included grade ≥3 myocardial infarction (3 percent), congestive heart failure (2 percent), and death due to cardiac events (1 percent) [46]. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Based on the results of this trial, the combination of avelumab plus axitinib was approved by the US FDA for first-line treatment of patients with advanced RCC.

Pembrolizumab — Single-agent immunotherapy with pembrolizumab (table 2) was studied in the KEYNOTE-427 trial [47]. In Cohort A of that study, 110 patients with advanced or metastatic clear cell RCC were treated with pembrolizumab (200 mg every three weeks). All patients had measurable disease and had not received prior systemic therapy. PD-L1 status was assessed using a combined positive score (CPS).

In the total study population, the ORR was 36 percent, which included 4 patients with a CR and 36 patients with a PR. The response rate was higher in patients with intermediate- or poor-risk disease compared with those with favorable-risk disease (40 versus 31 percent). Additionally, CPS ≥1 percent was associated with higher response rates. Two-year PFS and OS were 22 and 71 percent, respectively.

Nivolumab — Single-agent immunotherapy with nivolumab (table 3) has activity in treatment-naïve advanced or metastatic clear cell RCC with response rates of up to 34 percent. These data are based on phase II trials evaluating a response-adapted strategy of initial therapy with single-agent nivolumab and salvage therapy with nivolumab plus ipilimumab in those without an objective response to nivolumab alone [48-50].

As an example, in a nonrandomized phase II trial (HCRN GU16-260), 123 patients with treatment-naïve metastatic clear cell RCC received single-agent nivolumab. Patients with objective responses (either partial or complete) continued nivolumab for up to two years or treatment intolerance [49]. Patients with either stable disease at one year or progressive disease received subsequent salvage therapy with nivolumab plus ipilimumab, followed by maintenance nivolumab for up to one year.

●At median follow-up of 28 months, among those treated with nivolumab, the ORR was 34 percent, median PFS was approximately eight months, and two-year OS was 78 percent.

●Compared with those with intermediate- or poor-risk disease, patients with favorable-risk disease had a higher PFS (median 32 versus 5 months) and ORR (57 versus 25 percent). In a subsequent preliminary analysis, at three years from enrollment, patients with favorable-risk disease also had longer treatment-free survival compared with those with intermediate- or poor-risk disease (mean 13 versus 8 months) [51].

●Median DOR was at least 28 months for all patients and 11 months for those with intermediate-risk disease. Of note, responses are ongoing in 17 of 20 (85 percent) patients with favorable-risk disease and three of four (75 percent) patients with poor-risk disease.

●Among the 35 patients who received salvage therapy with nivolumab plus ipilimumab, objective responses were seen in four patients (11 percent).

A separate phase II trial (OMNIVORE) used a similar response-adapted treatment approach in a similar population; in this study, the ORRs for initial therapy with nivolumab and salvage therapy with nivolumab plus ipilimumab were 17 and 4 percent, respectively [48].

Atezolizumab plus bevacizumab — There is no established role for atezolizumab plus bevacizumab in patients with metastatic RCC. Based on results from a phase II study [52], a randomized phase III trial (IMmotion151) comparing atezolizumab plus bevacizumab with sunitinib was conducted in 915 treatment-naïve patients with advanced or metastatic RCC [53,54]. In the entire study population, compared with sunitinib, atezolizumab plus bevacizumab improved PFS (median 11 versus 8 months; HR 0.83, 95% CI 0.70-0.97) [53] but did not confer an OS benefit [54].

Although atezolizumab plus bevacizumab did not show sufficient clinical advantages over antiangiogenic therapy to merit regulatory approval, these data provide valuable information about predictive biomarkers for response to angiogenesis inhibitors and immunotherapy. These biomarkers may ultimately be used to guide patient selection for subsequently approved regimens [53-56].

Less preferred treatment options

Interleukin 2 and other interleukins — Immunotherapy with high-dose bolus interleukin 2 (IL-2) can activate an immune response against RCC, which results in tumor regression in a minority of patients. Although treatment is associated with severe toxicity, responses often persist for many years, even in the absence of additional therapy, and the majority of complete responders remain free of relapse long term.

While high-dose IL-2 was considered an important option for carefully selected patients who were able to tolerate the toxicity associated with this approach and who had access to this treatment, its current role in the setting of more active and better tolerated checkpoint inhibitor immunotherapy approaches is undefined. IL-2 still could be an option in patients whose disease has progressed on initial immunotherapy-based regimens [57-59]. Other interleukins that have been evaluated include IL-4 [60], IL-6 [61], pegylated IL-10 [62], and IL-12 [63,64]. The encouraging results seen in animal studies with the combination of IL-12 plus IL-2 [65] have not been confirmed in human clinical trials [66].

In seven phase II studies, high-recombinant IL-2 was administered as an intravenous infusion every eight hours over five consecutive days for two cycles beginning on days 1 and 15. Responding patients and those with stable disease were retreated approximately every 12 weeks for a maximum of three courses [57,58]. In a combined analysis of 259 patients, 30 PRs (12 percent) and 23 CRs (9 percent) were seen. Among the patients who achieved a CR, 19 of 23 (83 percent) remained free of recurrence at last follow-up. The four patients who relapsed all did so within the first four years after treatment. By contrast, all patients who had a PR eventually recurred, predominantly within the first three years. Similar results were seen in another series of 212 patients treated with high-dose IL-2, in which an overall response rate of 20 percent was observed. This included 16 patients (8 percent) with a CR and a median survival of over 10 years [67].

Results from several large randomized trials subsequently provided additional support for this approach compared with lower dose schedules of IL-2 and combinations with interferon alfa (IFNa) [68,69].

However, treatment with IL-2 was associated with severe toxicity affecting multiple organ systems (table 5A-B) [70]. These complications included hypotension, cardiac arrhythmia, metabolic acidosis, fever, nausea and vomiting, dyspnea, edema, oliguria and renal failure, neurotoxicity, and dermatologic complications. Use of high-dose regimens required treatment in a setting where blood pressure support could be provided. Several experimental approaches were tried in an effort to separate the toxicity of IL-2 from its antitumor activity, but these approaches did not prove useful in a clinical setting [71-78].

Interferon alpha — The use of interferon alpha (interferon alpha-2a and interferon alpha-2b) has largely been replaced by immunotherapy with checkpoint inhibitors and molecularly targeted agents. Data suggest minimal efficacy for this agent in patients with metastatic RCC [79-85]. Additionally, access to interferon alpha-2b is limited as the manufacturer has discontinued production of this agent.

Nivolumab plus ipilimumab and cabozantinib — We do not offer the triplet combination of nivolumab plus ipilimumab and cabozantinib as initial therapy for metastatic RCC. In a randomized trial, this combination improved progression-free survival but increased toxicity.

Nivolumab plus ipilimumab and cabozantinib was evaluated in a phase III trial (COSMIC-313) of 855 patients with treatment-naïve, IMDC intermediate- or high-risk metastatic clear cell RCC. At median follow-up of 20 months, the addition of cabozantinib to nivolumab plus ipilimumab improved progression-free survival (PFS; median not reached versus 11 months; hazard ratio 0.73, 95% CI 0.57-0.94), and objective response rates (43 versus 36 percent), but increased grade ≥3 toxicity (79 versus 56 percent) [86]. Subgroup analyses suggest that clinical benefit for the combination is primarily seen in those with intermediate-risk disease. Data for overall survival are immature.

SUBSEQUENT THERAPY — The choice of therapy at relapse is dependent on prior therapy received.

Prior immunotherapy with or without antiangiogenic therapy — For patients who progress after initial immunotherapy containing regimen, with or without prior antiangiogenic therapy, we recommend subsequent therapy with an antiangiogenic agent rather than the combination of immunotherapy plus an antiangiogenic agent, as the latter approach does not improve progression-free survival (PFS) or overall survival (OS) and increases toxicity.

While we prefer cabozantinib (if not previously administered) [87-89], other options include axitinib, sunitinib, pazopanib, tivozanib, or lenvatinib with everolimus. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Preferred VEGFR inhibitors'.)

Patients may also be offered combined nivolumab plus ipilimumab (table 4) if they have no prior exposure to ipilimumab [90]. The addition of ipilimumab to nivolumab may "boost" response rates after progression on single-agent nivolumab, as was demonstrated in the TITAN-RCC (Tailored ImmunoTherapy Approach with Nivolumab in advanced Renal Cell Carcinoma) study [50] as well as other studies [49,90,91]. As data are limited for this approach, clinical trial enrollment is encouraged. (See 'Nivolumab plus ipilimumab' above.)

Based on initial studies [89], an open-label, randomized phase III trial (CONTACT-3) was conducted to evaluate atezolizumab plus cabozantinib versus cabozantinib alone in 522 patients advanced or metastatic renal cell carcinoma who had progressed on immunotherapy with or without antiangiogenic therapy [87]. All patients recently progressed on immunotherapy (either as first- or second-line therapy or within six months of completing adjuvant immunotherapy) and had no prior treatment with cabozantinib or more than one immunotherapy agent. Among the 520 patients who progressed on first-line therapy, nivolumab plus ipilimumab was used most frequently (29 percent); followed by pembrolizumab plus axitinib (12 percent); nivolumab monotherapy (3 percent); avelumab plus axitinib, lenvatinib plus pembrolizumab, and bempegaldesleukin plus nivolumab (2 percent each). Among the 244 patients who progressed on second-line therapy, nivolumab was used most frequently (90 percent) after initial therapy with sunitinib or pazopanib (29 and 15 percent, respectively), followed by nivolumab plus ipilimumab (3 percent) and pembrolizumab plus axitinib (2 percent). Only two patients progressed after adjuvant immunotherapy.

At median follow-up of 15 months, the addition of atezolizumab to cabozantinib failed to improve PFS (median 11 months each; HR 1.03, 95% CI 0.83-1.28) or OS (median OS 26 months versus not evaluable; HR 0.94, 95% CI 0.70-1.27). The addition of atezolizumab to cabozantinib also increased toxicity (grade ≥3 toxicity 56 versus 47 percent; serious treatment-related adverse events 24 versus 12 percent). Limitations of this study include the use of atezolizumab (a programmed cell death ligand 1 [PD-L1] inhibitor) that has not conferred an OS benefit in the treatment of advanced RCC, and the immediate rechallenge with immunotherapy, which may have been inhibited by long-term programmed cell death 1 (PD-1) receptor occupancy from the prior immunotherapy agent.

Prior antiangiogenic therapy alone — For patients who progress on initial treatment with an antiangiogenic agent alone and without previous exposure to checkpoint inhibitor immunotherapy, we suggest treatment with nivolumab rather than further targeted therapy (table 3). Although data are limited, we also offer the combination of nivolumab plus ipilimumab (table 4) as an alternative option, based on phase I data from the CheckMate 016 trial and other observational data [90,92]. (See 'Nivolumab' below and 'Nivolumab plus ipilimumab' above.)

For those who are ineligible for immunotherapy, we offer an alternative vascular endothelial growth factor receptor (VEGFR) inhibitor. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Preferred VEGFR inhibitors'.)

Nivolumab — For those who progress on initial treatment with an antiangiogenic agent alone without previous exposure to checkpoint inhibitor immunotherapy, we suggest treatment with nivolumab (table 3). Nivolumab improves overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and quality of life compared with everolimus in this population.

In the phase III CheckMate 025 trial, 821 patients were randomly assigned to nivolumab (3 mg/kg every two weeks) or everolimus (10 mg/day) [93-97]. All patients had received one or two prior antiangiogenic therapies. With a median follow-up of 64 months, relative to everolimus, single-agent nivolumab resulted in the following [97]:

●Improved OS (median 25.8 versus 19.7 months, five-year OS 26 versus 18 percent, hazard ratio [HR] 0.73, 95% CI 0.62-0.85), regardless of PD-L1 expression and other prognostic factors.

●Improved five-year PFS (5 versus 1 percent; HR 0.84, 95% CI 0.72-0.99), although median PFS was similar between the two groups.

●Higher ORR (23 versus 4 percent), including rare complete responses (CRs; 1 versus 0.5 percent).

●Longer treatment-free interval among responders who came off treatment without subsequent systemic therapy (12.7 versus 4.1 months).

●Lower rate of grade ≥3 toxicity (21 versus 37 percent) and improved quality of life in extended follow-up. The most frequent grade ≥3 toxicities were fatigue and anemia (2 percent each).

Additional responses may be seen if nivolumab is continued after initial progression. In the CheckMate 025 study, nivolumab therapy was also permitted after Response Evaluation Criteria in Solid Tumors (RECIST) progression if clinical benefit was observed [96]. If subsequent assessment confirmed disease progression, therapy was discontinued. In total, 78 percent (316 of 406) of patients treated with nivolumab had progressed, and 48 percent (153 of 316) of these patients were treated for ≥4 weeks after first progression. Post-progression, 13 percent of patients who continued on nivolumab treatment experienced ≥30 percent tumor burden reduction from first progression. The actual contribution of the continued therapy to these delayed responses remains to be determined.

Prior immunotherapy and antiangiogenic therapy

Belzutifan — For patients who progress on both immunotherapy and antiangiogenic therapy, we offer belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). In patients with treatment-refractory clear cell RCC, belzutifan improves PFS with an acceptable toxicity profile [98]. This agent is also used to treat patients with von Hippel-Lindau disease-related clear cell RCC, hemangioblastomas, and pancreatic neuroendocrine tumors. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Based on data from phase I and II trials [99-101], belzutifan was evaluated in an open-label phase III trial (LITESPARK-005) of 746 patients with advanced or metastatic clear cell RCC who progressed on up to three lines or prior therapy, including an immune checkpoint inhibitor and antiangiogenic therapy [98]. Patients were randomly assigned to either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily. In preliminary results, at median follow-up of 26 months, relative to everolimus, belzutifan improved PFS (median 5.6 months each, 18-month PFS 23 versus 9 percent; HR 0.74, 95% CI 0.63-0.88) and ORRs (23 versus 4 percent). OS was similar between the two treatment arms (median 21 versus 18 months; HR 0.88, 95% CI 0.73-1.07). Although grade ≥3 toxicities were similar in both treatment arms (62 percent each), belzutifan was discontinued less frequently due to toxicity (6 versus 15 percent).

Belzutifan is approved by the US Food and Drug Administration (FDA) for advanced RCC following treatment with a PD-1 or PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor [102].

SPECIAL CONSIDERATIONS

Cytoreductive (debulking) nephrectomy — In the era of effective checkpoint inhibitor immunotherapy and antiangiogenic therapy, the role of cytoreductive or debulking nephrectomy (ie, removal of the primary tumor) is limited to select treatment-naïve patients with metastatic RCC. The criteria for selecting patients for cytoreductive nephrectomy prior to initiation of immunotherapy are discussed separately. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Patient selection for cytoreductive nephrectomy'.)

Although initial data supported this approach prior to administration of interferon alfa (IFNa) [81,103,104], the addition of cytoreductive nephrectomy to antiangiogenic therapy in those with treatment-naïve metastatic disease did not improve overall survival (OS) in two randomized trials [105,106]. Additionally, in a subgroup analysis of the CheckMate 214 trial, prior nephrectomy was not associated with improved survival outcomes among patients treated with nivolumab plus ipilimumab [24].

These and other data on cytoreductive nephrectomy in those with metastatic RCC are discussed separately. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Cytoreductive nephrectomy'.)

Brain metastases — The treatment approach to patients with brain metastases from renal cell carcinoma is discussed separately. (See "Overview of the treatment of renal cell carcinoma", section on 'Brain metastases, treatment naïve'.)

Bone metastases — For patients with renal cell carcinoma metastatic to bone, we offer a bone resorption inhibitor to reduce the risk of pathologic fractures and other skeletal-related events [107]. Options include either a bisphosphonate (such as pamidronate, zoledronic acid, or ibandronate) or a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (such as denosumab). Patients should be counseled on the potential risks of bone resorption inhibitors prior to initiating therapy, which are discussed separately. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

Patients with chronic kidney disease — Most patients with chronic kidney disease (CKD) at baseline can be safely treated with systemic regimens used for advanced or metastatic RCC [108]. Immune checkpoint inhibitors (ICIs; such as pembrolizumab, nivolumab, ipilimumab, and avelumab) are antibodies that do not require dose adjustments for baseline altered kidney function, including end-stage kidney disease. For antiangiogenic agents (such as axitinib, cabozantinib, and lenvatinib), clinicians should adjust the dose of therapy as needed based on the patient's baseline kidney function. (See "Assessment of kidney function".)

Similar to the general population, patients with CKD should be closely monitored for nephrotoxicity after treatment initiation, such as ICI-associated acute kidney injury and proteinuria or nephrotic syndrome with antiangiogenic agents. Further details on these toxicities are discussed separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Kidney' and "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'Antiangiogenic agents'.)

EXPERIMENTAL APPROACHES

Pembrolizumab plus bevacizumab — The combination of pembrolizumab plus bevacizumab has efficacy in patients with metastatic RCC, but this approach remains investigational. In an open-label phase II trial of 48 treatment-naïve patients, the ORR for this combination was 61 percent, including one patient with a complete response; median PFS was 21 months [109]. There were no unexpected toxicities; the toxicity profile mirrored that of the individual agents.

Nivolumab plus axitinib — The combination of nivolumab plus axitinib has efficacy in patients with metastatic RCC, but this approach remains investigational. In preliminary results of a phase I/II trial of 44 patients with treatment-naïve advanced RCC, the ORR for this combination was approximately 69 percent [110].

Vaccines — Approaches to re-engage immune recognition of tumor through autologous cellular immunotherapy have no established role in the treatment of those with advanced RCC. The addition of rocapuldencel-T (an autologous dendritic cell immunotherapy) to sunitinib did not improve OS in a phase III trial, despite promising results from an earlier phase II trial [111,112]. Similarly, the addition of a cancer vaccine (IMA901) to sunitinib did not improve OS in a similar patient population [113].

Biomarkers for selecting therapy — The use of biomarkers and gene expression profiling to prospectively select patients with advanced RCC for systemic therapy has been investigated in a phase II trial (BIONIKK) [114]. Further data are needed before incorporating the use of biomarkers into routine clinical practice.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Renal cell carcinoma (kidney cancer) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for treatment in advanced renal cell carcinoma – For most patients with advanced clear cell renal cell carcinoma (RCC), systemic therapy is typically initiated promptly when unresectable disease, either metastatic or locally advanced, is present. The decision to start systemic therapy and the selection of agent(s) depend on disease-related symptoms, patient comorbidities, and tumor risk stratification (algorithm 1 and table 1). (See 'Selection of initial therapy' above.)

●Favorable-risk disease with limited disease burden – For patients with treatment-naïve, favorable-risk disease with limited disease burden, we suggest close active surveillance, rather than initiation of systemic therapy, to determine the pace of disease (Grade 2C). Surveillance allows the deferral of therapy and its associated toxicity until more compelling disease progression is documented. (See 'Limited disease burden' above and 'Active surveillance' above.)

Alternatively, for those with limited disease burden who desire a more aggressive management approach, options include either single-agent antiangiogenic therapy (typically sunitinib or pazopanib) or single-agent immunotherapy (with either pembrolizumab (table 2) or nivolumab (table 3)). (See 'Limited disease burden' above.)

●Choice of initial systemic therapy

•Favorable-risk disease, substantial disease burden – For patients with treatment-naïve, favorable-risk disease who are symptomatic and/or have more rapidly progressive disease, we suggest either pembrolizumab plus axitinib, nivolumab plus cabozantinib, or lenvatinib plus pembrolizumab rather than other regimens (Grade 2C). (See 'Substantial disease burden' above and 'Pembrolizumab plus axitinib' above and 'Nivolumab plus cabozantinib' above and 'Lenvatinib plus pembrolizumab' above.)

Other acceptable options include nivolumab plus ipilimumab (table 4) (for those willing to tolerate the potential toxicities of immunotherapy to potentially achieve a complete response [CR]) and avelumab plus axitinib (which improves progression-free survival [PFS] and objective response rates [ORR], although an overall survival [OS] benefit has not been established). (See 'Substantial disease burden' above and 'Nivolumab plus ipilimumab' above and 'Avelumab plus axitinib' above.)

Antiangiogenic therapy that incorporates a vascular endothelial growth factor receptor (VEGFR) inhibitor is also an alternative option in patients who are ineligible for or decline immunotherapy. (See 'Ineligible for immunotherapy (favorable-risk)' above.)

•Intermediate- or poor-risk disease – For patients with treatment-naïve intermediate- or poor-risk disease, we recommend checkpoint inhibitor immunotherapy-based regimens over antiangiogenic therapy alone (Grade 1B). Our choice of therapy is primarily determined by the presence of symptomatic or life-threatening disease burden and patient clinical characteristics. (See 'Intermediate- and poor-risk disease' above.)

-Patients with symptomatic or life-threatening disease burden – For patients with symptomatic or life-threatening disease burden, we suggest either lenvatinib plus pembrolizumab or nivolumab plus cabozantinib rather than other regimens (Grade 2C) due to higher ORRs in randomized trials, to obtain a rapid treatment response. (See 'Patients with symptomatic or life-threatening disease burden' above and 'Lenvatinib plus pembrolizumab' above and 'Nivolumab plus cabozantinib' above.)

-Patients without symptomatic, life-threatening disease burden – For patients without symptomatic or life-threatening disease burden, we suggest nivolumab plus ipilimumab (table 4) rather than combination immunotherapy and antiangiogenic therapy (Grade 2C), as this approach offers the opportunity for curative intent therapy by providing durable responses, preserving OS benefit, and improving treatment-free survival. (See 'Patients without symptomatic, life-threatening disease burden' above and 'Nivolumab plus ipilimumab' above.)

For those who are not anticipated to tolerate the toxicities of nivolumab plus ipilimumab (eg, those with active autoimmune conditions or limited mobility), the combination of immunotherapy plus antiangiogenic therapy is an appropriate alternative. Options include lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, or pembrolizumab plus axitinib. These regimens have high ORR and improve OS, but responses are less durable than nivolumab plus ipilimumab. (See 'Lenvatinib plus pembrolizumab' above and 'Nivolumab plus cabozantinib' above and 'Pembrolizumab plus axitinib' above.)

•Ineligible for immunotherapy (intermediate- or poor-risk disease) – For those with intermediate- and poor-risk disease who are ineligible for or choose to forego initial treatment with immunotherapy combinations, we offer therapy that incorporates an antiangiogenic agent. Preferred options include lenvatinib plus everolimus or cabozantinib. (See 'Ineligible for immunotherapy (intermediate- and poor-risk)' above.)

●Subsequent therapy – For patients who progress after initial therapy, the choice of treatment depends on prior therapy (see 'Subsequent therapy' above):

•Prior immunotherapy, with or without an antiangiogenic agent – For patients who progress after an initial immunotherapy containing regimen, with or without prior antiangiogenic therapy, we recommend subsequent therapy with an antiangiogenic agent rather than the combination of immunotherapy plus an antiangiogenic agent (Grade 1B), as the latter approach failed to improve OS and increased toxicity in a randomized trial While we prefer cabozantinib (if not previously administered), other options include axitinib, sunitinib, pazopanib, tivozanib, and lenvatinib plus everolimus. (See 'Prior immunotherapy with or without antiangiogenic therapy' above.)

Patients may also be offered combined nivolumab plus ipilimumab (table 4) if they have no prior exposure to this combination. (See 'Nivolumab plus ipilimumab' above.)

•Prior antiangiogenic agent alone – For patients who progress after initial treatment with an antiangiogenic agent without previous exposure to immunotherapy, we suggest nivolumab (table 3) rather than further lines of targeted therapy (Grade 2C), as nivolumab improved overall survival over everolimus in this setting. Although data are limited, we also offer the combination of nivolumab plus ipilimumab (table 4) as an alternative option. (See 'Nivolumab' above and 'Nivolumab plus ipilimumab' above.)

For those who are ineligible for immunotherapy, we offer an alternative antiangiogenic agent. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Preferred VEGFR inhibitors'.)

•Prior immunotherapy and antiangiogenic therapy – For patients who progress on both immunotherapy and antiangiogenic therapy, we offer belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). (See 'Belzutifan' above.)