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Immunotherapy of renal cell carcinoma
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Immunotherapy of renal cell carcinoma
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Literature review current through: Nov 2017. | This topic last updated: Oct 20, 2017.

INTRODUCTION — Surgical resection of localized renal cell carcinoma (RCC) can be curative for localized disease, but many patients eventually recur. In addition, many RCCs are clinically silent for much of their course, and the initial diagnosis is often delayed until disease is either locally advanced and unresectable or metastatic. The prognosis 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 disease.

Immunotherapy using high-dose interleukin-2 (IL-2) is a treatment option for carefully selected good-performance patients who have access to a facility able to manage the toxicity associated with this approach. Based upon results from a randomized phase III trial discussed below, immunotherapy with nivolumab, an anti-programmed cell death 1 (PD-1) agent, has a role for patients who were initially treated with a molecularly targeted agent. The integration of nivolumab into the management of patients with advanced or metastatic RCC is the subject of ongoing research.

This topic will review the data supporting the roles of IL-2 and the checkpoint inhibitor nivolumab. Interferon-alfa (IFNa) and other experimental approaches are discussed more briefly.

An overview of the treatment approach to RCC, prognostic factors in RCC, and the use of anti-angiogenic and molecularly targeted therapy are discussed separately. (See "Overview of the treatment of renal cell carcinoma" and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma".)

RATIONALE FOR IMMUNOTHERAPY — The fields of immunology and oncology have been linked since the late 19th century, when the surgeon William Coley reported that an 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 renal cell carcinomas (RCCs) can evoke an immune response that occasionally results in spontaneous and dramatic remissions in metastases, particularly in the lung [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.

Immunotherapy with monoclonal antibodies directed against the programmed cell death 1 (PD-1) protein has become an integral part of the management of advanced melanoma and non-small cell lung cancer, and these findings are now being extended to a large number of other malignancies, including advanced RCC. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Anti-PD-1 monoclonal antibodies' and "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Immune activation and checkpoint inhibition'.)

High-dose bolus IL-2 remains an option for carefully selected favorable-prognosis patients with access to this form of therapy. Nivolumab has an established role for patients who had been treated with a vascular endothelial growth factor (VEGF) receptor inhibitor regardless of whether they had received high-dose IL-2. Additional trials with nivolumab and other checkpoint inhibitors are extending these findings and will be required to define the optimal way to integrate these agents into patient management. (See 'Interleukin-2' below and 'Nivolumab' below.)

CHOICE OF THERAPY — The integration of immunotherapy into the overall management of patients with advanced clear cell renal cell carcinoma (RCC) and its timing relative to molecularly targeted therapy are discussed in detail separately and summarized in the following table and algorithm (table 1 and algorithm 1). The role of immunotherapy in the treatment of RCC as discussed in this topic is consistent with guidelines from the Society for Immunotherapy of Cancer [3]. (See "Overview of the treatment of renal cell carcinoma", section on 'Advanced RCC'.)

INTERLEUKIN-2

High-dose bolus IL-2 — The recommendation for the use of high-dose bolus interleukin-2 (IL-2) is based upon its ability to induce durable, high-quality remissions in a minority of patients [4,5].

In seven phase II studies, recombinant IL-2 (600,000 to 720,000 international units per kg) was administered as a 15-minute intravenous (IV) infusion every eight hours over five consecutive days (up to 14 consecutive doses). A course of therapy consisted of such 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. In 259 patients, 30 partial responses (12 percent) and 23 complete responses (9 percent) were seen [4,5]:

Among the patients who achieved a complete response, 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 of the patients who had a partial response 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 complete response and a median survival of over 10 years [6].

Results from several large randomized trials were subsequently reported:

NCI Trial – The National Cancer Institute (NCI) conducted a large-scale randomized phase III trial comparing the standard high-dose bolus IL-2 schedule with a low-dose IV bolus regimen using 10 percent of the standard dose and with an outpatient regimen using subcutaneous IL-2 [7]. The response rate was significantly higher with high-dose therapy (21 versus 13 percent with the low-dose schedule), but there were no differences in overall survival among the three groups.

Cytokine Working Group Trial – The Cytokine Working Group (CWG) trial compared high-dose bolus IL-2 with outpatient administration of IL-2 plus interferon-alfa (IFNa; both administered as a subcutaneous injection) in a phase III trial of 193 patients [8]. A significantly higher objective response rate was seen with high-dose bolus IL-2 compared with the outpatient schedule (23 versus 10 percent), and eight patients treated with high-dose IL-2 achieved a complete response and 10 were progression-free at three years. No overall survival advantage was observed for high-dose IL-2.

Predictors of response — Responses to high-dose IL-2 are often of long duration and high quality, which must be balanced against the cost, limited access, and toxicity associated with high-dose IL-2 treatment. Thus, efforts have been made to identify clinical, histologic, and molecular characteristics that can identify the patient subsets that are most likely to benefit from this approach.

Clinical factors — Clinical factors that reflect a large tumor burden or rapid disease progression are associated with less frequent responses that are of shorter duration. These factors include the presence of more than one site of metastatic disease, a progression-free interval of less than one year, and the presence of liver or mediastinal lymph node involvement [9]. Patients with all of these characteristics had >70 percent chance of rapid disease progression and a median survival of six months in one series.

Prior nephrectomy and time from nephrectomy to relapse are important predictors of improved survival in patients receiving IL-2 therapy. In one report, patients who began immunotherapy at least six months after nephrectomy had the best median survival and a 46 percent three-year survival rate [10].

Other factors associated with a favorable prognosis include a good performance status and the absence of bone metastases [11]. Clinical or laboratory observations after the initial treatment that correlate with a subsequent antitumor response and an improved prognosis include the development of thrombocytopenia [12], thyroid dysfunction [13], rebound lymphocytosis [14], low circulating levels of monocytes and granulocytes [15], and elevation of tumor necrosis factor (TNF) and interleukin-1 (IL-1) [16].

Histology and carbonic anhydrase IX expression — Responses to immunotherapy are typically observed in patients with clear cell renal cell carcinomas (RCCs) [17]. In the prospective, single-arm SELECT trial, 120 patients were treated with high-dose IL-2 [18]. Objective responses were seen in 34 of 115 patients (30 percent) with clear cell histology but 0 of 5 with non-clear cell histology. As a consequence, most oncologists do not use IL-2 therapy in patients with non-clear cell histology.

The patients most likely to benefit from IL-2 treatment are those with clear cell carcinomas. Responses were less likely in those with non-clear cell carcinoma and those with clear cell carcinoma with papillary features, no alveolar features, and/or greater than 50 percent granular features [17]. Retrospective studies suggested high levels of carbonic anhydrase IX (CAIX) expression were associated with a more favorable prognosis and potentially a greater likelihood of a response to immunotherapy [19,20]. Although the prospective SELECT trial demonstrated no major activity in a non-clear cell population, it was unable to validate the ability of other histologic features, CAIX expression, or both to predict responsiveness to IL-2 [18]. (See "Prognostic factors in patients with renal cell carcinoma", section on 'Molecular markers'.)

Sarcomatoid RCC — Sarcomatoid features or sarcomatoid dedifferentiation can be seen in all types of RCC specimens. The role of immunotherapy in patients with the sarcomatoid variant of RCC is unclear. One review of 31 consecutive cases of sarcomatoid RCC found that those treated with nephrectomy followed by high-dose IL-2 had a median survival of more than ten months, which was significantly longer than that of patients undergoing surgery alone or any other form of immunotherapy [21]. Other series report an objective response in 25 to 33 percent of patients receiving systemic immunotherapy [22]. Nonetheless, it is generally believed that durable responses to IL-2 immunotherapy are unlikely in patients with tumors containing sarcomatoid features.

Toxicity — Treatment with IL-2 is associated with severe toxicity affecting multiple organ systems. These complications include hypotension, cardiac arrhythmias, metabolic acidosis, fever, nausea and vomiting, dyspnea, edema, oliguria and renal failure, neurotoxicity, and dermatologic complications. Use of high-dose regimens requires treatment in a setting where blood pressure support can be provided. Guidelines are available for the clinical management of these complications (table 2A-B) [23].

The mechanisms underlying IL-2 toxicity are not fully understood. Several mechanisms have been proposed:

IL-2 is a strong stimulator of proinflammatory cytokines (eg, IL-1, tumor necrosis factor alpha [TNFa], and interferon-gamma [IFNg]) [24-26] and nitric oxide [27]. These substances may mediate much of the treatment-related toxicity.

A protein fragment of the IL-2 molecule that has tentatively been identified may be responsible for vasopermeability [28].

In a series of 18 patients, serum levels of angiopoietin 2 rose progressively in all cases with high-dose IL-2 therapy [29]. Elevated levels of serum angiopoietin 2 have previously been identified in septic patients with vascular leak syndrome.

By contrast, the antitumor response is thought to be mediated via cellular immune mechanisms, raising the possibility of dissociating toxicity from antitumor efficacy by combining cytokine inhibitors with IL-2.

Several experimental approaches have been tried in an effort to separate the toxicity of IL-2 from its antitumor activity, but these approaches have not proven useful in a clinical setting [30-37].

CHECKPOINT INHIBITORS — Nivolumab has been approved for the treatment of advanced renal cell carcinoma (RCC) based upon improvement in overall survival in a phase III trial. Other checkpoint inhibitors have demonstrated clinical activity, but data are more limited, and these agents are not yet approved for this indication [38].

Nivolumab — Nivolumab is an anti-programmed cell death-1 (PD-1) antibody that has received regulatory approval for patients with advanced melanoma and non-small cell lung cancer based upon a demonstration of improved overall survival. In a phase III trial, nivolumab improved overall survival compared with everolimus in patients with advanced clear cell RCC who had progressed after prior anti-angiogenic therapy. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Nivolumab' and "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Nivolumab'.)

Efficacy of nivolumab — Initial clinical studies of nivolumab in patients with advanced clear cell RCC demonstrated important clinical activity and provided the rationale for a phase III trial [39,40].

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) [41-44]. All patients had received one or two prior anti-angiogenic therapies (72 and 28 percent, respectively) with sunitinib, pazopanib, or axitinib (59, 30, and 12 percent, respectively). The trial was stopped early based upon improved overall survival in a planned interim analysis.

With a minimum follow-up of 13 months, the following results were observed:

Overall survival was significantly increased with nivolumab compared with everolimus (median, 25.0 versus 19.6 months, hazard ratio [HR] 0.73, 95% CI 0.57-0.93). There was no difference in progression-free survival (median, 4.6 versus 4.4 months, HR 0.88, 95% CI 0.75-1.03).

The objective response rate was greater with nivolumab (25 versus 5 percent, odds ratio 5.98, 95% CI 3.68-9.72). There were 103 objective responses with nivolumab, four of which were complete (1 percent of the total cohort), and 99 were partial (24 percent). For those treated with everolimus, there were 22 objective responses, all of which were partial.

Fewer patients had grade 3 or 4 toxicity with nivolumab compared with everolimus (19 versus 37 percent). The most frequent adverse event in patients treated with nivolumab was fatigue, which was present in 33 percent of patients, but was severe (grade 3 or 4) in only 2 percent of cases. The most frequent adverse event with everolimus was fatigue (88 percent), and the most frequent grade 3 or 4 toxicity was anemia (8 percent of cases). (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Expression of the PD-1 ligand 1 (PD-L1) on tumor cells was not associated with overall survival benefit to nivolumab, and those with ≥1 percent expression and those with <1 percent expression had a similar survival benefit compared with everolimus.

In a further subset analysis, the improvement in overall survival and objective response rate with nivolumab compared with everolimus was consistent across multiple prognostic factors, including risk groups, age, number and sites of metastases, and type and duration of prior therapy [43].

In a secondary analysis of 706 patients enrolled in the trial, treatment with nivolumab was associated with improvement in quality of life, whereas those randomly assigned to everolimus had a deterioration in quality of life compared with their baseline [42].

Patients treated with nivolumab may have prolonged survival. In an analysis of patients treated in the phase I and II studies that was presented at the 2016 American Society of Clinical Oncology (ASCO) meeting, approximately one-third had survived with a minimum of four years follow-up [45]. Long-term survivors included a significant number of patients who had stable disease or progressive disease as their best response to nivolumab therapy.

Duration therapy — The patterns of response to treatment with checkpoint inhibitor immunotherapy agents differ from those with molecularly targeted agents or cytotoxic chemotherapy, and immune response criteria were developed for patients with advanced melanoma (table 3). (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)

Analyses of the patients from the phase II and III trials suggest that some patients with RCC may also have tumor regression or disease stabilization with continued treatment beyond progression, based upon Response Evaluation Criteria in Solid Tumors (RECIST) criteria [44,46].

In the phase III CheckMate 025 study, nivolumab therapy was also permitted after RECIST progression if clinical benefit was observed [44]. If the subsequent assessment confirmed 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.

At this point, there are no data to suggest that patients who had received prior HD IL-2 would respond differently to nivolumab therapy than those who were immunotherapy-naïve.

Dosage — In November 2015, nivolumab was approved for RCC by the US Food and Drug Administration (FDA) on the basis of this trial [47]. Although the original approval of nivolumab was 3 mg/kg based upon the phase III trial, the FDA subsequently modified the approved dosage regimen to 240 mg as a flat dose every two weeks, which is similar to the 3 mg/kg intravenous dose, based upon population pharmacokinetics and dose/exposure-response analyses [48].

Nivolumab plus ipilimumab — In patients with advanced melanoma, the combination of nivolumab plus ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitor, is more effective than nivolumab alone, although this combination is associated with significantly more toxicity. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy'.)

The potential benefit and safety of combined checkpoint inhibition in previously untreated patients with advanced RCC were initially suggested by a phase I study [49]. Based upon that study, a phase III trial was conducted in which previously untreated patients with advanced or metastatic RCC were randomly assigned to nivolumab plus ipilimumab or to sunitinib. The combination of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) was given every three weeks for four doses and was then followed by nivolumab (3 mg/kg) [50]. Sunitinib was given at a dose of 50 mg/kg per day for four weeks out of every six-week cycle. Results with a minimum follow-up of 17.5 months were presented at the 2017 European Society of Medical Oncology (ESMO) meeting:

For the 847 patients with intermediate- or poor-risk disease, there was a significant improvement in the objective response rate with nivolumab plus ipilimumab by independent review (42 versus 27 percent). Median progression-free survival was increased as well, but it did not reach statistical significance (11.6 versus 8.4 months, HR 0.82, 95% CI 0.64-1.05).

However, the progression-free survival and response benefit appeared to be enhanced in patients with tumors having PD-L1 expression ≥1 percent. The enhanced benefit relative to sunitinib appeared to be partially driven by the reduced activity of sunitinib in patients with PD-L1-expressing tumors compared with those with PD-L1-negative tumors.

For the 214 patients with intermediate- or poor-risk disease and tumor PD-L1 expression ≥1 percent, improvement with the combination was more pronounced (objective response rate 58 versus 25 percent, median progression-free survival 22.8 versus 5.9 months, HR 0.48, 95% CI 0.28-0.82). The complete response rate in this group was 16 percent.

For the 562 patients with intermediate- or poor-risk disease and tumor PD-L1 expression <1 percent, there was no significant difference between the combination and sunitinib (objective response rate for the combination 37 versus 28 percent for sunitinib, median progression-free survival 11 versus 10.4 months, HR 1, 95% CI 0.74-1.36). However, there was still a 7 percent complete response rate, and overall survival for this subgroup was not reported.

For the 249 patients with favorable-risk disease, the combination of nivolumab plus ipilimumab was less effective than sunitinib (objective response rate 29 versus 52 percent, progression-free survival 15.3 versus 25.1 months, HR 2.17, 95% CI 1.46-3.22). However, survival data were also not reported for this subgroup.

Side effects and quality of life data also favored the combination of nivolumab plus ipilimumab over sunitinib.

The combination of nivolumab plus ipilimumab has not received regulatory approval for use in patients with advanced or metastatic RCC, and its use should be restricted to formal clinical trials. Further, there are very limited data on the activity of nivolumab monotherapy in treatment-naïve patients with advanced RCC.

Pembrolizumab — Pembrolizumab is another PD-1-targeted antibody that has received regulatory approval in patients with advanced melanoma. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Pembrolizumab'.)

Two randomized phase II trials are being conducted in patients with advanced RCC to determine whether pembrolizumab has a role in patients with advanced RCC. In one (NCT02089685), pembrolizumab is being evaluated alone and in combination with pegylated interferon-alfa (IFNa); in the other (NCT02014636), pembrolizumab is being studied alone and in combination with pazopanib.

Atezolizumab — Atezolizumab, a monoclonal antibody that targets the PD-1 ligand, has also demonstrated activity in patients with advanced RCC and is undergoing further development. (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitors'.)

The most extensive data come from a phase I study, in which 70 patients with metastatic RCC were treated with atezolizumab [51]. Among the 62 patients evaluable for efficacy, the rate of partial response was 15 percent, and the median duration of response was 17 months. The one- and two-year overall survival rates were 81 and 58 percent, respectively.

Combined antiangiogenic plus checkpoint inhibitor therapy — Efforts to improve further the results of checkpoint inhibition immunotherapy are looking at various combination approaches, particularly with antiangiogenic therapy [52-54]. Randomized trials will be required to further assess the activity of these combinations and to define their role in the treatment of advanced RCC.

Atezolizumab plus bevacizumab — A phase II trial randomly assigned 305 previously untreated patients with locally advanced or metastatic RCC to one of three arms, atezolizumab with or without bevacizumab versus sunitinib, with crossover from the single-agent arms to the combination of atezolizumab plus bevacizumab permitted at time of progression [52,53].

Data were presented at the 2017 ASCO meeting with a median follow-up of 20.7 months. The objective response rates for atezolizumab plus bevacizumab, atezolizumab alone, and sunitinib were 32, 25, and 29 percent, respectively. For patients with PD-L1 expression ≥1 percent (approximately 55 percent of the intention to treat population), the response rates were 46, 28, and 27 percent, respectively. The response rates for patients crossing over to the combination were 28 percent for those who had progressed after sunitinib and 24 percent for those who had progressed after atezolizumab. Progression-free survival after crossover was 8.8 months.

A phase III study of atezolizumab and bevacizumab versus sunitinib in previously untreated metastatic RCC patients is underway to evaluate the clinical efficacy of this combination in the first-line setting (NCT02420821).

Pembrolizumab plus axitinib — In a phase I study with an expansion cohort, 52 treatment-naïve patients were treated with the combination of pembrolizumab, an anti-PD-1 antibody, and axitinib. Initial results were presented at the ESMO 2016 meeting [55].

Objective responses were observed in 37 patients (71 percent), including 3 complete and 34 partial responses. Overall, 94 percent of patients exhibited tumor shrinkage. Progression-free survival data were immature, with only 14 (26.9 percent) events for the overall analysis, but follow-up was at a minimum 15.1 months. Toxicity was largely related to axitinib. Grade 3 potentially immune-related adverse effects occurred in 19.2 percent of patients. Immune-related ≥grade 3 adverse events included elevations in ALT and AST (two each), and diarrhea and colitis (one each).

This combination is being compared with sunitinib in a phase III trial (NCT02853331, KEYNOTE-426), which is ongoing.

Avelumab plus axitinib — In an expansion cohort of a phase I study, 55 treatment-naïve patients with favorable or intermediate-risk advanced RCC were treated with the combination of avelumab, an anti-PD-L1 antibody, and axitinib [54]. Initial results were presented at the 2017 ASCO meeting.

Objective responses were observed in 32 patients (58 percent), including 3 complete responses and 29 partial responses. With a median follow-up of 52 weeks, the median progression-free survival was 6.7 months. The combination was well tolerated, with the most common immune-related toxicity being hypothyroidism manifested by an elevated thyroid-stimulating hormone (TSH; 21.8 percent of patients).

The combination of avelumab plus axitinib is being compared with sunitinib in a phase III trial (NCT02684006).

Studies of sunitinib in combination with nivolumab, and pazopanib in combination with either nivolumab or pembrolizumab were stopped early because of apparent synergistic fatigue and liver toxicity [56,57].

INTERFERON-ALFA — The use of interferon-alfa (IFNa) has largely been replaced by molecularly targeted agents and immunotherapy with high-dose interleukin-2 (IL-2) or nivolumab. (See 'Interleukin-2' above and 'Nivolumab' above and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma".)

The activity of monotherapy with IFNa in metastatic renal cell carcinoma (RCC) was evaluated in several large trials [9,58-61]. Using a variety of preparations, doses, and schedules, the overall response rate was as high as 15 percent; the median time to response was about four months, and most responses were partial and rarely persisted beyond one year. In a meta-analysis that included four studies involving a total of 644 patients, treatment with IFNa was superior to controls (odds ratio for death at one year 0.56, 95% CI 0.40-0.77 and an overall hazard ratio for death 0.74, 95% CI 0.63-0.88) [62]. The median improvement in overall survival was 3.8 months.

Combinations of IFNa with other agents (interleukin-2 [IL-2], bevacizumab, chemotherapy) have not resulted in a substantial further clinical benefit. These approaches have not demonstrated an improvement in overall survival compared with IFNa alone or a comparable level of durable long-term remissions compared with high-dose IL-2 [63].

OTHER IMMUNOTHERAPY APPROACHES

Vaccines — Novel approaches to re-engage immune recognition of tumor through autologous cellular immunotherapy are under active development in advanced renal cell carcinoma (RCC) patients.

A phase II study in 21 intermediate- and poor-risk metastatic RCC patients utilized autologous dendritic cell (DC) collection and fresh tumor from nephrectomy specimens for RNA isolation [64]. Patients undergoing debulking nephrectomy were treated with sunitinib and serial intradermal injections of AGS-003, an autologous DC immunotherapy in which the DCs are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. Treatment was continued until disease progression; the median progression-free survival was 11 months (95% CI 6.0-19.4), and the median overall survival was 30 months (95% CI 9.4-57.1).

Based upon these results, the phase III ADAPT study (NCT01582672) is being conducted, in which patients with metastatic RCC undergoing debulking nephrectomy are randomly assigned to sunitinib or sunitinib plus AGS-003. Patients in both arms are treated with standard-of-care sunitinib; patients in the experimental arm are also treated with eight intradermal injections in the first year followed by boosters every three months. Accrual completed in 2015 and the primary endpoint is overall survival.

In another approach, a cancer vaccine IMA901 based upon tumor-associated peptides was administered as first-line therapy to patients with metastatic RCC who were HLA-A*02 positive. This was given as an intradermal vaccination for up to 10 doses, each in conjunction with 75 micrograms of granulocyte macrophage colony-stimulating factor (GM-CSF).

Based upon positive results in a phase II study, 339 patients were randomly assigned to sunitinib or to sunitinib plus IMA901 and GM-CSF [65]. Overall survival, the primary endpoint of the trial, was not improved with the addition of the IMA901 vaccine compared with sunitinib alone (median, 33.2 months versus not reached, hazard ratio [HR] 1.34, 95% CI 0.96-1.86, p = 0.08)

Other interleukins — Other interleukins that have been evaluated include IL-4 [66], IL-6 [67], and IL-12 [68,69]. The encouraging results seen in animal studies with the combination of IL-12 plus IL-2 [70] have not been confirmed in human clinical trials [71].

CYTOREDUCTIVE (DEBULKING) NEPHRECTOMY — Patients presenting with metastatic renal cell carcinoma (RCC) generally have a poor prognosis. However, there are case reports of regression of metastases after removal of the primary tumor (cytoreductive or debulking nephrectomy), although this is seen in 1 percent of patients or less [72].

More importantly, two randomized trials demonstrated a survival benefit following removal of the primary tumor in carefully selected patients with metastatic RCC who subsequently underwent immunotherapy with interferon-alfa (IFNa) [59,73]. A survival benefit has not been established for cytoreductive nephrectomy in patients with non-clear cell tumors [74].

The results of these trials and the criteria for patient selection are discussed separately. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Nephrectomy'.)

ADJUVANT IMMUNOTHERAPY — The role of adjuvant therapy in renal cell carcinoma (RCC) is discussed separately. Adjuvant immunotherapy following definitive local therapy does not have a role in the management of patients with completely resected high-risk RCC outside the context of a formal clinical trial. (See "Overview of the treatment of renal cell carcinoma", section on 'Adjuvant therapy'.)

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 5th to 6th 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 10th to 12th 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 — The integration of different systemic treatment modalities for the management of advanced clear cell renal cell carcinoma (RCC) is discussed separately (table 1 and algorithm 1). (See "Overview of the treatment of renal cell carcinoma", section on 'Systemic therapy of clear cell RCC'.)

For patients with advanced clear cell RCC, a good Karnofsky performance status (KPS; ≥80 percent) (table 4), and intact organ function, we suggest high-dose interleukin-2 (IL-2) therapy or enrollment in an anti-programmed cell death 1 (PD-1) immunotherapy clinical trial rather than targeted therapy (Grade 2B). (See 'Interleukin-2' above and "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma".)  

The patients most likely to benefit from IL-2 treatment are those with clear cell carcinomas. Responses were less likely in those with non-clear cell carcinoma and clear cell carcinoma with papillary features, no alveolar features, and/or greater than 50 percent granular features. (See 'Predictors of response' above.)

For patients with metastatic disease at presentation who are candidates for immunotherapy, we suggest debulking nephrectomy prior to treatment (Grade 2B). (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Nephrectomy'.)

For patients with advanced clear cell RCC who have progressed on antiangiogenic therapy, we recommend immunotherapy with nivolumab rather than everolimus (Grade 1A). We suggest treatment with nivolumab before treatment with cabozantinib (Grade 2C) due to the low toxicity profile of nivolumab monotherapy in phase III trials. We also currently suggest treatment with nivolumab over lenvatinib plus everolimus (Grade 2C) due to the small sample size of the trial driving the approval of lenvatinib plus everolimus and the lack of follow up studies. (See 'Efficacy of nivolumab' above.)

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