The Treatment of Metastatic Renal Cell Carcinoma

Background: Approximately 15 000 people receive a diagnosis of renal cell carcinoma (RCC) in Germany each year; in 20–30% of cases, metastatic RCC (mRCC) is already present at the time of diagnosis. This disease in the metastatic stage is still mainly treated palliatively, yet the multimodal therapeutic landscape has changed markedly over the past 15 years, with the approval of many new treatments for patients with mRCC.

Methods: This review is based on prospective studies retrieved by a selective search in PubMed and the ASCO and ESMO databases and on the German and European oncological and urological guidelines for RCC.

Results: Drugs are the mainstay of treatment. mRCC can be treated with a combination of two immune checkpoint inhibitors (CPIs), a CPI and a tyrosine-kinase inhibitor (TKI) (evidence level IA), or a TKI as monotherapy (evidence level IIC–IC). With prognosis-based sequential drug treatment, a mean progression-free survival of 12 to 24 months and an overall survival of approximately 50 months can be achieved from the time of initiation of first-line therapy. Aside from pharmacotherapy, the multidisciplinary tumor board should evaluate the indications for local treatments such as cytoreductive nephrectomy, metastasectomy, and radiotherapy, depending on the individual prognostic constellation and the patient’s present condition.

Conclusion: Optimal individualized decisions require a high level of expertise and the collaboration of a multidisciplinary tumor board. Older prognostic parameters currently play a leading role in decision-making, while predictive parameters and molecular markers are not yet adequately validated.

In 2020, 4830 women and 9330 men in Germany received a diagnosis of renal cell carcinoma (RCC. Their mean age on diagnosis was 68 in men and 71 in women. The main etiological risk factors are smoking, high blood pressure, and obesity (1). Approximately 60% of cases are incidentally discovered because of the widespread use of medical imaging; as a result, many newly diagnosed patients are still in an early tumor stage. On diagnosis, 20–30% of patients have metastatic renal cell carcinoma (mRCC) (e1, e2). Only approximately 20% have the typical symptoms and signs of the disease (macrohematuria, flank pain, and a palpable mass). Despite early diagnosis and the potential for a surgical cure, recurrences arise in 20–40% of patients, often in the first three years, but after five years or more in up to 10% of cases (2, e3).

The definition of renal cell carcinoma (RCC) in the current WHO classification includes 39 morphologically or molecularly defined subtypes (3). Clear-cell RCC is the most common subtype, accounting for approximately 80% of cases (2). The next most common are papillary and chromophobe RCC, along with sarcomatoid dedifferentiated RCC (which, however, is not classified as a separate entity). Research on drugs for RCC has focused on clear-cell RCC; rarer subtypes have only recently been given consideration in drug development (2, 4).

mRCC presents an interdisciplinary therapeutic challenge. For the selection of an optimal treatment, a multidisciplinary tumor board with experience in this tumor entity is essential (2, 5). For example, treatments in addition to surgery need to be discussed even when the disease in the local stage. Neoadjuvant therapy yields no benefit; the Keynote-564 trial has shown, however, that adjuvant pembrolizumab, or additive pembrolizumab after metastasectomy with curative intent, has greater benefit than placebo, after several studies of the same question failed to reach their endpoint. In the comparison of pembrolizumab with placebo after 57 months of observation, the risk of recurrence was 28% lower, i.e., disease-free survival (DFS) was higher, and overall survival (OS) was higher as well (DFS HR: 0.72, 95% confidence interval: [0.59; 0.87]; OS 91.2% versus 86.0%, HR 0.62, [0.44; 0.87], p = 0.0024) (Figure 1) (6, 7, e4). Local treatments are used for synchronous metastases (2, 5, 8).

Figure 1

Treatment algorithm for metastatic renal cell carcinoma, mRCC

The most important changes in recent years in the treatment of metastatic renal cell carcinoma have come with the approval of many new drugs (eTable) (9).

eTable

Drug treatment options approved by the EMA (as of November 2023)

These effective treatments now enable much longer overall survival than before; with optimal exploitation of the available options, overall survival is approximately 50 months (Table 1) (e5).

Table 1

Summary of the relevant parameters in the main approval trials for medern combination therapy

Learning objectives

This article should enable the reader to:

• understand the relevance of the biological heterogeneity of renal cell carcinoma,
• gain an overview of drug treatment for metastatic RCC, and
• know the main considerations for the choice of n appropriate sequence of systemic treatments.

Methods

The relevant literature since 2003 was selectively searched for review articles, phase 2 and 3 trials, and guidelines (the German S3 guideline and the guidelines of the ESMO [European Society of Medical Oncology] and EAU [European Association of Urology]) (2, 5, 10, 11). The searching terms “RCC” and “mRCC” were used to identify relevant articles in PubMed and the ASCO (American Society of Clinical Oncology) and ESMO databases.

The elements of treatment

A multimodal treatment approach

Individualized treatment planning, mostly with palliative intent, should take account of the patient’s comorbidities, disease-specific factors (e.g., remission pressure, histology, location of metastases, any prior adjuvant therapy), the prognosis of the tumor disease, and the patient’s personal goals for treatment in order to make the most of the available options in each case (2, 5, 10, 11). These and other parameters enter into the decision-making process of the multidisciplinary tumor board regarding treatment (5, 2, 10, 11). In particular, the risk score of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) has proven useful for routine use in prognostication; it partly reflects the biological heterogeneity of these tumors (Table 2) (12). The median survival was found to be 43.2 months for low-risk patients, 22.5 months for those at intermediate risk, and 7.8 months for those at high risk (12). These survival figures, however, are derived from an era in which the treatment was mainly with tyrosine kinase inhibitors (TKI) directed against the vascular endothelial growth factor receptor (VEGFR) and no longer accurately reflect the outcomes that are achievable with contemporary therapies, even if the separation of patients into three prognostic classes remains valid. The observed difference of 35.4 months between the median overall survival times of patients with the best and worst prognoses reveals the heterogeneous biological course of the disease and indicates the need for individualized treatment. For example, cytoreductive nephrectomy (CN) may be indicated in patients with a good prognosis who have synchronous metastases, or else a strategy of active surveillance may be chosen if the remission pressure is low (2, 13, 14). In favorable risk constellations, local treatments are also beneficial. For patients at high risk, i.e., those with the worst prognosis, systemic drug treatment is the treatment of choice in view of the high efficacy of the currently available drugs (2, 5).

Table 2

IMDC score and prognosis depending on the risk profile. Each individual parameter is assigned one point

Building-blocks of treatment

Active surveillance

As renal cell carcinoma takes a heterogeneous course, the question of when to begin treatment must be raised at the outset. In carefully selected patients, postponing drug treatment can delay drug-related toxicity and improve the patient’s quality of life without worsening the outcome or rendering the treatment less effective. The prerequisites are a favorable IMDC risk group without symptoms and low tumor growth kinetics (2, 14, e6). Retrospective analyses suggest that up to 20% of patients may be suitable for active surveillance (13, 14, e6). This is a strategy of regular diagnostic monitoring so that the need to initiate treatment can be detected when it arises. A prospective phase 2 trial showed that, in experienced centers, the treatment of selected patients can be safely postponed for a median of 15 months [10.6; 25] (13). This strategy was implemented only after interdisciplinary discussion; no objective criteria have been validated for the identification of suitable patients. The risks and benefits must be carefully weighed with the close involvement of the patients themselves, as a postponement of treatment can be an emotional burden. In sum, active monitoring is a useful component of treatment in centers with the appropriate expertise (2, 5, 14, 15).

Cytoreductive nephrectomy as of 2024

Cytoreductive nephrectomy (CN) is an intervention in which tumor tissue in the kidney is removed with the preservation of as much functional renal tissue as possible. In the era of less effective systemic cytokine therapies for synchronous metastatic RCC, renal resection was a standard treatment, on the basis of two randomized phase 2 trials with methodological limitations (e7, e8). Both the utility and the proper timing of CN are now under debate, firstly, because of the limitations of the prospective SURTIME and CARMENA trials and, secondly, because of the much more effective systemic treatments that are now available (16, 17). The SURTIME trial involved a comparison of up-front systemic treatment with sunitinib (a TKI that was the standard systemic drug at that time), followed by CN, with these two treatments in the reverse order, i.e., sunitinib-CN versus CN-sunitinib. The findings suggested possible non-inferiority with respect to the progression-free rate (PFR) at 28 days (43% and 42%, respectively), but an advantage of the former with respect to the secondary endpoint of median overall survival (mOS) the mOS was 32.4 and 15.0 months, respectively, with a hazard ratio of 0.57 (17). On the other hand, the CARMENA trial, in which most of the included patients had high-risk mRCC and were thus a priori less likely to benefit from CN, showed no advantage of CN-sunitinib over sunitinib alone (mOS 13.9 months and 18.4 months, respectively). Yet exploratory subgroup analyses of the CARMENA trial indicate that CN is useful in mRCC patients with low tumor burden and intermediate risk (18). More recent exploratory data still indicate that CN is beneficial, although its timing in the treatment sequence is under debate (19, 5). In summary, CN is a treatment option for symptomatic, synchronously metastasized mRCC in patients who are at low risk and who have local metastases that can be treated with curative intent (so-called oligometastasis). In patients who are at intermediate risk or (rarely) high risk, the multidisciplinary tumor board can consider CN as a measure to be taken after systemic treatment is initiated (Figure 1).

Local treatments for metastatic renal cell carcinoma

Other local treatments for mRCC aside from CN should be evaluated (interventional-radiological, radiotherapeutic, or surgical) and carried out when indicated. For patients with limited metastatic (oligometastatic) disease, such treatments can be provided with curative intent; for other patients, they may be an option for palliation. RCC most commonly metastasizes to the lungs (45%), bones (30%), lymph nodes (22%), liver (20%), and central nervous system (CNS) (8%), with involvement of multiple organs reported in 38% of patients (2, 20, e3). It is difficult to construct an evidence-based definition of an oligometastatic situation, i.e., one in which local treatment should be considered. In the mostly retrospective series on local treatment for metastases, oligometastasis was taken to mean the presence of no more than five tumors (21, 8). A Delphi-based expert consensus defined oligometastasis as no more than five metastases in no more than two organ systems (8, 21, 22). Local treatments for oligometastatic disease can achieve long-term remission in 20–40% of cases of isolated hepatic or pulmonary metastases (8, 22). The interventional-radiologic embolization of metastases can also be helpful as a preoperative measure (5). In the end, the decision whether to treat metastases locally must be determined on the basis of resectability, the interval between the initial diagnosis and the metastasis, and tumor dynamics or symptoms. Palliative radiotherapy is among the standard treatment options, particularly for bone and CNS metastases (5, 2, 11, 10). Decisions of this nature should be made by a multidisciplinary tumor board.

Drug treatment

Drug treatment prolongs overall survival and is therefore the primary component of treatment (Table 1, Figure 1). The pathophysiology of RCC often involves a loss or inactivation of the von Hippel—Lindau gene, which leads to the increased expression of pro-angiogenetic factors including vascular endothelial growth factor (VEGF); this provides a rationale for systemic treatment directed against VEGF (23). On the basis of this concept, hypoxia-induced factor 2 alpha (HIF2a) inhibitors have been approved for the treatment of patients with von Hippel—Lindau disease and are in the development stage against mRCC (24). Mammalian target of rapamycin (mTOR) inhibitors are a further substance class: mTOR is important for cell growth, proliferation, and metabolism and has been identified as a suitable target for systemic treatment. Despite the improving understanding of molecular genetic mechanisms, there are not yet any predictive molecular markers that can be reliably used for the selection of treatment. Checkpoint inhibitors (CPI) are a further substance class that currently plays a leading role. The targets of CPI include, among others, programmed death receptor-1 (PD-1), PD-1 ligands (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). The evolution of systemic treatment from VEGF-targeted monotherapy to mTOR inhibitors to CPI, and onward to combination therapies with and without CPI, has led to the approval of a variety of therapeutic options (eTable) (9).

Systemic treatment algorithm

Combined treatment options in the first-line situation

Once the indication for systemic treatment has been established, a treatment is selected on the basis of the patient’s risk class (low, intermediate, high). Combination therapies including CPI are available for all three classes; these have been found to prolong survival significantly, except for combinations with axitinib and avelumab (eTable, Table 1, Figure 1) (2, e9, e10, e11, e12, 25, 26, 27, 28).

Possibilities include a combination of a CPI with another CPI (nivolumab and ipilimumab, only in the intermediate- and poor-prognosis groups), or else a CPI/TKI combination therapy in which a PD-1 (nivolumab, pembrolizumab) or PD-L1 (avelumab) inhibitor is paired with a second- (axitinib) or third-generation TKI (lenvatinib, cabozantinib) (Table 1) (25, 26, 27, 28, 29, e5, e9– e20). Aside from combination therapies, which play the most prominent role, TKI monotherapy is also an option in all prognostic groups, especially the low-risk group (25).

As to the question of CPI/CPI versus CPI/TKI, the evidence to date does not single out any particular combination as the best for first-line treatment. Rather, a combination can be chosen in the individual case based on the specific features of the patient and the envisioned treatment (Table 1, Diagram 2). These include, for example, the long-term response, disease control, the toxicity spectrum, and the health-related quality of life HrQoL).

Deciding on a combination for first-line treatment

Prolonging overall survival is a main goal of treatment. Combination therapies have yielded significant gains in this area (median OS, 44.8–53.7 months; HR of combination therapies compared to TKI therapy with sunitinib, with regard to OS, 0.7–0.88) (Table 1) (25, 26, 27, 28, 29, e5, e9, e10, e11, e12, e13, e14, e15, e16, e17, e18, e19, e20). The antineoplastic effects of dual CPI therapy appear to persist even if the treatment has to be discontinued because of adverse reactions to the drug; this has not been documented to date for CPI/TKI combinations. Also, after dual induction with CTLA4 and PD-1 blockade, dual CPI therapy is de-escalated to single CPI after four cycles, and this yields rarer adverse events than CPI/TKI therapy, which is associated with persistent toxicity specifically resulting from TKI (25, 26, 27, 28, 29). If the goal of treatment is long-term tumor control with the prospect of a sustained effect, dual CPI appears to be superior (median duration of response 82.8 months, [54.1-NE, not estimable])(Table 1, Figure 2). However, the risk of non-response is higher (approximately 19%) with dual CPI than with CPI/TKI combinations.

Figure 2

Relevant considerations for the selection of treatment, based on differentiating aspects of first-line therapy trials and effects on survival curves

Approximately 20% of patients are symptomatic or have a tumor-site-specific risk of compression or infiltration of adjacent structures (e21). Both of these situations call for effective tumor control. CPI/TKI combinations have yielded high objectifiable tumor response rates (ORR: 50–70%) compared to that of a CPI/CPI combination (39%) (25, 26, 27, 28, 29). TKI/CPI therapies are also clearly superior to the dual CPI combination with respect to the primary treatment failure rate, particularly when a third-generation TKI is used. CPI/TKI combinations are thus the treatment of choice in cases with urgent remission pressure (Table 1, Figure 2).

The HrQoL is a multidimensional quantitative assessment of the patient‘s subjective experience while under treatment and across time. Although comparisons across studies are not fully interpretable because of differences in method, dual CPI therapy seems to bring about a better HrQoL after six months than TKI monotherapy (25).

Meanwhile, no superiority over TKI monotherapy has been demonstrable for the CPI/TKI combinations, especially those with axitinib. The third-generation PD-1-CPI/TKI combinations, however, displayed a trend toward better HrQoL in comparison to TKI monotherapy, mainly because of more effective tumor control (Table 1, Figure 2) (29, 30).

Options for second-line therapy

If there is clinically significant progression during first-line treatment, the appropriate second-line treatment is hard to choose, as the pertinent second-line studies are no longer directly applicable because of the major changes in the first-line situation. In general, when there is progression during first-line treatment, it is recommended that a drug that has not yet been used should be given. After one or two TKI treatments, the PD-1 inhibitor nivolumab can be used. After CPI/TKI or CPI/CPI treatment, an as yet unused TKI or lenvatinib/everolimus should be considered. The approval situation should be taken into account. Independently of this, for second-line treatment after a CPI-based combination, the most reliable evidence supports the high efficacy of cabozantinib. In other situations, preference should be given to as yet unused drugs (e22, 31, 32).

Special considerations for non-clear-cell renal cell carcinoma

Although a number of phase 2 trials and subgroup analyses focusing on non-clear-cell types of mRCC have been performed in recent years, the data concerning these entities remain sparse. The phase 2 trials have demonstrated the efficacy ofCPI combinations (lenvatinib/pembrolizumab, nivolumab/cabozantinib, nivolumab/ipilimumab: ORR 19.6– 49%) (4, 33, 34, 35). Monotherapy with cabozantinib, a TKI, is also effective. The phase 2 Sunniforecast trial is intended to determine which combination, if any, is superior to the others (e23). mTOR inhibitors are to be recommended for the chromophobe subtype, which seems less responsive to CPI (10, 2). CPI-based treatment is generally given for sarcomatoid differentiation.

Follow-up and supportive care

Once a treatment has been initiated, it is generally continued over the long term until there is either disease progression or dose-limiting toxicity. In the approval studies for the PD1/TKI combinations, PD-1 was discontinued after 2 years. The specific adverse drug reactions (ADRs) of CPIs and TKIs may make it necessary to modify the treatment. Proper treatment follow-up therefore requires a good knowledge of the typical side effects of each drug and their management (Figure 3). The ADRs of tyrosine kinase inhibitors typically arise early and in dose-dependent fashion; once the TKI is discontinued, they usually subside at a rate depending on the half-life of the drug. ADRs of CPI treatment arise after a delay, perhaps even months after the treatment has been terminated; yet the ADRs of dual CPI treatment, like those of TKI treatment, generally arise in the first three months. Adverse reactions to TKIs are mainly managed by dose adjustment and ADR-specific supportive treatment, while severe ADRs of CPI often necessitate the interruption or cessation of treatment and sometimes immune suppression, usually with steroids but more rarely with TNFα blockers or other drugs (36, 10, 2). It is important to determine which drug is causing the adverse reaction, especially if it is of a type that could be due to either CPI or TKI (Figure 3).

Figure 3

Substance-specific adverse drug reactions and overlapping toxicities

The early detection of immune phenomena necessitates regular, meticulous follow-up with history-taking and physical examination as well as the monitoring of laboratory values (36). Appropriate baseline imaging must be performed before the start of treatment. Follow-up checks should be carried out at regular intervals, i.e., every 6 to 12 weeks. If the images show tumor enlargement, the possibility of pseudoprogression should be considered, and the question of starting further treatment should be carefully weighed if the patient is clinically stable. In principle, the possibility of participating in a clinical trial should also be evaluated before any treatment is decided on. Oligoprogression can be treated with additive local therapy; this should be discussed by a multidisciplinary tumor board (10). In case of marked progression of disease, a switch to exclusively symptomatic treatment should be discussed in close interdisciplinary consultation. Matters to be considered include the expected success or lack of success of treatment, the sequence of treatments, and patient preferences in the palliative situation as well, so that patients can be counseled on palliative care as soon as this becomes relevant (2, 10).

Overview

mRCC is a challenging disease that calls for multidisciplinary management and multimodal treatment approaches. This tumor entity was hardly treatable a mere 20 years ago; today, highly effective drugs are at the forefront of the many available therapeutic options. When these are appropriately used, patients’ lives can be markedly prolonged at the cost of only moderate treatment-related side effects, while a good quality of life is sustained for as long as possible.

Conflict of interest statement
JB has served as a paid consultant for BMS, Eisai, Ipsen, Merck KgA, and MSD and has received lecture honoraria from Apogepha, MSD, Ipsen, Pfizer, and BMS. He has received reimbursement of travel costs from Ipsen, Merck, and KgA. He is a member of the advisory board of MSD. He is vice-president of the RCC guideline committee and the urological spokesman of the interdisciplinary working group on renal cell carcinoma (Interdisziplinäre Arbeitsgruppe Nierenzellkarzinom, IAGN) of the German Cancer Society.

CD serves as a paid consultant for epha, BMS, Eisai, EUSA Pharm, Ipsen, Merck Serono, MSD, and Pfizer. He receives honoraria for lectures, presentations, manuscript writing, and/or continuing medical education events from Apogepha, BMS, Ipsen, MSD, and Pfizer. He receives reimbursement of travel costs from MSD and Pfizer.

PI receives research support from Bayer, BMS, Ipsen, Merck Serono, Pfizer, and Roche. He serves as a paid consultant for Bayer, Bristol Myers Squibb, ClinSol, EISAI, EMD-Serono, EUSA, H5-Oncology, Ipsen, Merck Serono (Global), Metaplan, MSD, Onkowissen, Pfizer, and Roche. He has received lecture honoraria from Apogepha, AstraZeneca Bayer (+Europe, Global), Bristol Myers Squibb, CORE2ED, DKG-Onkoweb, EISAI, EUSA, FoFM, Id-Institut, Ipsen (Europe), Merck Serono (+Europe, Global), Merck Sharp & Dohme, MedKom, MTE-Academy, MedWiss, New Concept Oncology, Onkowissen-tv.de, Pharma Mare, Pfizer, Roche, ThinkWired!, Schmitz-Communikation, StreamedUP!, Solution Academy, and Vivantis. He has received financial support for attending scientific meetings from Ipsen, B, and Merck Serono. He serves on the advisory boards of Bayer, Bristol Myers Squibb, ClinSol, EISAI, EMD-Serono, EUSA, H5-Oncology, Ipsen, Merck Serono (Global), Metaplan, MSD, Onkowissen, Pfizer, and Roche. He is a spokesman for the working groups on genitourinary tumors, medical oncology, and renal cell carcinoma (IAG-N) of the German Cancer Society.

SZ receives consultant’s fees and support for continuing medical education sessions from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celegne, Eisai, EUSA, Gilead, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, and Roche (lifetime). She has received reimbursement of travel expenses from Amgen, Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Merck, MSD, and Pfizer.

VG serves as a paid consultant for Apogepha, BMS, EISAI, Merck Serono, MSD, Novartis, Pfizer, and Roche. He has received honoraria for presentations from Apogepha, BMS, EISAI, Merck Serono, MSD, Novartis, Pfizer, and Roche and reimbursement of travel expenses from Ipsen, Merck, and Pfizer. He serves on the advisory boards of Apogepha, BMS, EISAI, Merck Serono, MSD, Novartis, Pfizer, and Roche. He serves on the board of directors of the working group on medical oncology of the German Cancer Society.

TCF declares that she has no conflict of interest.

Manuscript received on 1 February 2024, revised version accepted on 8 July 2024.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. Philipp Ivanyi

Medizinische Hochschule Hannover, OE 6860

Abteilung für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

Carl-Neuberg-Str. 1, D-30625 Hanover, Germany

Cite this as:
Ivanyi P, Fröhlich T, Grünwald V, Zschäbitz S, Bedke J, Doehn C: The treatment of metastatic renal cell carcinoma. Dtsch Arztebl Int 2024; 121: 576–86. DOI: 10.3238/arztebl.m2024.0147

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