**3. Systemic treatment of metastatic renal cell carcinoma**

The current guidelines from the National Comprehensive Cancer Network Metastatic (NCCN) continue to identify nephrectomy as an important initial consideration, even in the context of metastatic disease. [19] The current recommendations are to consider patients for nephrectomy and/or oligmetastatectomy prior to initiation of systemic therapy whenever appropriate. [20] The traditional teaching is that cytoreductive nephrectomy lead to improved outcome from systemic therapy. This is based on phase III data that showed an improvement in response to IFN-α following nephrectomy in the metastatic setting. In the era of targeted therapy / anti-VEGF therapies, the validity of this practice has been called into question. [20] Clinical trials are underway to address this very question.

Beyond surgery, the only systemic options available prior to the era of targeted therapy consisted of interleukin-2 (IL-2) and interferon-α (IFN-α). Other treatments that had been trialed included chemo- and hormonal therapy have all been discouraging. [21]

IFN-α classically caused flu-like syndrome, depression and in some cases suicidal ideation and is certainly onerous especially in the patients with poorer performance status. [1, 22] IL-2, the other cytokine has a small long term survival benefit of 4%. This is however at the cost of potentiallylifethreateningtoxicitiessuchashypotension,oliguria,capillaryleaksyndromewith secondary multi-organ failure, somnolence and confusion. [23] Not surprisingly, the underly‐ ing enthusiasm for cytokine agents as frontline therapy in metastatic RCC has been replaced by tyrosine kinase inhibitors / targeted therapy which has a more favourable toxicity profile. [24]

The targeted therapies used in metastatic RCC consist of 1. Anti-VEGFs, which are monoclonal antibodies that bind directly to VEGF and related peptides and therefore removing them from the circulation (bevacizumab) and 2. Small molecule tyrosine kinase inhibitors (SMTKIs) that target the down-stream tyrosine kinase signaling pathways, are involved in promotion of tumour angiogenesis, endothelial growth, proliferation and ultimately tumour survival and metastasis. [25] The SMTKIs that have been approved for use in 2012 include sunitinib, sorafenib, pazopanib and axitinib.

### **3.1. Small molecular tyrosine kinase inhibitors**

### *3.1.1. Sunitinib*

transcription factor and consists of two subunits: HIF α-subunit and the HIF β-subunit (also known as aryl hydrocarbon receptor nuclear translocator (ARNT) protein). In the presence of normal oxygen tension (or normoxic state), HIF-α is hydroxylated. pVHL-E3 ubiquitin ligase complex targets the hydroxylated HIF-α for proteosomal degradation. [4] VHL protein

VHL gene mutation or hypermethylation leads to intracellular accumulation of HIF-α subu‐ nits.[7]HIF-αsubunits,aftertranslocationintothenucleus,actinconcertwiththeHIF-βsubunits, andformtranscriptionalfactor complexes thatinduce transcriptionofhypoxia-response genes. [8] The endpoint is an increase in the production of pro-angiogenic factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor alpha and beta (TGF-α and TGF-β). [9] By increasing angiogenesis through VHL-

Papillary carcinomas are commonly bilateral, multifocal and frequently present as small, early stage tumours. [11] They can be further subdivided histologically into papillary types I and II with underlying different genetics and molecular pathways. [12] Type I papillary renal cancers are linked to activating mutations of the methyl-nitroso-nitroguanidine induced (MET) oncogene. [13] The MET oncogene mutations activate the intracellular kinase domains and subsequently trigger the hepatocyte growth / MET pathway. [13] Type II papillary renal cancers on the other hand are associated with mutations of the fumarate hydratase (FH) tumour suppressor gene. [14] Mutational inactivation of the FH tumour suppressor gene leads to a pseudo-hypoxic state and up-regulation of the HIF α-subunits. The accumulation of fumarate is induced by the mutated FH enzyme. That in turn causes inhibition of HIF-prolyl hydroxylase(HPH), an enzymatic regulator of the intracellular HIF-α. Inactivation of the HPH disrupts the hydroxylation of HIF leading to failure of recognition by pVHL and subsequent VHL-dependent proteosomal degradation of HIFs. Accumulation of HIF leads to over-

Chromophobe renal cell cancers accounts for 4% of all RCCs. [1] The exact pathogenesis is not established. It is thought that the VEGF-angiogenic pathway is implicated based on the elevated levels of VEGF and its receptors in this type of RCC. The KIT oncogene and the folliculin gene linked to the familial form of chromophobe/oncocytic RCC hybrid (Brit-Hogg-Dubé-Syndrome), are extra molecular targets identified in this variant [16, 17] Collecting duct

The current guidelines from the National Comprehensive Cancer Network Metastatic (NCCN) continue to identify nephrectomy as an important initial consideration, even in the context of metastatic disease. [19] The current recommendations are to consider patients for nephrectomy and/or oligmetastatectomy prior to initiation of systemic therapy whenever appropriate. [20]

RCC are very rare and the underlying pathogenesis has not been established. [18]

functions as the substrate-recognition subunit of this complex. [5, 6]

HIF pathway the tumour increases its potential to survive and progress. [10]

expression of pro-angiogenic factors and tumour proliferation. [15]

**3. Systemic treatment of metastatic renal cell carcinoma**

**2.2. Non clear-cell variant**

158 Renal Tumor

Sunitinib is a multi-kinase inhibitor targeting numerous VEGF receptors (VEGF-1, 2, 3) and additionaltyrosinekinase receptors (PDGFR, c-Kit,FLT-3,CSF-1R, andRET)[26-29]Earlytrials showed sunitinib to be effective in patients with advanced malignancies including RCC. [30]

### *3.1.1.1. Sunitinib intermittent dosing*

A phase II study of sunitinib in patients with cytokine-refractory metastatic RCC assessed the clinical efficacy and safety of sunitinib as second-line therapy. [31] Sixty three patients who previously failed cytokine-based therapy received 50mg of sunitinib for 4 weeks followed by a 2 week scheduled break, in a 6 week cycle. A partial response of 40% (n=25) (PR) and a stable disease response for ≥ 3 months in 27% (n=17) of the patients were reported. The median time to progression and survival were 8.7 months and 16.4 months respectively. [31]

A second but larger phase II trial of 106 patients similarly confirmed promising activities of sunitinib in cytokine refractory, metastatic RCC. An overall objective response of 44% was observed with 1% (n=1) of patients demonstrated a CR and 44% showed PR. [32] A further 22% (n=23) of patients showed SD for ≥ 3 months. The median response for the 46 responders was 10 months whilst the median progression free survival (PFS) was 8.3 months [32]

response of 7.2 months. The median PFS observed was 8.2 months and the OS was 19.8 months. Tolerability and QOL between the morning and evening dose were similar. However, grade 3 diarrhea, fatigue and hand-foot syndrome were more common in the evening dosing patients. The continuous schedule may benefit patients who are not able to tolerate the

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Another trial assessing continuous vs. intermittent sunitinib dosing was the EFFECT phase II study. In this trial patients with locally recurrent clear-cell RCC or metastatic RCC, treatment naïve patients, were randomly assigned to standard dosing (50mg/day; 4 weeks on, 2 weeks off) and continuous dosing (37.5mg/day). The intermittent schedule when compared with the continuous schedule showed a trend to improved ORR (32.2% vs. 28.1%; p=0.444) and median PFS (8.5 months vs. 7.0 months; p=0.070). No difference were noted between the median OS (23.1 months vs. 23.5 months, p=0.615). [38] Interestingly the median OS was lower than the phase III sunitinib vs. INF-α trial which had a median OS of 26 months. The phase III trial had a higher number of patients with better baseline prognostic features (better performance status and more patients had underwent nephrectomy), which may account for better survival

Sorafenib (Nexavar, BAY 43-9006) is an oral multi-kinase inhibitor that targets multiple nonreceptor as well as receptor kinases. These include BRAF and CRAF, non-receptor serine threonine kinases which belong to the RAF/Mek/ERK signaling pathway and also receptor tyrosine kinases including VEGFR2, VEGFR3, PDGFR, fetal liver tyrosine kinase 3 (FLT-3)… and c-kit. [2] In a phase II randomized discontinuation trial of patients with metastatic RCC who had failed previous systemic therapies, sorafenib at a dose of 400 mg BD showed significant disease-stabilizing activity. [39] In another phase II trial, patients with metastatic RCC on sorafenib (initial starting dose of 400mg BD and escalating to 600mg BD on progres‐ sion) were compared with INF-α in the first line setting. PFS was similar in both arms, although in the sorafenib arm, patients experienced greater rates of tumour size reduction, superior quality of life and better treatment tolerance. [40] Subsequently in a phase 3 trial (TARGET) 903 patients with metastatic clear-cell RCC who had progressed on previous treatment were randomized to receive either placebo or sorafenib (400mg BD). Compared with the placebo group, the sorafenib group demonstrated a higher ORR (57% vs. 34%) and PFS was signifi‐ cantly longer (5.5 months vs. 2.8 months; HR=0.44; p<0.01). [41] This improvement was independent of age (over or under 70 years), prognostic risk, prior cytokine therapy, and previous cardiovascular disease. [41] In this trial, patients in the placebo arm crossed over to sorafenib when progression of disease was diagnosed. In the first interim analysis, a trend towards better OS was noted in patients taking sorafenib, and this was unchanged in the final analysis (17.8 vs. 15.2 months, respectively, HR= 0.88; *p* = 0.146). [42] After censoring for the patients who had crossed over on progression from the placebo arm, the OS was significantly longer in the sorafenib arm (17.8 vs. 14.3 months; HR = 0.78; *p* = 0.029). [41] Sorafenib has also been accessed in a real-world setting through open-label expanded access studies in Europe (The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCS) and North America

intermittent sunitinib 50mg regimen. [33]

results. [33, 38]

*3.1.2. Sorafenib*

These results led to a phase III trial comparing sunitinib with INF-α that was deemed standard of care at the time for patients with metastatic clear cell RCC. [33] Seven hundred and fifty treatment naїve patients with clear-cell histology and good performance status (ECOG 0 or 1) were randomized in a 1:1 ratio to receive either sunitinib (dose as per earlier studies) or INFα (9 × 10<sup>6</sup> units subcutaneously thrice weekly). [32, 34] The median duration of treatment was 6 months (1-15 months) in the sunitinib group and 4 months (1-13 months) in the IFN-α group. The median PFS assessed by an independent third-party review was 11 months in the sunitinib group and 5 months in the IFN-α group, corresponding to a hazard ratio (HR) of 0.42 (95% CI 0.32–0.54; p < 0.001). [33] The investigators' assessment showed similar results. An updated analysis published in 2009 has shown the ORR of 47% for sunitinib and 12% for IFN-α (p < 0.000001), with a median PFS of 11 months and 5 months, respectively, for sunitinib and IFNα (p < 0.000001), similar to the original report. [35] These results were uniformly seen, regard‐ less of the patients' age, gender and prognostic category. Patients on sunitinib also experienced a median OS in excess of 2 years. The OS was 26.4 months for sunitinib and 21.8 months for IFN-α (p = 0.051). [33] However, a dedicated exploratory analysis of patients on both treatment arms who did not receive post-study cancer treatment showed the median OS with sunitinib was twice as long as IFN-α (28.1 months versus 14.1 months respectively, p=0.003). [33] Based on these significant findings, sunitinib replaced IFN-α as first line treatment for stage IV RCC.

In a real-world setting, sunitinib has proven its efficacy in an expanded-access program, designed to allocate access to sunitinib in patients with metastatic RCC who would otherwise be excluded from clinical trials. [33, 36] Four thousand five hundred patients were enrolled in this international, open labeled study. The cohort importantly included older patients (≥ 65 years old; n=1414), those with poorer ECOG status (≥ 2; n=582), non clear-cell histology (n=288) and with brain metastases (n=320). [36] Patients with poor performance status and brain metastases prior to this had been excluded in all sunitinib trials.

The median number of treatment cycles and treatment duration were 5 cycles and 15.6 months respectively. 56% of patients received more than 6 months of sunitinib treatment. The survival data closely resembled the phase III study with an observed median PFS and OS of 10.9 months and 18.4 months respectively. [33] No differences were noted in median PFS and OS between patients with or without prior cytokine therapy. Importantly, the subgroup analysis of i. elderly patients demonstrated median PFS and OS of 11.3 and 18.2 months respectively. [33] ii. patients with poorer performance status, the median PFS and OS were 5.1 months and 6.7 months respectively and finally in patients with brain metastases with an overall poorer prognosis, a median PFS of 5.6 months and median OS of 9.2 months were observed. [33]

### *3.1.1.2. Sunitinib continuous dosing*

The efficacy of continuous sunitinib dosing was examined in an open-label multicenter phase II trial. [37] In this study 107 patients were randomly assigned to either morning or evening daily dose of 37.5mg for a median duration of 8.3 months. 43% of patients had their dose reduced due to grade 3-4 adverse events. The ORR was 20% with a median duration of response of 7.2 months. The median PFS observed was 8.2 months and the OS was 19.8 months. Tolerability and QOL between the morning and evening dose were similar. However, grade 3 diarrhea, fatigue and hand-foot syndrome were more common in the evening dosing patients. The continuous schedule may benefit patients who are not able to tolerate the intermittent sunitinib 50mg regimen. [33]

Another trial assessing continuous vs. intermittent sunitinib dosing was the EFFECT phase II study. In this trial patients with locally recurrent clear-cell RCC or metastatic RCC, treatment naïve patients, were randomly assigned to standard dosing (50mg/day; 4 weeks on, 2 weeks off) and continuous dosing (37.5mg/day). The intermittent schedule when compared with the continuous schedule showed a trend to improved ORR (32.2% vs. 28.1%; p=0.444) and median PFS (8.5 months vs. 7.0 months; p=0.070). No difference were noted between the median OS (23.1 months vs. 23.5 months, p=0.615). [38] Interestingly the median OS was lower than the phase III sunitinib vs. INF-α trial which had a median OS of 26 months. The phase III trial had a higher number of patients with better baseline prognostic features (better performance status and more patients had underwent nephrectomy), which may account for better survival results. [33, 38]

### *3.1.2. Sorafenib*

22% (n=23) of patients showed SD for ≥ 3 months. The median response for the 46 responders was 10 months whilst the median progression free survival (PFS) was 8.3 months [32]

These results led to a phase III trial comparing sunitinib with INF-α that was deemed standard of care at the time for patients with metastatic clear cell RCC. [33] Seven hundred and fifty treatment naїve patients with clear-cell histology and good performance status (ECOG 0 or 1) were randomized in a 1:1 ratio to receive either sunitinib (dose as per earlier studies) or INFα (9 × 10<sup>6</sup> units subcutaneously thrice weekly). [32, 34] The median duration of treatment was 6 months (1-15 months) in the sunitinib group and 4 months (1-13 months) in the IFN-α group. The median PFS assessed by an independent third-party review was 11 months in the sunitinib group and 5 months in the IFN-α group, corresponding to a hazard ratio (HR) of 0.42 (95% CI 0.32–0.54; p < 0.001). [33] The investigators' assessment showed similar results. An updated analysis published in 2009 has shown the ORR of 47% for sunitinib and 12% for IFN-α (p < 0.000001), with a median PFS of 11 months and 5 months, respectively, for sunitinib and IFNα (p < 0.000001), similar to the original report. [35] These results were uniformly seen, regard‐ less of the patients' age, gender and prognostic category. Patients on sunitinib also experienced a median OS in excess of 2 years. The OS was 26.4 months for sunitinib and 21.8 months for IFN-α (p = 0.051). [33] However, a dedicated exploratory analysis of patients on both treatment arms who did not receive post-study cancer treatment showed the median OS with sunitinib was twice as long as IFN-α (28.1 months versus 14.1 months respectively, p=0.003). [33] Based on these significant findings, sunitinib replaced IFN-α as first line treatment for stage IV RCC. In a real-world setting, sunitinib has proven its efficacy in an expanded-access program, designed to allocate access to sunitinib in patients with metastatic RCC who would otherwise be excluded from clinical trials. [33, 36] Four thousand five hundred patients were enrolled in this international, open labeled study. The cohort importantly included older patients (≥ 65 years old; n=1414), those with poorer ECOG status (≥ 2; n=582), non clear-cell histology (n=288) and with brain metastases (n=320). [36] Patients with poor performance status and brain

metastases prior to this had been excluded in all sunitinib trials.

*3.1.1.2. Sunitinib continuous dosing*

160 Renal Tumor

The median number of treatment cycles and treatment duration were 5 cycles and 15.6 months respectively. 56% of patients received more than 6 months of sunitinib treatment. The survival data closely resembled the phase III study with an observed median PFS and OS of 10.9 months and 18.4 months respectively. [33] No differences were noted in median PFS and OS between patients with or without prior cytokine therapy. Importantly, the subgroup analysis of i. elderly patients demonstrated median PFS and OS of 11.3 and 18.2 months respectively. [33] ii. patients with poorer performance status, the median PFS and OS were 5.1 months and 6.7 months respectively and finally in patients with brain metastases with an overall poorer prognosis, a median PFS of 5.6 months and median OS of 9.2 months were observed. [33]

The efficacy of continuous sunitinib dosing was examined in an open-label multicenter phase II trial. [37] In this study 107 patients were randomly assigned to either morning or evening daily dose of 37.5mg for a median duration of 8.3 months. 43% of patients had their dose reduced due to grade 3-4 adverse events. The ORR was 20% with a median duration of Sorafenib (Nexavar, BAY 43-9006) is an oral multi-kinase inhibitor that targets multiple nonreceptor as well as receptor kinases. These include BRAF and CRAF, non-receptor serine threonine kinases which belong to the RAF/Mek/ERK signaling pathway and also receptor tyrosine kinases including VEGFR2, VEGFR3, PDGFR, fetal liver tyrosine kinase 3 (FLT-3)… and c-kit. [2] In a phase II randomized discontinuation trial of patients with metastatic RCC who had failed previous systemic therapies, sorafenib at a dose of 400 mg BD showed significant disease-stabilizing activity. [39] In another phase II trial, patients with metastatic RCC on sorafenib (initial starting dose of 400mg BD and escalating to 600mg BD on progres‐ sion) were compared with INF-α in the first line setting. PFS was similar in both arms, although in the sorafenib arm, patients experienced greater rates of tumour size reduction, superior quality of life and better treatment tolerance. [40] Subsequently in a phase 3 trial (TARGET) 903 patients with metastatic clear-cell RCC who had progressed on previous treatment were randomized to receive either placebo or sorafenib (400mg BD). Compared with the placebo group, the sorafenib group demonstrated a higher ORR (57% vs. 34%) and PFS was signifi‐ cantly longer (5.5 months vs. 2.8 months; HR=0.44; p<0.01). [41] This improvement was independent of age (over or under 70 years), prognostic risk, prior cytokine therapy, and previous cardiovascular disease. [41] In this trial, patients in the placebo arm crossed over to sorafenib when progression of disease was diagnosed. In the first interim analysis, a trend towards better OS was noted in patients taking sorafenib, and this was unchanged in the final analysis (17.8 vs. 15.2 months, respectively, HR= 0.88; *p* = 0.146). [42] After censoring for the patients who had crossed over on progression from the placebo arm, the OS was significantly longer in the sorafenib arm (17.8 vs. 14.3 months; HR = 0.78; *p* = 0.029). [41] Sorafenib has also been accessed in a real-world setting through open-label expanded access studies in Europe (The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCS) and North America (NA-ARCCS). Both studies showed that sorafenib provides similar benefits in first- and second- or later line patient populations and the safety profile was similar to that reported in clinical trials. [43-45] Ongoing clinical trials comparing sorafenib with other treatment options in the first line setting are currently being undertaken. [46]

*3.1.4. Axitinib*

of axitinib.

with sorafenib. [56]

**3.2. Anti-VEGF**

*3.2.1. Bevacizumab*

53% in <5 year survivors. [54]

Axitinib, an oral agent that inhibits VEGF receptor-1, -2 and -3, is active in cytokine-refractory metastatic RCC. Two complete and 21 partial responses (ORR of 44.2%) were reported in 52 patients taking axitinib 5mg twice daily in a second line treatment study. The median response duration was 23 months and median OS was 29.9 months. [53] The 5 year survival rate was 20.6%. The ten patients surviving for more than five years had an ORR of 100% compared with 30% in <5 year survivors. They took axitinib for longer (median 5.8 years vs. 0.67 years) and were fitter, with baseline ECOG PS of 0 in 80% of the longer term survivors compared with

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In a phase II trial, 213 patients were allocated on axitinib 5mg BD for four weeks, after which some eligible patients were randomly assigned to further stepwise dose titration (5 to 7 to 10mg BD) according to tolerability of either axitinib or placebo. Individuals who did not meet the eligibility criteria were treated in a separate arm without dose titration. [55] The inclusion criteria for randomisation after the initial dose schedule of axitinib for 4 weeks were blood pressure ≤ 150/90 mmHg and less or equal to 2 concurrent anti-hypertensive medications. No grade 3 or 4 toxicities from the initial dose and no dose reductions required in the first 4 weeks

The most important outcomes of this study were a higher drug exposure, of more or equal 150 ng-h/ml serum concentration, and was associated with a higher RR (59% vs. 40%) and an improvement in PFS (14 vs. 11 months). Patients with a higher diastolic blood pressure (90mmHg) and an increase in diastolic blood pressure on day 15 of the first cycle had better outcomes in ORR and PFS. The final results of this phase II trial are pending and will determine

In a phase III second line treatment study (AXIS), 723 patients with progressive disease after one first line treatment (sunitinib, bevacizumab, temsirolimus or cytokines) randomly received axitinib at doses titrated from 5mg up to 10mg BD or sorafenib 400mg BD. [56] The ORR was 19.4% for axitinib vs. 9.4% for sorafenib (p=0.0001) and a significantly longer median PFS (6.7 versus 4.7 months, p<0.0001) was seen in patients on the axitinib arm. In patients who had previously received cytokines PFS with axitinib was 12.1 months vs. 6.5 months with sorafenib, which was significant (p<0.0001). This also occurred in those having prior sunitinib (4.8 vs. 3.4 months, p=0.0107). As part of the same trial, patient-reported kidney specific symptom and function assessments were secondary endpoints. [57] Outcomes were similar for both drugs during treatment, however due to the significantly longer PFS with axitinib, this delayed worsening of the composite endpoint of cancer symptoms, progression or death compared

Bevacizumab is a humanized monoclonal antibody that inhibits the VEGF molecule and therefore targeting all the receptor to which it binds. [58] ) A randomized, double-blind, phase

if the titratrion strategy is associated with improved clinical outcomes

The role of sorafenib as second line treatment for advanced RCC has also generated significant interest. Sorafenib was compared directly with temsirolimus in the INTORSECT trial. [47] This is the first head-to-head trial comparing a VEGF inhibitor to an mTOR inhibitor. This trial enrolled 551 patients with advanced RCC with good performance status who had progressed after first-line sunitinib therapy. The median PFS with temsirolimus was 4.28 months and 3.91 months with sorafenib. The median OS for temsirolimus cohort was 12.7 months compared to 16.6 months in the sorafenib arm. These results highlighted that temsirolimus did not show superiority over sorafenib in the primary end-point of PFS and the secondary end-point of OS. [47] To date, sorafenib is considered a reasonable first-line treatment option especially in elderly patients or patients with cardiovascular diseases or other co-morbidities. [46, 48]

### *3.1.3. Pazopanib*

Pazopanib is an oral tyrosine kinase inhibitor that targets VEGF-1, -2, and -3 receptors, PDGFα and -β receptors, and c-kit. [49] A phase II study enrolled 225 patients with metastatic RCC: (69% were treatment naïve, and 31% had received previous treatment with cytokine- or bevacizumab-containing regimen). In this study, the ORR was 35%, median duration of response was 68 weeks and median PFS was 52 weeks. This trial showed durable activity and tolerability of pazopanib in patients with advanced RCC. (Hutson *et al*, 2010) In a phase III study, 435 patients with locally advanced, and/or metastatic RCC were randomized to receive oral pazopanib or placebo (54% were treatment naïve and 46% were cytokine pretreated). The PFS was significantly prolonged with pazopanib compared with placebo (median PFS 9.2 vs. 4.2 months; HR=0.46; 95% CI, 0.34 to 0.62; p < 0.0001), with similar results shown in both the Treatment naïve subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P <.0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; p < 0.001). In the pazopanib arm, the ORR was 30% compared with 3% in the placebo arm (p < 0.001). The median duration of response was longer than 1 year. [50] The final median OS were 22.9 vs. 20.5 months in the pazopanib and placebo arms respectively (p=0.224). The lack of significant difference could be due to the early, frequent, and prolonged crossover to pazopanib in patients originally randomized to placebo. [50, 51] Whilst the role of pazopanib as a frontline agent for metastatic RCC is being established, it remains unclear how it compares with sunitinib in terms of efficacy. This was addressed in an open-label study (COMPARZ) where pazopanib was compared head-to-head with sunitinib in 1100 patients with locally advanced and/or metastatic RCC. Pazopanib demonstrated similar efficacy or non-inferiority to sunitinib in terms of PFS with duration of more than 10 months. Both agents resulted in side-effects, however fatigue and skin ulcers occurred less frequently for pazopanib than with sunitinib. The quality of life (QoL) favoured pazopanib and demonstrated better tolerance for pazopanib than sunitinib. [52]

### *3.1.4. Axitinib*

(NA-ARCCS). Both studies showed that sorafenib provides similar benefits in first- and second- or later line patient populations and the safety profile was similar to that reported in clinical trials. [43-45] Ongoing clinical trials comparing sorafenib with other treatment options

The role of sorafenib as second line treatment for advanced RCC has also generated significant interest. Sorafenib was compared directly with temsirolimus in the INTORSECT trial. [47] This is the first head-to-head trial comparing a VEGF inhibitor to an mTOR inhibitor. This trial enrolled 551 patients with advanced RCC with good performance status who had progressed after first-line sunitinib therapy. The median PFS with temsirolimus was 4.28 months and 3.91 months with sorafenib. The median OS for temsirolimus cohort was 12.7 months compared to 16.6 months in the sorafenib arm. These results highlighted that temsirolimus did not show superiority over sorafenib in the primary end-point of PFS and the secondary end-point of OS. [47] To date, sorafenib is considered a reasonable first-line treatment option especially in elderly patients or patients with cardiovascular diseases or other co-morbidities. [46, 48]

Pazopanib is an oral tyrosine kinase inhibitor that targets VEGF-1, -2, and -3 receptors, PDGFα and -β receptors, and c-kit. [49] A phase II study enrolled 225 patients with metastatic RCC: (69% were treatment naïve, and 31% had received previous treatment with cytokine- or bevacizumab-containing regimen). In this study, the ORR was 35%, median duration of response was 68 weeks and median PFS was 52 weeks. This trial showed durable activity and tolerability of pazopanib in patients with advanced RCC. (Hutson *et al*, 2010) In a phase III study, 435 patients with locally advanced, and/or metastatic RCC were randomized to receive oral pazopanib or placebo (54% were treatment naïve and 46% were cytokine pretreated). The PFS was significantly prolonged with pazopanib compared with placebo (median PFS 9.2 vs. 4.2 months; HR=0.46; 95% CI, 0.34 to 0.62; p < 0.0001), with similar results shown in both the Treatment naïve subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P <.0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; p < 0.001). In the pazopanib arm, the ORR was 30% compared with 3% in the placebo arm (p < 0.001). The median duration of response was longer than 1 year. [50] The final median OS were 22.9 vs. 20.5 months in the pazopanib and placebo arms respectively (p=0.224). The lack of significant difference could be due to the early, frequent, and prolonged crossover to pazopanib in patients originally randomized to placebo. [50, 51] Whilst the role of pazopanib as a frontline agent for metastatic RCC is being established, it remains unclear how it compares with sunitinib in terms of efficacy. This was addressed in an open-label study (COMPARZ) where pazopanib was compared head-to-head with sunitinib in 1100 patients with locally advanced and/or metastatic RCC. Pazopanib demonstrated similar efficacy or non-inferiority to sunitinib in terms of PFS with duration of more than 10 months. Both agents resulted in side-effects, however fatigue and skin ulcers occurred less frequently for pazopanib than with sunitinib. The quality of life (QoL) favoured pazopanib and demonstrated better

in the first line setting are currently being undertaken. [46]

*3.1.3. Pazopanib*

162 Renal Tumor

tolerance for pazopanib than sunitinib. [52]

Axitinib, an oral agent that inhibits VEGF receptor-1, -2 and -3, is active in cytokine-refractory metastatic RCC. Two complete and 21 partial responses (ORR of 44.2%) were reported in 52 patients taking axitinib 5mg twice daily in a second line treatment study. The median response duration was 23 months and median OS was 29.9 months. [53] The 5 year survival rate was 20.6%. The ten patients surviving for more than five years had an ORR of 100% compared with 30% in <5 year survivors. They took axitinib for longer (median 5.8 years vs. 0.67 years) and were fitter, with baseline ECOG PS of 0 in 80% of the longer term survivors compared with 53% in <5 year survivors. [54]

In a phase II trial, 213 patients were allocated on axitinib 5mg BD for four weeks, after which some eligible patients were randomly assigned to further stepwise dose titration (5 to 7 to 10mg BD) according to tolerability of either axitinib or placebo. Individuals who did not meet the eligibility criteria were treated in a separate arm without dose titration. [55] The inclusion criteria for randomisation after the initial dose schedule of axitinib for 4 weeks were blood pressure ≤ 150/90 mmHg and less or equal to 2 concurrent anti-hypertensive medications. No grade 3 or 4 toxicities from the initial dose and no dose reductions required in the first 4 weeks of axitinib.

The most important outcomes of this study were a higher drug exposure, of more or equal 150 ng-h/ml serum concentration, and was associated with a higher RR (59% vs. 40%) and an improvement in PFS (14 vs. 11 months). Patients with a higher diastolic blood pressure (90mmHg) and an increase in diastolic blood pressure on day 15 of the first cycle had better outcomes in ORR and PFS. The final results of this phase II trial are pending and will determine if the titratrion strategy is associated with improved clinical outcomes

In a phase III second line treatment study (AXIS), 723 patients with progressive disease after one first line treatment (sunitinib, bevacizumab, temsirolimus or cytokines) randomly received axitinib at doses titrated from 5mg up to 10mg BD or sorafenib 400mg BD. [56] The ORR was 19.4% for axitinib vs. 9.4% for sorafenib (p=0.0001) and a significantly longer median PFS (6.7 versus 4.7 months, p<0.0001) was seen in patients on the axitinib arm. In patients who had previously received cytokines PFS with axitinib was 12.1 months vs. 6.5 months with sorafenib, which was significant (p<0.0001). This also occurred in those having prior sunitinib (4.8 vs. 3.4 months, p=0.0107). As part of the same trial, patient-reported kidney specific symptom and function assessments were secondary endpoints. [57] Outcomes were similar for both drugs during treatment, however due to the significantly longer PFS with axitinib, this delayed worsening of the composite endpoint of cancer symptoms, progression or death compared with sorafenib. [56]

### **3.2. Anti-VEGF**

### *3.2.1. Bevacizumab*

Bevacizumab is a humanized monoclonal antibody that inhibits the VEGF molecule and therefore targeting all the receptor to which it binds. [58] ) A randomized, double-blind, phase II trial of 116 patients (placebo controlled, low-dose 3mg/kg or high dose 10mg/kg) showed that bevacizumab significantly prolonged the time to progression of disease in patients with metastatic RCC. [59, 60]

two mTOR inhibitors registered for the treatment of metastatic RCC, namely temsirolimus

New Systemic Treatment Approaches for Metastatic Renal Cell Carcinoma

Temsirolimus is an analogue to sirolimus (rapamycin) which has been used with success as an immunosuppressive agent in renal transplantation. [65] Temsirolimus is a parenteral preparation and is administered as a weekly intravenous infusion at 25mg. It is metabolised by CYP3A4 to active metabolite sirolimus and has a half-life of about 9 to 27 hours. [65]

Based on the encouraging results from Phase I and II trials of temsirolimus either alone, or in combination with IFN-α, an international multicentre phase III trial was conducted. [8, 66] Six hundred and twenty six treatment naïve patients with poor prognostic factors were rando‐

units s.c. thrice weekly) or the combination of temsirolimus (15 mg weekly) and IFN-α (6 × 10<sup>6</sup> thrice weekly). Patients were required to have least three the following 6 predictors short survival: a serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range, a hemoglobin level below the lower limit of the normal range; a corrected serum calcium level of more than 10 mg per deciliter (2.5 mmol per liter), a time from initial diagnosis of RCC to randomization of less than 1 year, a Karnofsky performance score of 60 or 70, or metastases in multiple organs. An important characteristic of recruitment of this study is the inclusion of up to 20% of non clear-cell renal cell histological subtype. This is the only rando‐ mised study available to date for patients with non clear-cell histology. Patients who received temsirolimus monotherapy had a longer median OS (10.9 vs. 7.3 months; p = 0.008) and PFS (3.8 vs. 1.9months; p<0.001) compared with those who received INF-α alone. [65] Finally those in the combination treatment arm had the most grade 3 or 4 adverse events leading to more dose reductions and delays. The median PFS in the temsirolimus, combination treatment and IFN-α alone were 3.8, 3.7 and 1.9 months, respectively, and the median OS was 10.9 months, 8.4 months and 7.3 months. [65] In this trial, older patients and patients with a higher serum

This trial did not address the role of temsirolimus as second-line agent in patients refractory to VGEF therapy. The only published prospective randomised trial looking at this cohort of patients was RECORD-1 which examined everolimus vs. placebo. [67] The data supporting the use of temsirolimus in second line treatment post VEGF agents are all derived from single

Everolimus is an oral mTOR inhibitor. It has activity against advanced clear-cell RCC in patients who have failed sorafenib, sunitinib or both. [67] In a double-blind, placebo controlled phase III trial (RECORD-1, in which 410 patients with advanced clear cell RCC who had progressed after sunitinib, sorafenib or both were randomized in a 2:1 ratio to everolimus 10 mg once daily or placebo with best supportive care. Independent of gender, age, previous treatment with sorafenib, sunitinib or both, prolongation of PFS (4.9 vs. 1.9 months; p< 0.0001)

units, with an increase to 18 × 10<sup>6</sup>

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165

mised to temsirolimus (25 mg i.v. weekly), IFN-α (3 × 10<sup>6</sup>

LDH (> 1.5 fold the upper limit of normal) had better OS. [65]

institution case series which demonstrated only a modest PFS of ~4 months.

and everolimus.

*3.3.1. Temsirolimus*

*3.3.2. Everolimus*

In a phase III trial (AVOREN), 649 patients with previously untreated metastatic RCC were randomized to receive bevacizumab (10 mg/kg infusion) and interferon alfa-2a versus placebo and interferon alfa-2a (IFN). A significant improvement in PFS, (10.2 vs. 5.4 months) and also ORR (31% vs. 13%, respectively; p < 0.0001) was observed in the bevacizumab arm compared with the IFN-α monotherapy arm. [61] Final OS analysis of this trial showed a trend towards improved OS (Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo). Patients (> 55%) in both arms received at least one post-protocol antineoplastic treatment, which could confound the OS analysis. [61]

Another concurrent phase III trial (CALGB 90206) but in a non-blinded fashion, randomized 732 patients previously untreated metastatic RCC to receive bevacizumab and IFN-α versus monotherapy with IFN-α. In this trial, the median PFS was 8.5 months in patients receiving bevacizumab plus IFN compared with 5.2 months for IFN monotherapy (p < 0.0001) and the ORR was similarly higher in the bevacizumab plus IFN arm than in the IFN monotherapy arm (25.5% vs. 13.1%, respectively; p< 0.0001). [62] Final analysis of this trial showed a median OS time of 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-alpha and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-alpha monotherapy (unstratified log-rank p = 0.097) Grade 3 and 4 toxicity (hypertension (HTN), anorexia, fatigue, and proteinuria) were significantly higher in the bevacizumab plus IFN-alpha arm. Patients who developed HTN on bevacizumab plus IFN-alpha had a significantly improved PFS and OS versus patients without HTN. [62]

Both of these trials showed clear benefits in the median PFS arms with an overlapping HR and doubling of PFS when comparing the placebo/IFN-α arm with bevacizumab/IFN-α arm. [63] The effects of crossover to the active bevacizumab arm in the AVOREN trial, as well as the permission of second-line therapies in both trials would account for the dilution of the actual OS benefit in both trials. [63] Based on the results of these trials, regulatory approval of bevacizumab plus IFN in advanced RCC has occurred in Europe in the United States.

### **3.3. mTOR inhibitors**

The mammalian target of rapamycin (mTOR) pathway is regulated by the PTEN tumour suppressor gene. It plays a significant role in angiogenesis and regulation of cell cycle. [8] mTOR activity is dependent on different factors, in particular to cellular stresses such as hypoxia, heat shock, oxidative stress, DNA damage and finally a change in the pH or osmotic cell pressure. [8] The mTOR pathway is downstream to phosphoinositide 3-kinase and akt pathway which is dysregulated in many malignancies. [8, 64] Activation of this pathway promotes mRNA translation and subsequent entry into the G1 phase of cell cycle. Another different but important function of mTOR is the production of HIF-1α which drives angiogenesis, survival and growth of malignant cells. The selective inhibition of this pathway by the mTOR inhibitors is facilitated by binding to the intracellular protein FK506 binding protein 12 (FKBP-12) resulting in inhibition of the kinase activity of the mTOR. [8] There are two mTOR inhibitors registered for the treatment of metastatic RCC, namely temsirolimus and everolimus.

### *3.3.1. Temsirolimus*

II trial of 116 patients (placebo controlled, low-dose 3mg/kg or high dose 10mg/kg) showed that bevacizumab significantly prolonged the time to progression of disease in patients with

In a phase III trial (AVOREN), 649 patients with previously untreated metastatic RCC were randomized to receive bevacizumab (10 mg/kg infusion) and interferon alfa-2a versus placebo and interferon alfa-2a (IFN). A significant improvement in PFS, (10.2 vs. 5.4 months) and also ORR (31% vs. 13%, respectively; p < 0.0001) was observed in the bevacizumab arm compared with the IFN-α monotherapy arm. [61] Final OS analysis of this trial showed a trend towards improved OS (Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo). Patients (> 55%) in both arms received at least one post-protocol anti-

Another concurrent phase III trial (CALGB 90206) but in a non-blinded fashion, randomized 732 patients previously untreated metastatic RCC to receive bevacizumab and IFN-α versus monotherapy with IFN-α. In this trial, the median PFS was 8.5 months in patients receiving bevacizumab plus IFN compared with 5.2 months for IFN monotherapy (p < 0.0001) and the ORR was similarly higher in the bevacizumab plus IFN arm than in the IFN monotherapy arm (25.5% vs. 13.1%, respectively; p< 0.0001). [62] Final analysis of this trial showed a median OS time of 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-alpha and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-alpha monotherapy (unstratified log-rank p = 0.097) Grade 3 and 4 toxicity (hypertension (HTN), anorexia, fatigue, and proteinuria) were significantly higher in the bevacizumab plus IFN-alpha arm. Patients who developed HTN on bevacizumab plus IFN-alpha had a significantly improved PFS and OS versus patients without

Both of these trials showed clear benefits in the median PFS arms with an overlapping HR and doubling of PFS when comparing the placebo/IFN-α arm with bevacizumab/IFN-α arm. [63] The effects of crossover to the active bevacizumab arm in the AVOREN trial, as well as the permission of second-line therapies in both trials would account for the dilution of the actual OS benefit in both trials. [63] Based on the results of these trials, regulatory approval of

The mammalian target of rapamycin (mTOR) pathway is regulated by the PTEN tumour suppressor gene. It plays a significant role in angiogenesis and regulation of cell cycle. [8] mTOR activity is dependent on different factors, in particular to cellular stresses such as hypoxia, heat shock, oxidative stress, DNA damage and finally a change in the pH or osmotic cell pressure. [8] The mTOR pathway is downstream to phosphoinositide 3-kinase and akt pathway which is dysregulated in many malignancies. [8, 64] Activation of this pathway promotes mRNA translation and subsequent entry into the G1 phase of cell cycle. Another different but important function of mTOR is the production of HIF-1α which drives angiogenesis, survival and growth of malignant cells. The selective inhibition of this pathway by the mTOR inhibitors is facilitated by binding to the intracellular protein FK506 binding protein 12 (FKBP-12) resulting in inhibition of the kinase activity of the mTOR. [8] There are

bevacizumab plus IFN in advanced RCC has occurred in Europe in the United States.

neoplastic treatment, which could confound the OS analysis. [61]

metastatic RCC. [59, 60]

164 Renal Tumor

HTN. [62]

**3.3. mTOR inhibitors**

Temsirolimus is an analogue to sirolimus (rapamycin) which has been used with success as an immunosuppressive agent in renal transplantation. [65] Temsirolimus is a parenteral preparation and is administered as a weekly intravenous infusion at 25mg. It is metabolised by CYP3A4 to active metabolite sirolimus and has a half-life of about 9 to 27 hours. [65]

Based on the encouraging results from Phase I and II trials of temsirolimus either alone, or in combination with IFN-α, an international multicentre phase III trial was conducted. [8, 66] Six hundred and twenty six treatment naïve patients with poor prognostic factors were rando‐ mised to temsirolimus (25 mg i.v. weekly), IFN-α (3 × 10<sup>6</sup> units, with an increase to 18 × 10<sup>6</sup> units s.c. thrice weekly) or the combination of temsirolimus (15 mg weekly) and IFN-α (6 × 10<sup>6</sup> thrice weekly). Patients were required to have least three the following 6 predictors short survival: a serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range, a hemoglobin level below the lower limit of the normal range; a corrected serum calcium level of more than 10 mg per deciliter (2.5 mmol per liter), a time from initial diagnosis of RCC to randomization of less than 1 year, a Karnofsky performance score of 60 or 70, or metastases in multiple organs. An important characteristic of recruitment of this study is the inclusion of up to 20% of non clear-cell renal cell histological subtype. This is the only rando‐ mised study available to date for patients with non clear-cell histology. Patients who received temsirolimus monotherapy had a longer median OS (10.9 vs. 7.3 months; p = 0.008) and PFS (3.8 vs. 1.9months; p<0.001) compared with those who received INF-α alone. [65] Finally those in the combination treatment arm had the most grade 3 or 4 adverse events leading to more dose reductions and delays. The median PFS in the temsirolimus, combination treatment and IFN-α alone were 3.8, 3.7 and 1.9 months, respectively, and the median OS was 10.9 months, 8.4 months and 7.3 months. [65] In this trial, older patients and patients with a higher serum LDH (> 1.5 fold the upper limit of normal) had better OS. [65]

This trial did not address the role of temsirolimus as second-line agent in patients refractory to VGEF therapy. The only published prospective randomised trial looking at this cohort of patients was RECORD-1 which examined everolimus vs. placebo. [67] The data supporting the use of temsirolimus in second line treatment post VEGF agents are all derived from single institution case series which demonstrated only a modest PFS of ~4 months.

### *3.3.2. Everolimus*

Everolimus is an oral mTOR inhibitor. It has activity against advanced clear-cell RCC in patients who have failed sorafenib, sunitinib or both. [67] In a double-blind, placebo controlled phase III trial (RECORD-1, in which 410 patients with advanced clear cell RCC who had progressed after sunitinib, sorafenib or both were randomized in a 2:1 ratio to everolimus 10 mg once daily or placebo with best supportive care. Independent of gender, age, previous treatment with sorafenib, sunitinib or both, prolongation of PFS (4.9 vs. 1.9 months; p< 0.0001) was found with everolimus over placebo. [67] However there was no statistically significant difference for median OS (14.8 months vs. 14.4 months) as majority (80%) of patients in the placebo plus best supportive arm were allowed to cross over after the unbinding at the second interim analysis. RECORD-1 trial proved the efficacy of mTOR inhibitors following VGEF therapy and as such received FDA approval for patients who have progressed following sunitinib / sorafenib. [67]

a higher incidence of grade 3 or 4 hypertension (26 vs. 17%), higher rates of dysphonia (21 vs. 5 %) and back pain (14 vs. 7%). However, tivozanib had less diarrhea (24 vs. 38%), hand and

New Systemic Treatment Approaches for Metastatic Renal Cell Carcinoma

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The highest tolerated dose of dovitinib is 500 mg daily on a 5-day on/ 2 day off schedule in 28 day cycles. A phase II study of dovitinib in clear-cell metastatic RCC and in patients previously treated with a VEGFR inhibitor and/or mTOR inhibitor was reported in 2011. [73] In 51 patients overall responses were PR in 8%, and SD ≥ 4 months in 37%. Median PFS and OS were 6.1 and 16 months respectively. The most common adverse events were nausea (73%; grade 3:9%), diarrhea (64%; grade 3:9%), vomiting (56%; grade 3: 5%), decreased appetite (48%; grade 3:7%), asthenia (36%; grade 3:12%), and fatigue (36%; grade 3: 10%). An on-going phase 3 trials is comparing dovitinib with sorafenib in patients who have had one previous VEGF- and mTOR-

A phase II of regorafenib in previously untreated metastatic or unresectable RCC patients has recently been published. [69]. Forty-eight of 49 patients enrolled were available for assessment of tumour response. Nineteen of these had an objective response (partial); (39.6%, 90% CI 27.7-52.5). Side-effects were noted in 98% of patients, and 35% experienced serious drugrelated events. Two patients had grade 4 adverse events related to treatment including two cardiac ischaemia or infraction, one hypomagnesaemia, and one chest/thoracic pain. The

With the increasing use of VEGF and mTOR inhibitors, it has been noted that patients eventually develop resistance / relapse after 6 months to 3 years of therapy. [25] This has been the driving force for the development of more novel anti-angiogenic agents or treat‐ ment strategies such as combination of the various targeted agents (combination of antiangiogenic agents or with mTOR inhibitors, chemotherapy or immunotherapy). [74] Combination therapies may lead to a more complete blockade of aberrant signaling and potentially delay / prevent the development of resistance observed with single-agent treatment. [74] Unfortunately, this invariably leads to increased toxicities as experienced in

**5.1. VEGF-ligands or receptor inhibitors / mTOR plus immunotherapy combination**

Two single arm phase II studies using sorafenib in combination with standard dose IFN-α showed higher ORR (approximately 30%) and longer PFS (7 – 12 months) when compared with phase III data of sorafenib monotherapy. [76, 77] However, in a randomized phase II trial

foot syndrome (15 vs. 71%) and alopecia (2 vs. 21%). [72]

**4.2. Dovitinib**

targeted therapy.

**4.3. Regorafenib**

authors advise close monitoring. [69]

some of the phase I trials. [75]

**5. Combination therapy in metastatic RCC**
