**6. Sequencing therapy in metastatic RCC**

of sorafenib vs. sorafenib and low-dose IFN-α in patients with advanced RCC, no statistically significant difference in ORR and PFS was noted in the two arms. [78] These results should be

Both AVOREN (n = 649) [79] and CALGB 90206 (n = 732) [80] compared bevacizumab / IFNα combination with IFN-α demonstrated that the PFS interval was significantly longer with bevacizumab plus IFN-α than with the IFN-α alone (AVOREN: 10.2 months versus 5.4 months, respectively; p = 0.0001; CALGB 90206: 8.5 months versus 5.2 months, respectively; p < 0.0001). The ORRs were 31% with bevacizumab plus IFN-α and 13% with placebo plus IFN-α (p = 0.0001) in the AVOREN study. In the CALGB 90206 trial, the ORRs were 25.5% with bevaci‐ zumab plus IFN-α and 13.1% with IFN-α (p < 0.0001). [74, 79, 80] The design of these trials however did not have a bevacizumab monotherapy arm and therefore the clinical efficacy of bevacizumab monotherapy remained unanswered. In an open-label phase 2 study (TORAVA), 171 patients with metastatic RCC were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly) or sunitinib (50 mg/day for 4 weeks followed by 2 weeks off) or the combination of IFN-α (9 x 106 IU three times per week) and bevacizumab (10 mg/kg every 2 weeks). PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C. Median PFS was 8.2 months (95% CI 7.0-9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C. The toxicity of the experimental regimen was high with over 50% of patients not able to tolerate the combination of bevacizumab and temsirolimus over several months. This combination failed to show any beneficial activity and was more toxic than the treatments used in the other arms, and therefore

The combination of temsirolimus and IFN-α was studied in a phase III trial. Six hundred and twenty six patients were randomized to receive of IFN-α alone, temsirolimus alone, or a combination of the two drugs. Median OS times in the IFN-α arm, the temsirolimus arm, and the combination-therapy arm were 7.3, 10.9, and 8.4 months, respectively. Unlike temsirolimus alone, the combination of temsirolimus plus IFN-α did not improve OS. Therefore the temsirolimus / IFN-α combination is not recommended as standard practice for treatment of

Lastly, in a global, open-labelled multi-centre phase IIIb trial (INTORACT), temsirolimus and bevacizumab was compared with interferon and bevacizumab as first-line treatment in 791 patients with predominantly clear-cell metastatic RCC. [82] At the interim analysis, 489 patients were assessed PFS events. Median PFS with temsirolimus / bevacizumab combination was 9.1 month compared to 9.3 months in the interferon / bevacizumab group. The median OS was 25.8 months in the temsirolimus and 25.5 months for the interferon group. [82]

Bevacizumab in combination with sorafenib and sunitinib has been evaluated in two phase I trials. In these trials although there were some promising results regarding the median time to progression and partial response rates in the combination arms, the adverse effects observed in the latter were prominent. [83, 84] The combination arm in both trials required dose

interpreted cautiously given the small number of patients in these studies. [78]

was not recommended as first line treatment in these patients. [81]

**5.2. VEGF-ligands or receptor inhibitors / mTOR combination**

advanced RCC. [65]

168 Renal Tumor

Sequential use of targeted agents has several potential benefits. Firstly, this approach could lead to a treatment continuum, secondly, it provides patients the opportunity to receive full doses of the targeted agents without affecting tolerability and finally, sequential targeting of different molecular pathways could potentially overcome any resistance that would arise from single target inhibition. [86]

### **6.1. Anti-angiogenic therapy after immunotherapy**

Few phase II trials using anti-angiogenic agents after progression on immunotherapy lead to promising results. [32, 59, 87] In a phase III trial (TARGET) patient who had progressed on cytokine therapy after receiving sorafenib, there was a notable doubling of PFS from 2.8 to 5.6 months. [41] Likewise, the utilization of axitinib post progression on cytokine in a phase II trial, lead to a TTP of 15.7 months. [77] There are no head-to-head data present to guide which agent is best utilized post cytokine therapy and a properly conducted phase III trial are required to share further insight into this treatment strategy.

### **6.2. mTOR blockade after anti-angiogenic therapy**

In this strategy, the RECORD-1 trial investigated the efficacy of everolimus vs. placebo with best supportive care post progression on sunitinib, sorafenib or both. Seventy one per cent of patients included in the trial had received prior sunitinib treatment and 55% sorafenib therapy. Patient on everolimus achieved addition of 3-month in terms of PFS regardless of prior treatment. No overall survival benefit was observed due to large numbers of cross over from placebo to everolimus arm (80%). [67]

RECORD-3, a phase III clinical trial recently closed to patient recruitment, randomly assigned patients to either everolimus or sunitinib. Upon first sign of progression, patients would cross over to sunitinib if they were on everolimus and to everolimus if previously on sunitinib. The primary end point of this trial was to evaluate whether PFS post first-line treatment for patients who received everolimus will be non-inferior to patients who receive sunitinib. [52]

### **6.3. Serial anti-angiogenic agents**

With the availability of multiple SMTKIs, an important focus ahead is in the identification of how to best utilize the TKIs in sequence. There is now increasing evidence supporting the sequential use of VEGF-targeted therapies.

non-stringent reporting of disease progression and the reliance of local practice may well

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The Advanced Renal Cell Carcinoma Sorafenib (ARCS) expanded access trial recruited patient with advanced RCC who were not eligible for other clinical trials. One hundred and fifty eight patients with papillary RCC were enrolled. Partial response of 3.4% and 5.6% were noted for patients with papillary and chromophobe RCC respectively. Eighty-seven patients (77.1% of the papillary RCC and 88.8% of the chromophobe RCC) demonstrated disease stability for a duration of more than 8 weeks. Despite only modest activity being noted, this trial has at least shared insight into the activity of sorafenib into the two most common non clear-cell variant. [44] Another trial that demonstrated TKI activity across the different histological subtypes were reported in a retrospective analysis of patients with metastatic papillary and chromo‐ phobe RCC who received either sunitinib and sorafenib as their initial frontline therapy. The reported ORR, PFS and OS were 10%, 8.9 months and 12.2 months respectively. A sub-analysis revealed a longer higher response rate for chromophobe variant (25%) compared to papillary variant (4.8%); (p=0.007). Similarly the PFS in the chromophobe population was longer (9.3 months) when compared with papillary population 6.6 months (p=0.07). There were no differences between the OS across both histologies. When stratified according to TKI type, the papillary population had a statistically longer PFS (11.9 months) with sunitinib compared to

Temsirolimus has demonstrated promising activity in both clear-cell and non-clear-cell RCC. The phase III trial undertaken by Hudes and colleagues, examined the efficacy of temsirolimus, IFN-α or combination of both in patients with poor MSKCC prognostic features. [65] Although majority of patients had clear-cell histology, approximately 20% of non-clear-cell variant were included in the clinical trial. An improvement in median OS and median PFS were seen in temsirolimus arm, across all histologies with a significant advantage in hazard ratio for OS in the temsirolimus. An updated sub-analysis of the study showed a hazard ratio of 0.55 and 0.36 for median OS and PFS respectively, clearly favouring temsirolimus over IFN-α monotherapy and IFN-α / temsirolimus combination arms. [94] The analysis also showed that 75% of the non clear-cell variant consisted of papillary subtype. This has led to subsequent FDA approval

Everolimus through RECORD-1 trial has reported efficacy in patient who progressed on one or two line of TKI. This has led to the development of an open-label, single arm, multi-centre phase II examining the efficacy of everolimus as first-line systemic therapy for patients with advanced papillary RCC. [8] This trial will stratify the histology into type I and II, and recruitment will hopefully show further insight into the treatment of papillary variant of RCC.

Epidermal growth factor receptor (EGFR) has been investigated as potential therapeutic target in metastatic RCC. Erlotinib, an anti-EGFR was examined in a phase II study of treatment naïve patients with locally advanced or metastatic papillary RCC. [95] Fifty two patients were registered and 45 were evaluable. The ORR was reported as 11% and the disease control rate was 64% with 5 partial responders and 24 patients with stable disease. The six month PFS was

of temsirolimus as treatment for non-clear-cell histology in advanced RCC.

30% and median survival of 27 months was documented. [95]

account for the discrepancy in the results.

sorafenib (5.1 months; p<0.001). [3]

In both phase II and III trials, axitinib has shown encouraging results in second-line setting in advanced RCC. [88] In an ongoing study, the Sequential Two-agent Assessment in Renal Cell Carcinoma Therapy (START), two hundred and forty treatment-naïve patients with clear-cell component metastatic RCC will be randomized into 6 arms to receive different 2-drug "sequences" of everolimus, bevacizumab, or pazopanib. The primary end point is the detection of the longest combination of the TTP. [89]

A retrospective study on RCC patients treated with sunitinib and sorafenib evaluated the effectiveness of switching from one TKI agent to the other after disease progression. In this study patients who received sunitinib followed by sorafenib experienced a shorter time to progression than patients who received sorafenib followed by sunitinib (risk ratio (RR) 3.0; p = 0.016). Similarly, the median OS was 102 weeks in patients who received sorafenib followed by sunitinib compared with 45 weeks in patients who received sunitinib followed by sorafenib (p = 0.061).[90]

An ongoing phase III trial (SWITCH trial) is currently being undertaken comparing sorafenib until progression followed by sunitinib and sunitinib until progression followed by sorafenib in the first line advanced RCC setting. The primary end point is the PFS and hopefully this trial will show further insight into which anti-VEGF treatment sequence will confer better clinical outcome in patients with metastatic RCC. [91]

### **7. Systemic treatment for non-clear cell renal cell carcinoma**

With clear-cell RCC being the predominant histological subtypes and non clear-cell (papillary and chromophobe) being represented only in ~10% of clinical trials, there is consequently a paucity of data regarding treatment for advance non-clear-cell RCC. [92] Novel target therapies have demonstrated promising results in clear-cell histologies, however their activities re‐ mained undefined in the non-clear-cell counterpart. Majority of the data is derived from expanded access trials, retrospective series, and subset analyses of major trials. [93] Patients with non clear-cell RCC were both excluded from the landmark phase III trials of sunitinib and sorafenib. The largest non clear-cell series were derived from the sunitinib and sorafenib expanded access trials, which allowed entry of non-clear-cell histologies. Gore and colleagues demonstrated sunitinib activity in the multi-centre, international, non-randomised expanded access compassionate trial. Of the 4500 patients enrolled, approximately 10% (n=437) had non clear-cell histology (not further characterized) were evaluated. An ORR of 11% was demon‐ strated (N=48) with 46 partial responders and 2 complete responders. Fifty sever percent had stable disease (N=250) for a t least 3 months. [36] The median OS was reported as 13.4 months. The ORR was notable lower, 11% compared to the reported 42 to 47% in the phase III trial. The non-stringent reporting of disease progression and the reliance of local practice may well account for the discrepancy in the results.

**6.3. Serial anti-angiogenic agents**

170 Renal Tumor

sequential use of VEGF-targeted therapies.

of the longest combination of the TTP. [89]

clinical outcome in patients with metastatic RCC. [91]

**7. Systemic treatment for non-clear cell renal cell carcinoma**

(p = 0.061).[90]

With the availability of multiple SMTKIs, an important focus ahead is in the identification of how to best utilize the TKIs in sequence. There is now increasing evidence supporting the

In both phase II and III trials, axitinib has shown encouraging results in second-line setting in advanced RCC. [88] In an ongoing study, the Sequential Two-agent Assessment in Renal Cell Carcinoma Therapy (START), two hundred and forty treatment-naïve patients with clear-cell component metastatic RCC will be randomized into 6 arms to receive different 2-drug "sequences" of everolimus, bevacizumab, or pazopanib. The primary end point is the detection

A retrospective study on RCC patients treated with sunitinib and sorafenib evaluated the effectiveness of switching from one TKI agent to the other after disease progression. In this study patients who received sunitinib followed by sorafenib experienced a shorter time to progression than patients who received sorafenib followed by sunitinib (risk ratio (RR) 3.0; p = 0.016). Similarly, the median OS was 102 weeks in patients who received sorafenib followed by sunitinib compared with 45 weeks in patients who received sunitinib followed by sorafenib

An ongoing phase III trial (SWITCH trial) is currently being undertaken comparing sorafenib until progression followed by sunitinib and sunitinib until progression followed by sorafenib in the first line advanced RCC setting. The primary end point is the PFS and hopefully this trial will show further insight into which anti-VEGF treatment sequence will confer better

With clear-cell RCC being the predominant histological subtypes and non clear-cell (papillary and chromophobe) being represented only in ~10% of clinical trials, there is consequently a paucity of data regarding treatment for advance non-clear-cell RCC. [92] Novel target therapies have demonstrated promising results in clear-cell histologies, however their activities re‐ mained undefined in the non-clear-cell counterpart. Majority of the data is derived from expanded access trials, retrospective series, and subset analyses of major trials. [93] Patients with non clear-cell RCC were both excluded from the landmark phase III trials of sunitinib and sorafenib. The largest non clear-cell series were derived from the sunitinib and sorafenib expanded access trials, which allowed entry of non-clear-cell histologies. Gore and colleagues demonstrated sunitinib activity in the multi-centre, international, non-randomised expanded access compassionate trial. Of the 4500 patients enrolled, approximately 10% (n=437) had non clear-cell histology (not further characterized) were evaluated. An ORR of 11% was demon‐ strated (N=48) with 46 partial responders and 2 complete responders. Fifty sever percent had stable disease (N=250) for a t least 3 months. [36] The median OS was reported as 13.4 months. The ORR was notable lower, 11% compared to the reported 42 to 47% in the phase III trial. The

The Advanced Renal Cell Carcinoma Sorafenib (ARCS) expanded access trial recruited patient with advanced RCC who were not eligible for other clinical trials. One hundred and fifty eight patients with papillary RCC were enrolled. Partial response of 3.4% and 5.6% were noted for patients with papillary and chromophobe RCC respectively. Eighty-seven patients (77.1% of the papillary RCC and 88.8% of the chromophobe RCC) demonstrated disease stability for a duration of more than 8 weeks. Despite only modest activity being noted, this trial has at least shared insight into the activity of sorafenib into the two most common non clear-cell variant. [44] Another trial that demonstrated TKI activity across the different histological subtypes were reported in a retrospective analysis of patients with metastatic papillary and chromo‐ phobe RCC who received either sunitinib and sorafenib as their initial frontline therapy. The reported ORR, PFS and OS were 10%, 8.9 months and 12.2 months respectively. A sub-analysis revealed a longer higher response rate for chromophobe variant (25%) compared to papillary variant (4.8%); (p=0.007). Similarly the PFS in the chromophobe population was longer (9.3 months) when compared with papillary population 6.6 months (p=0.07). There were no differences between the OS across both histologies. When stratified according to TKI type, the papillary population had a statistically longer PFS (11.9 months) with sunitinib compared to sorafenib (5.1 months; p<0.001). [3]

Temsirolimus has demonstrated promising activity in both clear-cell and non-clear-cell RCC. The phase III trial undertaken by Hudes and colleagues, examined the efficacy of temsirolimus, IFN-α or combination of both in patients with poor MSKCC prognostic features. [65] Although majority of patients had clear-cell histology, approximately 20% of non-clear-cell variant were included in the clinical trial. An improvement in median OS and median PFS were seen in temsirolimus arm, across all histologies with a significant advantage in hazard ratio for OS in the temsirolimus. An updated sub-analysis of the study showed a hazard ratio of 0.55 and 0.36 for median OS and PFS respectively, clearly favouring temsirolimus over IFN-α monotherapy and IFN-α / temsirolimus combination arms. [94] The analysis also showed that 75% of the non clear-cell variant consisted of papillary subtype. This has led to subsequent FDA approval of temsirolimus as treatment for non-clear-cell histology in advanced RCC.

Everolimus through RECORD-1 trial has reported efficacy in patient who progressed on one or two line of TKI. This has led to the development of an open-label, single arm, multi-centre phase II examining the efficacy of everolimus as first-line systemic therapy for patients with advanced papillary RCC. [8] This trial will stratify the histology into type I and II, and recruitment will hopefully show further insight into the treatment of papillary variant of RCC.

Epidermal growth factor receptor (EGFR) has been investigated as potential therapeutic target in metastatic RCC. Erlotinib, an anti-EGFR was examined in a phase II study of treatment naïve patients with locally advanced or metastatic papillary RCC. [95] Fifty two patients were registered and 45 were evaluable. The ORR was reported as 11% and the disease control rate was 64% with 5 partial responders and 24 patients with stable disease. The six month PFS was 30% and median survival of 27 months was documented. [95]

Collecting duct tumour is a very aggressive but rare variant of aggressive but rare variant of RCC. The largest data is derived from a phase II multi-centre trial of 23 treatment naïve patients who received platinum based chemotherapy with gemcitabine. The choice of chemotherapy is that of a platinum doublet based on some similarities to transitional cell carcinoma of the bladder. The ORR was 26% with a median PFS and OS of 7.1 months and 10.5 months respectively.[18] There is no data to support the use of TKI in this variant of tumour.

included pooled efficacy and safety data (n=544, n=4917) from four trials of patients with metastatic RCC treated with sunitinib 50mg/d (4 week on / 2 week off), it was observed that patients who had a systolic BP ≥to 140mmHg and a diastolic blood pressure of ≥ 90mmHg had better outcomes compared to those without treatment induced hypertension The ORR were 54.8% in the treatment induced hypertension cohort vs. 8.7% in the normotensive patients. The median PFS was 12.5 vs. 2.5 months in the hypertensive and normotensive respectively and similarly the median OS was 30.9 months in the hypertensive group vs. 7.2 months in the normotensive group. [105] The rates of AEs were similar between patients with and without hypertension. However patients with high BP experienced more frequent renal adverse events (5% vs. 3%). [105] More importantly, no difference in outcome (PFS and ORR) was noted

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Treatment induced arterial hypertension is also correlated with good clinical outcomes in patients treated with bevacizumab for metastatic colorectal cancer [106] but this has not been

Fatigue is a very frequent side-effect seen with the targeted agents used in metastatic RCC [74, 96, 107] The incidence of fatigue in phase III studies ranged from 14% to 51% for all grades and

There is no direct treatment available to alleviate treatment induced fatigue. Monitoring and treating patients for any aggravating or reversible factors (i.e. anaemia, anxiety, hypothyroid‐ ism, depression may help. If grade 3–4 fatigue persists, dose reduction or cessation of the

Fatigue is another potential biomarker in patients with metastatic RCC treated with sunitinib. A retrospective analysis of pooled data from 770 patients who received sunitinib in 5 clinical trials for metastatic RCC revealed that the development of grade 1-2 fatigue was linked with

In a retrospective registry of metastatic RCC, 705 and 365 patients treated with sunitinib and sorafenib respectively were assessed for outcomes of the disease in those who developed hand and foot syndrome. In the sunitinib group, the median OS was 43 months for those with the hand and foot syndrome vs. 31 months (p=0.027) in those without. The PFS in patients with the dermatological toxicity was 20.8 months vs. 11.1 months (p=0.007) in those without. In the sorafenib group, no differences was noted in median OS for those that did and did not experience hand foot syndrome (27.9 vs. 24.6 months (p=0.244). The PFS was 12.2 vs. 8.8 months (p=0.050) with a difference of 3.4 months in those that experienced hand foot syndrome. In multivariable cox regression analysis, hand and foot syndrome was associated with longer OS

in the sunitinib group. In sorafenib, the survival benefits were less convincing. [110]

significantly longer time to progression and improved overall survival. [109]

regardless of whether patients received treatment for their hypertension. [105]

investigated widely in metastatic RCC.

treatment should be considered. [96, 108]

**8.3. Hand and foot syndrome as biomarker**

**8.2. Fatigue**

up to 11% for grade 3–4.

*8.2.1. Fatigue as a biomarker*
