**4. Metastatic systemic treatment options**

#### **4.1. Overview**

The treatment objective in metastatic cancer is different to the primary setting. Treatment is palliative and the benefits, in terms of progression-free and overall survival, must be carefully balanced against the quality of life of the patient and potential side effects that any treatment may cause. The evolution of therapies has led to an increase in the median overall survival in metastatic RCC to beyond 2 years, and is likely to increase further as more treatments are developed [15–17].

#### **4.2. Tyrosine kinase inhibitors**

Tyrosine kinase inhibitors (TKIs) are a mainstay of targeted treatment in renal cell carcinoma. The drugs are designed to inhibit tyrosine kinases and enzymes, which themselves activate pathways of growth within the tumour cell. There are many different targets for TKIs, and in renal cell carcinoma, agents are targeted at vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and the mammalian target of rapamycin (mTOR). Over half of patients have abnormalities in the von Hippel Lindau (VHL) gene, which leads to an increased expression of hypoxia inducible factors (HIF) [18]. In turn, accumulation of HIF switches on hypoxia-inducible genes such as VEGF and PDGF, and further downstream, mTOR. Expression of VEGF and mTOR drives tumour growth and angiogenesis [18].

The most commonly used TKIs employing VEGF are sorafenib, sunitinib, pazopanib, axitinib, and cabozantinib, and employing mTOR everolimus and temsirolimus. The action of these agents at a cellular level is illustrated in **Image 1**. Multiple clinical trials have shown the efficacy of these agents in RCC and are summarised in **Table 2**. The most commonly observed side effects for TKI therapy are rash, diarrhoea, hypertension, fatigue, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) [19–26].

(ORR) were around 10–15% [17]. More recently, studies have investigated Nivolumab, a fully human IgG4 anti-programmed cell death-1 antibody (anti-PD-1) that selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and RCC [17, 32]. In the CheckMate 025 study, patients were randomised to receive either nivolumab or everolimus, OS was 25 vs. 19 months in favour of nivolumab, and less grade 3 or 4 toxicity was seen in the nivolumab arm [33]. This trial led to the FDA approval of nivolumab for RCC in 2015 with

**Image 1.** A graphic showing how loss of the von Hippel Lindau (VHL) protein results in up regulation of hypoxia induced factors (HIF) and in turn vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF)

Medical Management of Renal Cell Cancer http://dx.doi.org/10.5772/intechopen.85931 159

After the success of single agent immunotherapy, attention turned to the investigation of combination immunotherapy in metastatic RCC. Here, nivolumab was used in combination with a second agent ipilimumab, a monoclonal antibody, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CheckMate 214 trial randomised nivolumab and ipilimumab against sunitinib. Median OS was not reached in the combination immunotherapy arm compared to the immunotherapy used for 26 months with sunitinib, and PFS was 11.6 vs.

The mechanism of action of the various immunotherapy agents can be complex. In short, they upregulate the body's own immune response against the 'foreign' tumour cells. For those

European approval quickly following.

and the actions of targeted therapies.

8.4 months in favour of combination immunotherapy [16].

Bevacizumab has also been used in renal cell cancer. Bevacizumab is a monoclonal antibody, which blockades the VEGF ligand, binding with VEGF-A. Initial trials of bevacizumab versus interferon alpha (IFN-) showed a progression-free survival (PFS) benefit, but no OS benefit as crossover was allowed on progression [27]. When used in combination, IFN- bevacizumab showed a higher response rate and PFS, but again OS was not demonstrated, and there was also significant toxicity [27]. Although it remains a first-line treatment option, in practice, due to the high toxicity of the treatment and efficacy of other first-line treatment options, it is rarely used. Trials also explored the combination of bevacizumab and mTOR inhibitors; however, no clinical benefit was determined and toxicity proved to be a limiting factor [28–31].

#### **4.3. Immunotherapy**

One of the most exciting areas of development in systemic therapy has been immunotherapy. The purpose of immunotherapy is to unmask the cancer to the body's own immune system. Historically, IFN- has been used in RCC with a modest effect, and overall response rates

**4. Metastatic systemic treatment options**

The treatment objective in metastatic cancer is different to the primary setting. Treatment is palliative and the benefits, in terms of progression-free and overall survival, must be carefully balanced against the quality of life of the patient and potential side effects that any treatment may cause. The evolution of therapies has led to an increase in the median overall survival in metastatic RCC to beyond 2 years, and is likely to increase further as more treatments are

Tyrosine kinase inhibitors (TKIs) are a mainstay of targeted treatment in renal cell carcinoma. The drugs are designed to inhibit tyrosine kinases and enzymes, which themselves activate pathways of growth within the tumour cell. There are many different targets for TKIs, and in renal cell carcinoma, agents are targeted at vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and the mammalian target of rapamycin (mTOR). Over half of patients have abnormalities in the von Hippel Lindau (VHL) gene, which leads to an increased expression of hypoxia inducible factors (HIF) [18]. In turn, accumulation of HIF switches on hypoxia-inducible genes such as VEGF and PDGF, and further downstream,

mTOR. Expression of VEGF and mTOR drives tumour growth and angiogenesis [18].

erythrodysesthesia syndrome (hand-foot syndrome) [19–26].

The most commonly used TKIs employing VEGF are sorafenib, sunitinib, pazopanib, axitinib, and cabozantinib, and employing mTOR everolimus and temsirolimus. The action of these agents at a cellular level is illustrated in **Image 1**. Multiple clinical trials have shown the efficacy of these agents in RCC and are summarised in **Table 2**. The most commonly observed side effects for TKI therapy are rash, diarrhoea, hypertension, fatigue, and palmar-plantar

Bevacizumab has also been used in renal cell cancer. Bevacizumab is a monoclonal antibody, which blockades the VEGF ligand, binding with VEGF-A. Initial trials of bevacizumab versus interferon alpha (IFN-) showed a progression-free survival (PFS) benefit, but no OS benefit as crossover was allowed on progression [27]. When used in combination, IFN- bevacizumab showed a higher response rate and PFS, but again OS was not demonstrated, and there was also significant toxicity [27]. Although it remains a first-line treatment option, in practice, due to the high toxicity of the treatment and efficacy of other first-line treatment options, it is rarely used. Trials also explored the combination of bevacizumab and mTOR inhibitors; however, no clinical benefit was determined and toxicity proved to be a limiting factor [28–31].

One of the most exciting areas of development in systemic therapy has been immunotherapy. The purpose of immunotherapy is to unmask the cancer to the body's own immune system. Historically, IFN- has been used in RCC with a modest effect, and overall response rates

**4.1. Overview**

158 Evolving Trends in Kidney Cancer

developed [15–17].

**4.3. Immunotherapy**

**4.2. Tyrosine kinase inhibitors**

**Image 1.** A graphic showing how loss of the von Hippel Lindau (VHL) protein results in up regulation of hypoxia induced factors (HIF) and in turn vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) and the actions of targeted therapies.

(ORR) were around 10–15% [17]. More recently, studies have investigated Nivolumab, a fully human IgG4 anti-programmed cell death-1 antibody (anti-PD-1) that selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and RCC [17, 32]. In the CheckMate 025 study, patients were randomised to receive either nivolumab or everolimus, OS was 25 vs. 19 months in favour of nivolumab, and less grade 3 or 4 toxicity was seen in the nivolumab arm [33]. This trial led to the FDA approval of nivolumab for RCC in 2015 with European approval quickly following.

After the success of single agent immunotherapy, attention turned to the investigation of combination immunotherapy in metastatic RCC. Here, nivolumab was used in combination with a second agent ipilimumab, a monoclonal antibody, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CheckMate 214 trial randomised nivolumab and ipilimumab against sunitinib. Median OS was not reached in the combination immunotherapy arm compared to the immunotherapy used for 26 months with sunitinib, and PFS was 11.6 vs. 8.4 months in favour of combination immunotherapy [16].

The mechanism of action of the various immunotherapy agents can be complex. In short, they upregulate the body's own immune response against the 'foreign' tumour cells. For those


who wish for a fuller explanation, the cellular mechanism of the immunotherapy agents is now outlined. In the tumour microenvironment, tumour neoantigens are released by cancer cells. These are captured by antigen presenting cells (APCs). These neoantigens cause the expression of major histocompatibility complexes (MHC) and T-cell receptors (TCRs) on the surface of CD8+ cytotoxic T cells. PD-1 expression is induced. Tumour cells can highly express PD-L1 and PD-L2, which can bind with PD-1 on the T cell and ultimately lead to T-cell exhaustion. Drugs such as nivolumab and pembrolizumab inhibit the interaction of PD-1 with PD-L1 and PD-L2, which results in enhanced T-cell cytotoxicity, increased cytokine, and tumour-associated macrophage activity. Anti-PD-L1 antibody therapies such as atezolizumab, durvalumab and avelumab, specifically target the interaction between PD-L1 and PD-1. Tumour neoantigens also cause peptides bound to MHC II molecules to be presented to CD4+ T helper cells. Through a series of co-stimulatory signals transmitted via CD28 T cells, CTLA-4 is upregulated. The upregulated CTLA-4 competes with CD28 to bind with CD80 and/or CD86 on the APC. The interaction of CTLA-4 with CD80 or CD86 results in inhibitory signalling, which in turn promotes tumour growth. Ipilimumab is an anti-CTLA-4 antibody; thus, it blocks CTLA-4, allowing an enhanced immune response [34]. A pictorial explanation of the mechanism of both CTLA-4 and PD-1 immunotherapy targeted agents is available in

**Line of treatment** **Disease-free survival (DFS) (months)**

Sunitinib 8.3 HR 1.41 p = 0.16

First line Everolimus 5.6

**Overall survival (OS) (months)**

161

Medical Management of Renal Cell Cancer http://dx.doi.org/10.5772/intechopen.85931

> Everolimus 13.2 Sunitinib 31.5 HR1.12 p = 0.60

Immunotherapy has a different safety profile from targeted TKI therapies or standard chemotherapies. Typically, autoimmune reactions are seen that can be varying and at times severe. The most common is diarrhoea and colitis, but pneumonitis and endocrine problems are also

There has also been some investigation in using the combinations of immunotherapy with targeted agents. Nivolumab was paired with pazopanib or sunitinib in the CheckMate 014 trial; however, toxicity was very high with 70% of patients experiencing a grade 3 or 4 toxicity and 25% discontinuing the treatment due to toxicity. This trial has led to caution in combining

**Image 2**.

observed.

immunotherapy and TKIs [35] (**Table 3**).

**Trial Drug Number of** 

Everolimus versus sunitinib

Armstrong et al.: everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, openlabel, randomised phase 2 trial [26]

**patients (n)**

(non-clear cell histology)

108

**Table 2.** Trials of tyrosine kinase inhibitors in the metastatic renal cancer setting.


**Table 2.** Trials of tyrosine kinase inhibitors in the metastatic renal cancer setting.

**Trial Drug Number of** 

Sunitinib versus interferon alpha

Pazopanib versus placebo

Sunitinib versus pazopanib

Interferon alpha versus temsirolimus versus

temsirolimus plus interferon alpha

Sorafenib versus placebo

Axitinib versus sorafenib

Cabozantinib versus everolimus 626 (poor prognosis)

Motzer et al.: sunitinib versus interferon alpha in metastatic renal cell carcinoma [19]

160 Evolving Trends in Kidney Cancer

Sternberg et al.: pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomised phase III trial [20]

Motzer et al.: pazopanib versus sunitinib in metastatic renal cell carcinoma [21]

Hudes et al.: temsirolimus, interferon alpha, or both for advanced renal cell carcinoma [22]

Escudier et al.: sorafenib in advanced clear cell renal cell carcinoma [23]

Rini et al.: comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial [24]

Choueiri et al.: cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3

trial [25]

**patients (n)**

**Line of treatment**

435 Treatment

750 First line Sunitinib 11

naive or cytokine pretreated

1110 First line Sunitinib 9.5

903 First line Sorafenib 5.5

723 Second line Axitinib 6.7

subsequent

658 Second line or

**Disease-free survival (DFS) (months)**

interferon alpha 5 HR 0.42 p < 0.001

Pazopanib 9.2 placebo 4.2 HR 0.46 P < 0.001

Pazopanib 8.8 HR 1.05

temsirolimus 5.5 temsirolimus plus interferon alpha

First line Interferon alpha 3.1

4.7

placebo 2.8 HR 0.44 P < 0.01

Sorafenib 4.7

Cabozantinib 7.4 everolimus 3.9 HR 0.051 p < 0.0001

**Overall survival (OS) (months)**

Sunitinib 28.7 Interferon alpha

Not available

Sunitinib 29.3 Pazopanib 28.4

Interferon alpha 7.3 temsirolimus 10.9 temsirolimus plus interferon alpha 8.4

Sorafenib not reached

Not available

Cabozantinib 18.8 everolimus 16.5 HR 0.66 p = 0.00026

placebo not reached HR 0.72 P < 0.001

HR 0.8209 p = 0.051

23.7

who wish for a fuller explanation, the cellular mechanism of the immunotherapy agents is now outlined. In the tumour microenvironment, tumour neoantigens are released by cancer cells. These are captured by antigen presenting cells (APCs). These neoantigens cause the expression of major histocompatibility complexes (MHC) and T-cell receptors (TCRs) on the surface of CD8+ cytotoxic T cells. PD-1 expression is induced. Tumour cells can highly express PD-L1 and PD-L2, which can bind with PD-1 on the T cell and ultimately lead to T-cell exhaustion. Drugs such as nivolumab and pembrolizumab inhibit the interaction of PD-1 with PD-L1 and PD-L2, which results in enhanced T-cell cytotoxicity, increased cytokine, and tumour-associated macrophage activity. Anti-PD-L1 antibody therapies such as atezolizumab, durvalumab and avelumab, specifically target the interaction between PD-L1 and PD-1. Tumour neoantigens also cause peptides bound to MHC II molecules to be presented to CD4+ T helper cells. Through a series of co-stimulatory signals transmitted via CD28 T cells, CTLA-4 is upregulated. The upregulated CTLA-4 competes with CD28 to bind with CD80 and/or CD86 on the APC. The interaction of CTLA-4 with CD80 or CD86 results in inhibitory signalling, which in turn promotes tumour growth. Ipilimumab is an anti-CTLA-4 antibody; thus, it blocks CTLA-4, allowing an enhanced immune response [34]. A pictorial explanation of the mechanism of both CTLA-4 and PD-1 immunotherapy targeted agents is available in **Image 2**.

Immunotherapy has a different safety profile from targeted TKI therapies or standard chemotherapies. Typically, autoimmune reactions are seen that can be varying and at times severe. The most common is diarrhoea and colitis, but pneumonitis and endocrine problems are also observed.

There has also been some investigation in using the combinations of immunotherapy with targeted agents. Nivolumab was paired with pazopanib or sunitinib in the CheckMate 014 trial; however, toxicity was very high with 70% of patients experiencing a grade 3 or 4 toxicity and 25% discontinuing the treatment due to toxicity. This trial has led to caution in combining immunotherapy and TKIs [35] (**Table 3**).

#### **4.4. Sequencing of agents**

The natural history of targeted agents in all cancers, and reflected here in RCC, is developing ultimate resistance. Therefore, a patient may undertake several lines of treatment. Both the European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) provide up-to-date guidelines advising oncologists of the latest evidence to help determine the most advantageous sequence of agents [36, 37]. At the time of publication, we would suggest a suitable sequence of therapies to be followed: first-line sunitinib or pazopanib (in poor-risk patients temsirolimus), second-line axitinib or nivolumab, with a preference to nivolumab in poor-risk patients, and third-line cabozantinib [36]. In non-cell histology, sunitinib is recommended first line, although few trials have specifically recruited

Medical Management of Renal Cell Cancer http://dx.doi.org/10.5772/intechopen.85931 163

We recognise that as new agents are developed and further research is conducted in this field, the advice may change. Another strategy that has been investigated is active surveillance. Patients with indolent metastatic disease may safely remain on surveillance until their disease begins to progress. A cohort study of patients with metastatic RCC on surveillance demon-

Historically, cytoreductive nephrectomy has been used in metastatic disease in a selected number of patients. It has been especially used in fit patients with asymptomatic, low burden of metastatic disease and troublesome local symptoms such as bleeding and pain [39]. However, publication of the CARMENA trial in 2018, where sunitinib versus cytoreductive nephrectomy plus sunitinib was evaluated, demonstrated non-inferiority of sunitinib alone [40]. The trial was designed to demonstrate non-inferiority and non-superiority of one investigational arm; however, it was noted that the median OS of sunitinib alone was 18.4 months versus 13.9 months as compared to sunitinib with nephrectomy [40]. Although further evaluation is required, and for symptomatic management, cytoreductive nephrectomy may still be beneficial in the metastatic setting, this new evidence has called into question the validity of this approach routinely used for patients in the contemporary systemic

An interesting development across oncology in all tumour groups has been the change in approach to the management of oligometastatic disease [41]. Oligometastatic disease is a term used to describe a patient with a small number of metastatic lesions; in most studies, this is defined as 1–3 or 1–5 lesions [41]. Aggressive resection of the metastasis can be attempted surgically or an increasing number of patients can be treated with high doses of radiotherapy using stereotactic ablative body radiotherapy (SABR) [41, 42]. Traditionally, RCC has been thought to be a radio-resistant disease; however, large ablative doses of radiotherapy used in an SABR technique induce different pathways of apoptosis and as such good long-term control can be achieved in certain patients. Metastasis in bone, lungs, brain, lymph nodes, and

non-clear cell histological subtypes for investigation [26, 36].

**5. Cytoreductive nephrectomy in the age of TKI**

**6. Oligometastatic disease in kidney cancer**

adrenal glands are all potentially treatable with SABR [43–45].

treatment setting.

strated a median time to starting systemic therapy of 14.9 months [38].

**Image 2.** Pictorial representation of the mechanism of action of immunotherapy agents.


**Table 3.** Immunotherapy trials in metastatic renal cell carcinoma.

Network (NCCN) provide up-to-date guidelines advising oncologists of the latest evidence to help determine the most advantageous sequence of agents [36, 37]. At the time of publication, we would suggest a suitable sequence of therapies to be followed: first-line sunitinib or pazopanib (in poor-risk patients temsirolimus), second-line axitinib or nivolumab, with a preference to nivolumab in poor-risk patients, and third-line cabozantinib [36]. In non-cell histology, sunitinib is recommended first line, although few trials have specifically recruited non-clear cell histological subtypes for investigation [26, 36].

We recognise that as new agents are developed and further research is conducted in this field, the advice may change. Another strategy that has been investigated is active surveillance. Patients with indolent metastatic disease may safely remain on surveillance until their disease begins to progress. A cohort study of patients with metastatic RCC on surveillance demonstrated a median time to starting systemic therapy of 14.9 months [38].
