**3. Development of systemic therapy in mRCC**

### **3.1. Chemotherapy**

The successes on other solid tumors led researches to the assumption chemotherapy would be effective also in mRCC. Chemotherapeutic trials were conducted between 1983 and 1993. Different agents; bleomycin, cisplatin, 5-FU, gemcitabine and vinblastine have been tested. Results were disappointing; less than 10% of patients had clinical benefit in all of these trials. Response rates in the range of 10 to 15% have been achieved with combination of two agents. Today chemotherapy has no role in the treatment of mRCC patients and is not part of the everyday clinical practice [2].

**3.3.1. Sunitinib**

**3.3.2. Pazopanib**

mRCC [2,14].

**3.3.3. Bevacisumab**

**3.3.4. Sorafenib**

prominent in the combination group [2,11,16,17].

first-line treatment of mRCC [2,9].

Sunitinib is a potent multi-kinase inhibitor including platelet-derived growth factor receptor (PDGFR) α and β, stem cell factor receptor (c-KIT), FMS-like tyrosine kinase-3 (FLT-3), VEGF receptors 1,2,3, colony stimulating factor (CSF-1R) and neurotropic factor receptor. Large multicentric phase 3 trial in which 750 patients were randomized in a 1:1 fashion between treatment with IFN-α and sunitinib, demonstrated its superiority over IFN-α. Overall response rate was 31% in the sunitinib and 6% in the IFN group (p<0.0001).The median PFS in the sunitinib group was 11 and in IFN-α 5 months. Difference was observed also in overall survival (median 26.8 months in sunitinib and 21.8 months in the IFN group, p=0.051). The most common adverse events were fatigue, diarrhea, mucositis, hand-foot syndrome and hyper‐ tension [12,13]. Sunitinib was approved by FDA in 2007 and is today standard of care in the

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191

Pazopanib is an oral multitargeted tyrosine kinase inhibitor that targets VEGFR 1,2,3, PDGFR α and β and c-KIT. Approval of pazopanib in 2009 was based on a phase III trial in which 435 patients were randomized (2:1) to receive either pazopanib 800 mg once daily or placebo. The median PFS of 9.2 months in the pazopanib group was significantly longer than in placebo group where PFS was 4.2 months (p<0.0001). Main side effects were diarrhoea in half, hyper‐ tension in 40% and nausea, anorexia, vomiting and fatigue in 20% of patients [14]. Grade 3 hepatotoxicity was also reported. Pazopanib is recommended in the first line treatment of

Bevacisumab is a recombinant monoclonal antibody that binds circulating VEGF protein and neutralizes it [15]. In the AVOREN trial 649 previously untreated patients were randomized to receive either bevacisumab every two weeks and IFN-α or placebo and IFN-α. Differences in PFS (10.2 vs. 5.4 months) and ORR (31 vs. 13%) were significantly better in bevacisumab group (p<0.0001 for both parameters) [16]. The second trial conducted by Cancer and Leukemia Group B was similar. PFS of 8.5 months in the bevacisumab was statistically significant better than in the IFN monotherapy group (PFS 5.2 months, p<0,0001). Differences were also demonstrated comparing ORR favoring bevacisumab group (25.5 vs. 13.1% p<0,0001). Fatigue, anorexia, hypertension and proteinuria were among the most common side effects and more

Sorafenib is a small molecule, oral multikinase inhibitor that inhibits VEGFR 1,2,3, PDGFR-β, RAF, serine/threonine intracellular kinase, FLT-3, cKIT and RET. Sorefenib was tested in a phase III trial (TARGET), 903 patients with mRCC resistant to standard therapy were random‐ ized to receive sorafenib twice daily or placebo. PFS in the sorafenib group was 5.5 months and in placebo group 2.8 months (p<0.000001). Difference in OS did not reach statistical

Several mechanisms have been discovered to be responsible to the resistance of RCC cells to chemotherapy. Beside increased detoxification, altered targets and impaired apoptosis pathways, increased expression of transporting proteins play an important role. P-glycopro‐ tein is a 170-kD membrane glycoprotein that acts as a pump that expels chemicals like vinblastine out of the cell [2].

### **3.2. Cytokines**

The interest in interferon in the treatment of RCC came when sporadic responses in patients with RCC on leucocyte interferon, were observed. Natural interferon produced from donor's leucocytes, was later substituted with recombinant. Different forms and dosages were tested and no major differences between them were observed. Uniformly response rates ranged from 0 to 29% with few complete and very few durable responses. Some trials suggested that certain group of patients have larger benefit (good performance status, prior nephrectomy and restricted metastases to the lungs), but this was not a uniform finding. Today interferon as mono-therapy is not widely used, because of the low efficacy coupled with high toxicity [2].

IL-2 was discovered in 1979 and it soon became clear that it could be effective in the treatment of RCC. Response rates of 33% have been reported in the initial trials. Later multicentric trials reported response rates in 7-19% of patients. In small number of patients responses were complete and durable; 7-9% of all patients did not relapse even after 10 years and these patients are considered to be cured from cancer. Unfortunately until today the selection of patients likely to have durable responses is not possible, because patient and tumor characteristics that predict best responses to IL-2 have not been identified yet [2]. Beside uncertain responses, unfavourable toxicity profile limits the use of IL-2. Patients treated with high doses of IL-2 may experience vascular leak syndrome, hypotension, multiorgan dysfunction and a variety of other toxicities. In the two decades, when IL-2 was the standard therapy of mRCC patients were selected on safety bases (performance status, co-morbidities), tumor histology (clear cell), risk scores (e.g. Memorial Sloan Kettering Cancer Center) and patient preferences [2,10].

### **3.3. VEGF targeted therapy**

It is not surprising that several agents targeting VEGF demonstrate activity in RCC. As described in previous sub chapter there is direct link between VHL mutation and up regulation of angiogenesis- promoting proteins including VEGF and PDGF. VEGF is the main factor responsible for tumor angiogenesis and PDGF is signalling protein for perycites, structural supporting cells for blood vessels. VHL is mutated in most of the patients with RCC [2,10,11].

### **3.3.1. Sunitinib**

Today chemotherapy has no role in the treatment of mRCC patients and is not part of the

Several mechanisms have been discovered to be responsible to the resistance of RCC cells to chemotherapy. Beside increased detoxification, altered targets and impaired apoptosis pathways, increased expression of transporting proteins play an important role. P-glycopro‐ tein is a 170-kD membrane glycoprotein that acts as a pump that expels chemicals like

The interest in interferon in the treatment of RCC came when sporadic responses in patients with RCC on leucocyte interferon, were observed. Natural interferon produced from donor's leucocytes, was later substituted with recombinant. Different forms and dosages were tested and no major differences between them were observed. Uniformly response rates ranged from 0 to 29% with few complete and very few durable responses. Some trials suggested that certain group of patients have larger benefit (good performance status, prior nephrectomy and restricted metastases to the lungs), but this was not a uniform finding. Today interferon as mono-therapy is not widely used, because of the low efficacy coupled with high toxicity [2].

IL-2 was discovered in 1979 and it soon became clear that it could be effective in the treatment of RCC. Response rates of 33% have been reported in the initial trials. Later multicentric trials reported response rates in 7-19% of patients. In small number of patients responses were complete and durable; 7-9% of all patients did not relapse even after 10 years and these patients are considered to be cured from cancer. Unfortunately until today the selection of patients likely to have durable responses is not possible, because patient and tumor characteristics that predict best responses to IL-2 have not been identified yet [2]. Beside uncertain responses, unfavourable toxicity profile limits the use of IL-2. Patients treated with high doses of IL-2 may experience vascular leak syndrome, hypotension, multiorgan dysfunction and a variety of other toxicities. In the two decades, when IL-2 was the standard therapy of mRCC patients were selected on safety bases (performance status, co-morbidities), tumor histology (clear cell), risk scores (e.g. Memorial Sloan Kettering Cancer Center) and patient preferences [2,10].

It is not surprising that several agents targeting VEGF demonstrate activity in RCC. As described in previous sub chapter there is direct link between VHL mutation and up regulation of angiogenesis- promoting proteins including VEGF and PDGF. VEGF is the main factor responsible for tumor angiogenesis and PDGF is signalling protein for perycites, structural supporting cells for blood vessels. VHL is mutated in most of the patients with

everyday clinical practice [2].

vinblastine out of the cell [2].

**3.3. VEGF targeted therapy**

RCC [2,10,11].

**3.2. Cytokines**

190 Renal Tumor

Sunitinib is a potent multi-kinase inhibitor including platelet-derived growth factor receptor (PDGFR) α and β, stem cell factor receptor (c-KIT), FMS-like tyrosine kinase-3 (FLT-3), VEGF receptors 1,2,3, colony stimulating factor (CSF-1R) and neurotropic factor receptor. Large multicentric phase 3 trial in which 750 patients were randomized in a 1:1 fashion between treatment with IFN-α and sunitinib, demonstrated its superiority over IFN-α. Overall response rate was 31% in the sunitinib and 6% in the IFN group (p<0.0001).The median PFS in the sunitinib group was 11 and in IFN-α 5 months. Difference was observed also in overall survival (median 26.8 months in sunitinib and 21.8 months in the IFN group, p=0.051). The most common adverse events were fatigue, diarrhea, mucositis, hand-foot syndrome and hyper‐ tension [12,13]. Sunitinib was approved by FDA in 2007 and is today standard of care in the first-line treatment of mRCC [2,9].

### **3.3.2. Pazopanib**

Pazopanib is an oral multitargeted tyrosine kinase inhibitor that targets VEGFR 1,2,3, PDGFR α and β and c-KIT. Approval of pazopanib in 2009 was based on a phase III trial in which 435 patients were randomized (2:1) to receive either pazopanib 800 mg once daily or placebo. The median PFS of 9.2 months in the pazopanib group was significantly longer than in placebo group where PFS was 4.2 months (p<0.0001). Main side effects were diarrhoea in half, hyper‐ tension in 40% and nausea, anorexia, vomiting and fatigue in 20% of patients [14]. Grade 3 hepatotoxicity was also reported. Pazopanib is recommended in the first line treatment of mRCC [2,14].

### **3.3.3. Bevacisumab**

Bevacisumab is a recombinant monoclonal antibody that binds circulating VEGF protein and neutralizes it [15]. In the AVOREN trial 649 previously untreated patients were randomized to receive either bevacisumab every two weeks and IFN-α or placebo and IFN-α. Differences in PFS (10.2 vs. 5.4 months) and ORR (31 vs. 13%) were significantly better in bevacisumab group (p<0.0001 for both parameters) [16]. The second trial conducted by Cancer and Leukemia Group B was similar. PFS of 8.5 months in the bevacisumab was statistically significant better than in the IFN monotherapy group (PFS 5.2 months, p<0,0001). Differences were also demonstrated comparing ORR favoring bevacisumab group (25.5 vs. 13.1% p<0,0001). Fatigue, anorexia, hypertension and proteinuria were among the most common side effects and more prominent in the combination group [2,11,16,17].

### **3.3.4. Sorafenib**

Sorafenib is a small molecule, oral multikinase inhibitor that inhibits VEGFR 1,2,3, PDGFR-β, RAF, serine/threonine intracellular kinase, FLT-3, cKIT and RET. Sorefenib was tested in a phase III trial (TARGET), 903 patients with mRCC resistant to standard therapy were random‐ ized to receive sorafenib twice daily or placebo. PFS in the sorafenib group was 5.5 months and in placebo group 2.8 months (p<0.000001). Difference in OS did not reach statistical significance. Major side effects of sorafenib were rash, hand-foot syndrome, fatigue, diarrhoea and hypertension [18].

### **3.3.5. Axitinib**

Axitinib is a second line inhibitor of VEGFR 1 and 2 and is approved in the second line treatment of mRCC. Axitinib was compared to sorafenib in a phase III trial (AXIX). 723 patients previously treated with suntinib, bevacisumab plus IFN, temsirolimus or cytokines that progressed, were randomized to receive axitinib or sorafenib 400 mg. Median PFS in the axitinib group was 6.7 months and was statistically significant better than in sorafenib group (4.7 months, p<0.0001). Patients in axitinib group had more hypertension, diarrhoea, dyspho‐ nia, fatigue and nausea, while patients in sorafenib had more hand foot syndrome, rash and alopecia [19].

### **3.4. mTOR targeted therapy**

Abnormal functioning of signaling pathways contributes to many malignancies including RCC [20-22]. The mammalian target of rapamycin (mTOR) is a protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription [2]. The disruption of mTOR signaling leads to suppression of the production of proteins that regulate progression of the cell trough the cell cycle and angiogenesis [22].

### *3.4.1. Temsirolimus*

Temsirolimus, an mTOR inhibitor was approved for the treatment of mRCC in the 2007. Global Advance Renal Cell Carcinoma (ARCC) was a phase III trial of temsirolimus in previously untreated mRCC. Patients were randomized to receive either IFN-α, temsirolimus or both. PFS in the groups receiving temsirolimus was significantly longer than in the IFN group (3.7 months in temsirolimus groups vs. 1.9 months in the IFN group; p=0.0019). Patients treated with temsirolimus alone had better overall survival than patients treated with IFN alone (10.9 months vs. 7.3 months, p=0.096). Toxicity was greater in the combination group and included rash, stomatitis, pain, infection, peripheral edema, thrombocytopenia, hyperlipidemia, hypercholesterolemia and hyperglycemia [20].

**4. Mechanism of resistance to targeted therapies**

and resistance [3].

**Sunitninib**

**Bevacisumab**

**Sorafenib**

**Axitinib**

**Everolimus**

**Temsirolimus**

Motzer et.al. (2007)

Escudier et.al. (2007)

Escuder et.al. (2006)

Rini et.al. (2011)

Motzer et.al. (2008)

Hudes et.al. (2007)

**Table 1.** Phase III trials of targeted agents in mRCC

TARGET

AXIS

RECORD-1

ARCC

(2010)

**Pazopanib** Sternberg et.al.

and extrinsic resistance [3].

Large advances in treatment results achieved with targeted therapies in mRCC are remarkable, but still between a third and two-thirds of patients with mRCC have tumors refractory to anti-VEGF and mTOR inhibitors from the beginning of treatment and all patients develop drug resistance and relapse some time during the course of their disease. Research of the mecha‐ nisms of resistance is very important in planning the development of new targeted agents [3, 23,24]. Most of information about drug resistance in mRCC known today is from the preclinical studies or studies on patients with different types of cancer, where targeted therapies are being in clinical practice for longer time (e.g. breast cancer). This is partially due to the rapid approval of targeted agents in mRCC which surpassed understanding of the mechanisms of response

**Author Name Treatment Arm Prior Therapy**

None

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193

None

Sunitinib or Bevacisumab+IFN or temsirolimus or cytokines

None

Sunitinib or Sorafenib

Placebo None or Cytokine

Placebo Cytokine

Sunitinib IFN-α

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma

Pazopanib

AVOREN Bevacisumab plus IFN-α

Sorafenib

Axitinib Sorafenib

Everolimus Placebo

Temsirolimus IFN-α

Temsirolimus plus IFN-α

Placebo plus IFN-α

Until now two types of resistance to targeted therapy have been determined, so called intrinsic

### *3.4.2. Everolimus*

Everolimus is an oral mTOR inhibitor approved for the treatment of mRCC in the second line after progression on sunitinib or sorafenib. Everolimus treatment was tested in phase III trial named RECORD-1. 410 patients which had progressed to previous treatment were randomly assigned to receive either everolimus or placebo. Median PFS in the everolimus group was 4.9 months, in placebo group 1.9 months (p<0.001). The median OS was not significantly different between the two groups (14.8 in everolimus and 14.4 in placebo group, p=0.126) The most common side effects of everolimus were stomatitis, rash, fatigue, asthenia and diarrhea [21,22].

Summary of phase III trials is presented in Tables 1 and 2.

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma http://dx.doi.org/10.5772/55694 193


**Table 1.** Phase III trials of targeted agents in mRCC

significance. Major side effects of sorafenib were rash, hand-foot syndrome, fatigue, diarrhoea

Axitinib is a second line inhibitor of VEGFR 1 and 2 and is approved in the second line treatment of mRCC. Axitinib was compared to sorafenib in a phase III trial (AXIX). 723 patients previously treated with suntinib, bevacisumab plus IFN, temsirolimus or cytokines that progressed, were randomized to receive axitinib or sorafenib 400 mg. Median PFS in the axitinib group was 6.7 months and was statistically significant better than in sorafenib group (4.7 months, p<0.0001). Patients in axitinib group had more hypertension, diarrhoea, dyspho‐ nia, fatigue and nausea, while patients in sorafenib had more hand foot syndrome, rash and

Abnormal functioning of signaling pathways contributes to many malignancies including RCC [20-22]. The mammalian target of rapamycin (mTOR) is a protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription [2]. The disruption of mTOR signaling leads to suppression of the production of proteins that

Temsirolimus, an mTOR inhibitor was approved for the treatment of mRCC in the 2007. Global Advance Renal Cell Carcinoma (ARCC) was a phase III trial of temsirolimus in previously untreated mRCC. Patients were randomized to receive either IFN-α, temsirolimus or both. PFS in the groups receiving temsirolimus was significantly longer than in the IFN group (3.7 months in temsirolimus groups vs. 1.9 months in the IFN group; p=0.0019). Patients treated with temsirolimus alone had better overall survival than patients treated with IFN alone (10.9 months vs. 7.3 months, p=0.096). Toxicity was greater in the combination group and included rash, stomatitis, pain, infection, peripheral edema, thrombocytopenia, hyperlipidemia,

Everolimus is an oral mTOR inhibitor approved for the treatment of mRCC in the second line after progression on sunitinib or sorafenib. Everolimus treatment was tested in phase III trial named RECORD-1. 410 patients which had progressed to previous treatment were randomly assigned to receive either everolimus or placebo. Median PFS in the everolimus group was 4.9 months, in placebo group 1.9 months (p<0.001). The median OS was not significantly different between the two groups (14.8 in everolimus and 14.4 in placebo group, p=0.126) The most common side effects of everolimus were stomatitis, rash, fatigue, asthenia and diarrhea [21,22].

regulate progression of the cell trough the cell cycle and angiogenesis [22].

and hypertension [18].

**3.3.5. Axitinib**

192 Renal Tumor

alopecia [19].

*3.4.1. Temsirolimus*

*3.4.2. Everolimus*

**3.4. mTOR targeted therapy**

hypercholesterolemia and hyperglycemia [20].

Summary of phase III trials is presented in Tables 1 and 2.
