Systemic therapy for advanced and metastatic clear cell renal cell 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 and metastatic 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 and metastatic non-clear cell renal cell 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 very few 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 classified as having favorable-risk disease, those with one or two are classified as having intermediate-risk disease, and those with three or more are classified as having poor-risk disease.

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, favorable-risk disease — 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. Limited disease burden is defined as a small number of low-volume metastatic lesions confined to one or two organs such as the lungs or the bones [7,8]. However, the decision to treat must take into account multiple factors, including the rate of growth, location of tumor (eg, proximity to vital organs with potential for damage), and symptoms. (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.)

●Combination immunotherapy regimen – A combination immunotherapy regimen used for those with substantial burden, favorable-risk disease. (See 'Substantial disease burden, favorable-risk disease' below.)

Substantial disease burden, favorable-risk disease — For patients with treatment-naïve, favorable-risk disease and more substantial disease burden that is not life-threatening (eg, rapidly progressive, involving the liver and/or bone, and/or severely symptomatic), we suggest nivolumab plus ipilimumab (table 4) rather than other systemic agents. In such patients, based on indirect comparisons of randomized trials, nivolumab plus ipilimumab is more likely to result in long-term benefits such as sustained complete responses (CRs), durable overall survival (OS), and longer treatment-free survival relative to combination immunotherapy plus antiangiogenic therapy, even if it does not produce more immediate, significant changes in objective response rates (ORR) and progression-free survival (PFS).

For the rare patient with favorable-risk disease and life-threatening disease burden, we suggest either axitinib plus pembrolizumab, cabozantinib plus nivolumab, or lenvatinib plus pembrolizumab rather than other systemic agents. These regimens are more likely to result in higher upfront treatment response and lower rates of progressive disease as best response, but they carry the risk of long-term toxicity from the antiangiogenic agent.

●Nivolumab plus ipilimumab – Nivolumab plus ipilimumab (table 4) is a reasonable option for patients with favorable-risk disease who are willing to tolerate the toxicities of combination immunotherapy and the potential risk of early disease progression to achieve longer treatment-free survival and more durable OS. In a phase III trial, among patients with favorable risk-disease, nivolumab plus ipilimumab resulted in sustained CR rates of 13 percent [9]. In extended follow-up of this trial, among those with favorable-risk disease and relative to sunitinib, nivolumab plus ipilimumab improved treatment-free survival and continued to sustain the separation between the tails of the Kaplan-Meier curves for OS at eight years (although the difference in eight-year OS was not statistically significant), despite having lower PFS and ORRs [9,10]. By contrast, in those with favorable-risk disease, immunotherapy plus antiangiogenic agents have not shown superior OS compared with sunitinib with extended follow-up. These findings illustrate that, in patients with favorable-risk disease, combination immunotherapy alone (without an antiangiogenic agent) is more likely to confer potential long-term benefits (eg, sustained CRs, durable OS, treatment-free survival), even if it does not produce more immediate, significant changes in ORR and PFS. (See 'Nivolumab plus ipilimumab' below.)

In RCC as well as other cancers, the potential for early disease progression (ie, shorter PFS) is seen with immunotherapy-only regimens. As such, patients with favorable-risk disease who are treated initially with nivolumab plus ipilimumab should be closely assessed for treatment response, and subsequent-line therapy should be promptly administered in those with disease progression. (See 'Prior immunotherapy with or without antiangiogenic therapy' below.)

●Immunotherapy plus antiangiogenic therapy – Combinations of immunotherapy and antiangiogenic therapy, such as axitinib plus pembrolizumab, cabozantinib plus nivolumab, or lenvatinib plus pembrolizumab, are reasonable options for patients who require an immediate treatment response or a delay in disease progression due to rapidly progressive or symptomatic disease and are willing to accept the potential long-term toxicities of prolonged antiangiogenic therapy. In extended follow-up of randomized trials, for those with favorable-risk disease, these regimens improved ORRs and PFS (which are important clinical endpoints that translate into a better quality of life) but none have shown superior OS compared with sunitinib. Results of the trials evaluating these regimens and their outcomes by subgroup are discussed separately. (See 'Axitinib plus pembrolizumab' below and 'Cabozantinib plus nivolumab' below and 'Lenvatinib plus pembrolizumab' 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. In patients with favorable-risk disease, none of the combination immunotherapy-based regimens (nivolumab plus ipilimumab, axitinib plus pembrolizumab, cabozantinib plus nivolumab, or lenvatinib plus pembrolizumab) have demonstrated a statistically significant improvement in OS compared with antiangiogenic therapy alone. (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:

Sarcomatoid histology — For patients with advanced and metastatic clear cell RCC with sarcomatoid histology, we offer initial therapy with nivolumab plus ipilimumab. RCCs with sarcomatoid histology are clinically aggressive tumors that are invariably classified as intermediate- or poor-risk disease. Further details are discussed separately. (See "Renal cell carcinoma with sarcomatoid features", section on 'Initial therapy (clear cell RCC with sarcomatoid features)'.)

Patients with symptomatic or life-threatening disease burden — For patients with symptomatic or life-threatening disease burden, we suggest either lenvatinib plus pembrolizumab or cabozantinib plus nivolumab 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 (over 70 percent) and cabozantinib plus nivolumab (over 50 percent), compared with other regimens. Lenvatinib plus pembrolizumab also results in a high CR rate (approximately 18 percent). (See 'Lenvatinib plus pembrolizumab' below and 'Cabozantinib plus nivolumab' 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 (lenvatinib plus pembrolizumab, cabozantinib plus nivolumab, or axitinib plus pembrolizumab) is an appropriate alternative. These regimens have high ORRs and improve OS, but treatment responses are less durable relative to nivolumab plus ipilimumab. There is also the risk of long-term toxicity from the antiangiogenic agent. (See 'Lenvatinib plus pembrolizumab' below and 'Cabozantinib plus nivolumab' below and 'Axitinib plus pembrolizumab' 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 axitinib plus pembrolizumab, 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. By 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.)

For those who are not anticipated to tolerate the toxicities of nivolumab plus ipilimumab, other alternatives include single-agent nivolumab or single-agent pembrolizumab. However, patients who select this approach should be cautioned about the risk of early disease progression with immunotherapy-only regimens, monitored closely for treatment response, and immediately switched to the appropriate subsequent-line therapy in the event of disease progression. (See 'Prior immunotherapy with or without antiangiogenic therapy' below.)

Randomized trials are necessary to compare nivolumab plus ipilimumab to single-agent immunotherapy in advanced and metastatic clear cell RCC. In indirect comparisons of clinical trials, the ORRs seen with nivolumab (34 percent) [11] and pembrolizumab (36 percent) [12] are similar to those seen with nivolumab plus ipilimumab (40 percent) [9]. In a noncomparative phase II trial (HCRN GU16-260), nivolumab also resulted in durable treatment-free survival [11]. (See 'Nivolumab' below and 'Pembrolizumab' below.)

While axitinib plus avelumab 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) [13]. (See 'Axitinib plus avelumab' 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 [14,15], 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'.)

Risk of early disease progression with immunotherapy-only regimens — There is a potential risk of early disease progression in those who are treated with regimen that only contain immunotherapy, regardless of risk stratification. All patients who are treated with immunotherapy-only regimens (eg, nivolumab plus ipilimumab; nivolumab; pembrolizumab) should be closely assessed for treatment response, and subsequent-line therapy should be promptly administered in those with early disease progression. (See 'Nivolumab plus ipilimumab' below and 'Pembrolizumab' below and 'Nivolumab' below.)

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 [16,17]. As an example, in a prospective phase II trial, 52 patients with treatment-naïve metastatic RCC underwent radiographic surveillance [16]. 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 [9,18-22]. 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 [10]. 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 objective response rate (ORR) and progression-free survival (PFS). These findings illustrate that combination immunotherapy alone can confer long-term benefits (sustained CR, durable OS, longer treatment-free survival) even if it does not produce more immediate, significant changes in PFS.

Subsequent maintenance therapy with up to two years of nivolumab (either administered intravenously [IV] or subcutaneously [nivolumab-hyaluronidase]) 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 [9,18-21,23]. Patients with brain metastases were excluded. The combination of nivolumab (3 mg/kg IV) plus ipilimumab (1 mg/kg IV) was given every three weeks for four doses, followed by single-agent nivolumab (3 mg/kg IV or a flat dose of 240 mg IV (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 99 months (over eight years), nivolumab plus ipilimumab, relative to sunitinib, had the following results [9]:

●Entire study population – Improved OS (seven-and-a-half-year OS 35 versus 25 percent, median 53 versus 38 months; hazard ratio [HR] 0.72, 95% CI 0.62-0.83). PFS was higher for the combination, although the results did not meet statistical significance (seven-and-a-half-year PFS 23 versus 11 percent, median 12 months each; HR 0.88, 95% CI 0.75-1.03). ORRs (40 versus 33 percent) and CR rates (12 versus 4 percent) were both higher for the combination. Duration of response (DOR) was also longer for the combination (median 76 versus 25 months, seven-and-a-half-year DOR 48 versus 19 percent; HR 0.52, 95% CI 0.38-0.72).

●Intermediate- or poor-risk disease – Improved OS and PFS (seven-and-a-half-year OS 33 versus 22 percent, median 47 versus 25 months; HR 0.69, 95% CI 0.59-0.81; seven-and-a-half-year PFS 25 versus 9 percent, median 12 versus 9 months; HR 0.73, 95% CI 0.61-0.87). ORRs (42 versus 28 percent) and CR rates (12 versus 3 percent) were both superior for the combination. Treatment-free survival is also twice as long for the combination (seven versus three months) [10].

●Favorable-risk disease – Higher OS, although the difference was not statistically significant (seven-and-a-half-year OS 43 versus 34 percent, median 78 versus 67 months; HR 0.82, 95% CI 0.60-1.13) with lower PFS (seven-and-a-half-year PFS 13 versus 17 percent, median 12 versus 29 months; HR 1.75, 95% CI 1.25-2.48). Lower ORRs (30 versus 52 percent) but higher CR rates (13 versus 7 percent) were seen for the combination. Notably, treatment-free survival is almost three times as long for the combination versus targeted therapy (11 versus 4 months) [10].

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, axitinib plus pembrolizumab [24] and lenvatinib plus pembrolizumab [25]). Most patients with a complete and/or ongoing treatment response can discontinue all therapy, and many experience prolonged treatment-free survival [10]. (See 'Axitinib plus pembrolizumab' below and 'Lenvatinib plus pembrolizumab' below.)

In a 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 [19].

Side effects and quality of life data (which is associated with improved OS [26]) also favored the combination of nivolumab plus ipilimumab over sunitinib [27]. The toxicity of this combination was consistent with that observed with its use for other indications. (See "Overview of toxicities associated with immune checkpoint inhibitors" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Toxicity'.)

Nivolumab (IV) in combination with ipilimumab (IV) is approved by the US Food and Drug Administration (FDA) for treatment-naïve patients with intermediate- or poor-risk advanced RCC [28]. 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.)

Nivolumab-hyaluronidase, a subcutaneous form of nivolumab, is also approved by the FDA in adult patients with intermediate- or poor-risk advanced RCC as maintenance therapy following combination treatment with IV nivolumab and ipilimumab. Nivolumab-hyaluronidase is not approved in combination with ipilimumab for the treatment of renal cell carcinoma [28]. Further details are discussed separately. (See 'Nivolumab-hyaluronidase (subcutaneous)' below.)

Axitinib plus pembrolizumab — For patients with advanced RCC without prior exposure to systemic therapy, the combination of axitinib plus pembrolizumab improves OS and PFS compared with sunitinib. This combination has not been directly compared with other immunotherapy-based combinations.

For axitinib plus pembrolizumab, 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 axitinib plus pembrolizumab versus sunitinib alone [24,29-31]. 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, axitinib plus pembrolizumab had the following results [24,29-31]:

●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 ORRs (61 versus 36 percent), and higher CR rate (12 versus 4 percent). The median 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 axitinib plus pembrolizumab 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 was lower with the combination than with sunitinib when adjusted for exposure time (63 versus 97 events per 100 person-months) [30]. In both groups, the most common grade ≥3 adverse events were diarrhea (10 versus 5 percent) and hypertension (22 versus 20 percent). Axitinib plus pembrolizumab demonstrated similar health-related quality of life outcomes compared with sunitinib [32].

Axitinib plus pembrolizumab is approved by the FDA as initial therapy for patients with advanced RCC, regardless of risk stratification [28].

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

Cabozantinib plus nivolumab — For patients with advanced RCC without prior exposure to systemic therapy, the combination of cabozantinib plus nivolumab improves OS and PFS compared with sunitinib. 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 cabozantinib plus nivolumab or sunitinib [14,15,33]. Cabozantinib was administered at 40 mg once daily until disease progression or unacceptable toxicity and nivolumab was administered at 240 mg IV every two weeks (up to a maximum of two years). Patient subgroups included those with favorable-, intermediate-, or poor-risk disease (based on the IMDC risk classification).

At a median follow-up of 44 months, compared with sunitinib, cabozantinib plus nivolumab had the following results [33]:

●Entire study population – Improved OS (three-year OS 59 versus 50 percent, median 50 versus 36 months; HR 0.70, 95% CI 0.56-0.87) and PFS (three-year PFS 23 versus 11 percent, median 17 versus 8 months; HR 0.59, 95% CI 0.49-0.71). The combination also demonstrated higher ORR (56 versus 28 percent) and CR rate (13 versus 5 percent). Median time to response was faster with the combination compared with sunitinib (2.8 versus 4.3 months).

●Intermediate- or poor-risk disease – Improved OS (three-year OS 59 versus 50 percent, median 50 versus 36 months; HR 0.75, 95% CI 0.56-1 for intermediate-risk disease; three-year OS 47 versus 25 percent, median 35 versus 11 months, 0.46, 95% CI 0.30-0.72 for poor-risk disease), improved PFS (three-year PFS 23 versus 13 percent, median 17 versus 9 months; HR 0.63, 95% CI 0.49-0.80 for intermediate-risk disease; three year PFS 28 versus 2 percent, median 10 versus 4 months; HR 0.37, 95% CI 0.24-0.57 for poor-risk disease), and higher ORR (56 versus 28 percent for intermediate-risk disease; 41 versus 10 percent for poor-risk disease).

●Favorable-risk disease – Similar OS (three-year OS 68 versus 70 percent, median not reached versus 48 months, HR 1.07, 95% CI 0.63-1.79), a non-statistically significant trend towards longer PFS (three-year PFS 21 versus 14 percent, median 21 versus 14 months; HR 0.72, 95% CI 0.49-1.05), and higher ORR (66 versus 44 percent).

Additionally, OS benefit results were consistent across other clinically relevant subgroups, including those with positive or negative programmed cell death ligand 1 (PD-L1) expression, with or without prior nephrectomy, and with or without bone metastases [15].

Grade ≥3 treatment-related adverse events occurred in 67 percent receiving cabozantinib plus nivolumab versus 55 percent receiving sunitinib. For cabozantinib plus nivolumab, 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) [14,15,33,34].

Cabozantinib plus nivolumab (IV) is approved by the FDA as initial therapy for patients with advanced RCC, regardless of risk stratification [28]. Nivolumab-hyaluronidase, a subcutaneous form of nivolumab, is also approved by the FDA in adult patients with advanced RCC as initial therapy, in combination with cabozantinib [28]. Further details are discussed separately. (See 'Nivolumab-hyaluronidase (subcutaneous)' below.)

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 [35,36]. Additionally, this combination demonstrated high CR rates.

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 [37-42].

Based on data from early phase trials [43-45], the combination of lenvatinib plus pembrolizumab was evaluated in an open-label phase III clinical trial (CLEAR) [35,36,46]. 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 [25,36]:

●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 [35]. 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 [47]. 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 pembrolizumab is approved by the FDA as initial therapy for patients with advanced RCC, regardless of risk stratification [28].

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 [35]. 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.

Axitinib plus avelumab — 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 'Axitinib plus pembrolizumab' above.)

Based on data from early phase clinical trials [48,49], axitinib plus avelumab 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 axitinib plus avelumab versus sunitinib [13,50].

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 axitinib plus avelumab was immune-related thyroid disorders (25 percent). Major cardiovascular toxicities occurred more frequently in those treated with the combination of axitinib plus avelumab compared with sunitinib (7 versus 4 percent) [51] and included grade ≥3 myocardial infarction (3 percent), heart failure (2 percent), and death due to cardiac events (1 percent). (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Based on the results of this trial, the combination of axitinib plus avelumab was approved by the FDA for first-line treatment of patients with advanced RCC [28].

Pembrolizumab — Single-agent immunotherapy with pembrolizumab (table 2) was studied in the KEYNOTE-427 trial [12]. 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 [12]. 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 [52-54].

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 [53]. 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 a 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 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) [11].

●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 [52].

Bevacizumab plus atezolizumab — There is no established role for bevacizumab plus atezolizumab in patients with metastatic RCC. Based on results from a phase II study [55], a randomized phase III trial (IMmotion151) comparing bevacizumab plus atezolizumab with sunitinib was conducted in 915 treatment-naïve patients with advanced or metastatic RCC [56,57]. In the entire study population, compared with sunitinib, bevacizumab plus atezolizumab improved PFS (median 11 versus 8 months; HR 0.83, 95% CI 0.70-0.97) [56] but did not confer an OS benefit [57].

Although bevacizumab plus atezolizumab 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 [56-59].

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 most complete responders remain free of relapse long term.

While high-dose IL-2 was previously 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 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 [60-62]. Other interleukins that have been evaluated include IL-4 [63], IL-6 [64], pegylated IL-10 [65], and IL-12 [66,67]. The encouraging results seen in animal studies with the combination of IL-12 plus IL-2 [68] have not been confirmed in human clinical trials [69].

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 [60,61]. 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 [70].

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) [71,72].

However, treatment with IL-2 was associated with severe toxicity affecting multiple organ systems (table 5A-B) [73]. These complications included hypotension, cardiac arrhythmia, metabolic acidosis, fever, nausea and vomiting, dyspnea, edema, oliguria and kidney 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 [74-81].

Interferon alfa — The use of IFNa-2a and IFNa-2b has largely been replaced by immune checkpoint inhibitors (ICIs) and molecularly targeted agents. Data suggest minimal efficacy in patients with metastatic RCC [82-88]. Additionally, interferon alfa-2b is no longer available as the manufacturer has discontinued production of this agent.

Cabozantinib plus nivolumab and ipilimumab — We do not offer the triplet combination of cabozantinib plus nivolumab and ipilimumab as initial therapy for metastatic RCC. In a randomized trial (COSMIC-313) of 855 patients with previously untreated intermediate- or poor-risk RCC, relative to nivolumab plus ipilimumab, this combination improved PFS [89] but (in preliminary results available in abstract form only) failed to improve OS [90] and increased toxicity.

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 an initial immunotherapy-containing regimen, with or without prior antiangiogenic therapy, we recommend second-line 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 [91-93] or lenvatinib plus everolimus, depending on the pace of the disease and prior treatment, tivozanib is an alternative. Other options include axitinib, sunitinib, pazopanib, or belzutifan. (See 'Cabozantinib' below and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Preferred VEGFR inhibitors' and 'Belzutifan' below.)

Patients may also be offered combined nivolumab plus ipilimumab (table 4) if they have no prior exposure to ipilimumab [94]. 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 [54] as well as other studies [53,94,95]. As data are limited for this approach, clinical trial enrollment is encouraged. (See 'Nivolumab plus ipilimumab' above.)

Cabozantinib — Based on initial studies [93], an open-label, randomized phase III trial (CONTACT-3) was conducted to evaluate atezolizumab plus cabozantinib versus cabozantinib alone in 522 patients with advanced or metastatic RCC who had progressed on immunotherapy with or without antiangiogenic therapy [91]. 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 axitinib plus pembrolizumab (12 percent); nivolumab monotherapy (3 percent); axitinib plus avelumab, 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; hazard ratio [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) [91]. 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.

Tivozanib — In an open-label phase III trial (TiNivo-2), 343 patients with advanced RCC that contained a clear cell component who progressed on one or two previous lines of therapy (including one immune checkpoint inhibitor [ICI]) were randomly assigned to either the combination of tivozanib plus nivolumab (a PD-1 inhibitor) or tivozanib monotherapy [96]. Most patients had received an ICI-containing regimen as the most recent line of therapy (71 percent). Among those who did not receive an ICI-containing regimen as the most recent line of therapy (29 percent), most were treated with an antiangiogenic agent (90 percent). The most frequently used first-line regimens were nivolumab plus ipilimumab and axitinib plus pembrolizumab, and the most frequently used second-line regimens were single-agent cabozantinib and single-agent nivolumab.

At a median follow-up of 12 months, the addition of nivolumab to tivozanib failed to improve PFS in the entire study population (median six versus seven months, HR 1.10, 95% CI 0.84-1.43), including those with an ICI-containing regimen as the most recent line of therapy (median PFS seven versus nine months, HR 1.10, 95% CI 0.80-1.52) [96]. Among those treated with a non-ICI-containing regimen as the most recent line of therapy, PFS was similar between the treatment arms (median 3.7 months each, HR 0.95, 95% CI 0.61-1.50). In the entire study population, OS for combination therapy versus tivozanib alone was 18 and 22 months respectively, although data are immature. objective response rates [ORRs] were similar between the two treatment arms (19 versus 20 percent). Grade ≥3 toxicity rates were also similar (61 versus 60 percent).

Further data on the efficacy of tivozanib as later-line therapy in advanced clear cell RCC are discussed separately. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Tivozanib'.)

Belzutifan — Belzutifan has been evaluated as subsequent-line therapy in patients with advanced and metastatic clear cell RCC who progress on both immunotherapy and antiangiogenic therapy. Based on these data, we also extrapolate its use as subsequent-line therapy for those who progress on immunotherapy alone. Further details are discussed separately. (See 'Belzutifan' below.)

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 second-line 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 [94,97]. (See 'Nivolumab (intravenous)' 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 (intravenous) — Nivolumab (administered intravenously [IV]) is a treatment option for those who progress on initial treatment with an antiangiogenic agent alone without previous exposure to checkpoint inhibitor immunotherapy (table 3). Nivolumab improves OS, PFS, 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 IV every two weeks) or everolimus (10 mg/day orally) [98-102]. 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 [102]:

●Improved OS (median 25.8 versus 19.7 months, five-year OS 26 versus 18 percent, 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 [101]. 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 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.

Nivolumab-hyaluronidase (subcutaneous) — Nivolumab-hyaluronidase, a subcutaneous form of nivolumab, is also available as an alternative to IV nivolumab in patients with advanced or metastatic RCC who progress on antiangiogenic agents [103]. Subcutaneous administration of ICIs is generally effective, well-tolerated, and requires shorter preparation and administration time compared with intravenous infusion. These benefits can enhance patient convenience and reduce the burden on health care resources.

In an open-label phase III trial (Checkmate 67T), 495 patients with treatment-refractory advanced or metastatic clear cell RCC and no prior exposure to immunotherapy were randomly assigned to either nivolumab-hyaluronidase (1200 mg coformulated with recombinant human hyaluronidase at 20,000 units administered subcutaneously every four weeks) or intravenous nivolumab (3 mg/kg every two weeks) [103]. At a minimum follow-up of eight months, nivolumab-hyaluronidase demonstrated noninferior pharmacokinetics and ORRs (24 versus 18 percent) relative to intravenous nivolumab.

Nivolumab-hyaluronidase is approved by the US Food and Drug Administration (FDA) for adult patients with advanced RCC who have received prior antiangiogenic therapy [28]. Other approved indications for nivolumab-hyaluronidase in advanced and metastatic RCC are discussed separately. (See 'Nivolumab plus ipilimumab' above and 'Cabozantinib plus nivolumab' above.)

Prior immunotherapy and antiangiogenic therapy

Belzutifan — For patients who progress on both immunotherapy and antiangiogenic therapy, we offer later-line therapy with 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 [104]. This agent is also used to treat patients with von Hippel-Lindau disease-related clear cell RCC, hemangioblastomas, and pancreatic neuroendocrine tumors. (See "Surveillance and management of von Hippel-Lindau disease".)

The preferred initial dosing for belzutifan is 120 mg orally once daily [105]. Based on data from phase I and II trials [106-108], 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 of prior therapy, including an ICI and antiangiogenic therapy [104]. Patients were randomly assigned to either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily. At a median follow-up of 18 months, relative to everolimus, belzutifan improved PFS (median 5.6 months each, 18-month PFS 24 [95% CI 19-29] versus 8 [95% CI 5-13] percent) and ORRs (22 versus 4 percent). At a median follow-up of 26 months, 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 also improved disease-specific symptoms and quality of life compared with everolimus [109].

Belzutifan is approved by the FDA for advanced RCC with a clear cell component following treatment with a PD-1 or PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor [28].

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) [84,110,111], 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 [112,113]. 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 [21].

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 RCC is discussed separately. (See "Overview of the treatment of renal cell carcinoma", section on 'Brain metastases, treatment naïve'.)

Bone metastases — For patients with RCC metastatic to bone, we offer a bone resorption inhibitor to reduce the risk of pathologic fractures and other skeletal-related events [114]. 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 [115]. 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 "Overview of toxicities associated with immune checkpoint inhibitors", section on 'Kidney' and "Nephrotoxicity of molecularly targeted agents and immunotherapy", section on 'Antiangiogenic agents'.)

EXPERIMENTAL APPROACHES

Combination therapies — Various regimens combining antiangiogenic therapy with other targeted agents or immunotherapy have been evaluated in clinical trials. Examples include bevacizumab plus pembrolizumab [116], axitinib plus nivolumab [117], axitinib plus toripalimab [118], and belzutifan plus cabozantinib [119]. The use of these regimens to treat metastatic RCC remains investigational.

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, and their use remains investigational. The addition of rocapuldencel-T (an autologous dendritic cell immunotherapy) to sunitinib did not improve overall survival (OS) in a phase III trial, despite promising results from an earlier phase II trial [120,121]. Similarly, the addition of a cancer vaccine (IMA901) to sunitinib did not improve OS in a similar patient population [122]. Other vaccine approaches are also being investigated, such as personalized cancer vaccines alone or in combination with immunotherapy [123].

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) [124]. 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.)

●Basics topic (see "Patient education: Kidney cancer (The Basics)")

●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 (RCC) – For most patients with advanced clear cell 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 (ie, a small number of low-volume metastatic lesions confined to one or two organs such as the lungs or bone) who are asymptomatic, 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, favorable-risk disease' above and 'Active surveillance' above.)

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

●Choice of initial systemic therapy

•Favorable-risk disease, substantial disease burden – For patients with treatment-naïve, favorable-risk disease and more substantial disease burden that is not life-threatening (eg, rapidly progressive, involving the liver and/or bone, and/or severely symptomatic), we suggest nivolumab plus ipilimumab (table 4) rather than other systemic agents (Grade 2C). In such patients, based on indirect comparisons of randomized trials, nivolumab plus ipilimumab is more likely to result in long-term benefits such as sustained complete responses (CR), durable overall survival (OS), and longer treatment-free survival than combination immunotherapy plus antiangiogenic therapy, even if it does not produce more immediate, significant changes in objective response rates (ORR) and progression-free survival (PFS). (See 'Substantial disease burden, favorable-risk disease' above.)

For the rare patient with favorable-risk disease and life-threatening disease burden, we suggest either axitinib plus pembrolizumab, cabozantinib plus nivolumab, or lenvatinib plus pembrolizumab rather than other systemic agents (Grade 2C). These regimens are more likely to result in higher upfront treatment response and lower rates of progressive disease as best response, but they carry the risk of long-term toxicity from the antiangiogenic agent. (See 'Substantial disease burden, favorable-risk disease' above.)

Antiangiogenic therapy that incorporates a vascular endothelial growth factor receptor (VEGFR) inhibitor (eg, lenvatinib plus everolimus, sunitinib, or pazopanib) is also an alternative option in patients who are ineligible for or decline immunotherapy. In patients with favorable-risk disease, none of the combination immunotherapy-based regimens (nivolumab plus ipilimumab, axitinib plus pembrolizumab, cabozantinib plus nivolumab, or lenvatinib plus pembrolizumab) have demonstrated a statistically significant improvement in OS compared with antiangiogenic therapy alone. (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, evidence of sarcomatoid histology and patient clinical characteristics. (See 'Intermediate- and poor-risk disease' above.)

-Sarcomatoid histology – For patients with sarcomatoid histology, we offer initial therapy with nivolumab plus ipilimumab. Further details are discussed separately. (See "Renal cell carcinoma with sarcomatoid features", section on 'Initial therapy (clear cell RCC with sarcomatoid features)' and 'Sarcomatoid histology' 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 cabozantinib plus nivolumab 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 'Cabozantinib plus nivolumab' 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), alternative options include the combination of immunotherapy plus antiangiogenic therapy (lenvatinib plus pembrolizumab, cabozantinib plus nivolumab, or axitinib plus pembrolizumab). These regimens have high ORR and improve OS, but responses are less durable than nivolumab plus ipilimumab and there is a risk of long-term toxicity from the antiangiogenic agent. (See 'Patients without symptomatic, life-threatening disease burden' above and 'Lenvatinib plus pembrolizumab' above and 'Cabozantinib plus nivolumab' above and 'Axitinib plus pembrolizumab' above.)

Other alternatives include single-agent nivolumab (table 3) or pembrolizumab (table 2). (See 'Patients without symptomatic, life-threatening disease burden' above and 'Nivolumab' above and 'Pembrolizumab' 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.)

•Risk of disease progression with immunotherapy-only regimens – There is a potential risk of early disease progression in those who are treated with regimen that only contain immunotherapy, regardless of risk stratification. All patients who are treated with immunotherapy-only regimens (eg, nivolumab plus ipilimumab; nivolumab; pembrolizumab) should be closely assessed for treatment response, and subsequent-line therapy should be promptly administered in those with early disease progression.

●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 second-line 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 randomized trials. While we prefer cabozantinib or lenvatinib plus everolimus, depending on the pace of the disease and prior treatment, tivozanib is an alternative. Other options include axitinib, sunitinib, pazopanib, or belzutifan. (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 second-line therapy with 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 (intravenous)' 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 later-line therapy with belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). (See 'Belzutifan' above.)