**5. Overcoming the resistance**

Sphingosine kinase (S1P) is also supposed to play a role in the resistance. S1P is an enzyme that catalyzes the formation of sphingosine-1-phosphate which is associated with cell prolif‐ eration, survival and angiogenesis. Plasma levels of S1P decrease after the start of sunitinib treatment and increase again upon the development of resistance. In pre-clinical models administering neutralizing antibodies against S1P to mice, delayed the growth of sunitinib-

Down-regulation of angiostatic factors is another mechanism of resistance to TKI-s. Treatment with sunitinib and sorafenib results in the increased expression of several IFN-inducible genes including the angiostatic chemokines CXCL 10 and CXCL 11 and tumor suppressor genes. Following the development of resistance, the expression of IFN-γ and several of IFN-inducible genes is reduced. Down regulation of these factors is associated with the development of

Recruitment of bone marrow-derived cells which can result in the development of new blood vessels is another possible mechanism of resistance. In pre-clinical studies recruitment of CD11b + GR1 + myeloid cells cells resulted in resistance development. There is also evidence that tumor vasculature can be protected from anti-angiogenic therapy by increased pericyte

Invasion of tumor in normal tissue and recruitment of normal tissue vasculature protect the tumors from anti-angiogenic therapy. It has been reported that the tumor of a patient experi‐ encing disease progression during antiangiogenic therapy had invaded the surrounding tissue and there had been increase of the vascularization from the normal tissue to the center of the

Resistance to mTOR inhibitors is far less explained. It is supposed to be the result of activation of feedback loops that promote the activation of molecular signaling pathways of survival, increased activity of mTOR-complex 2, up-regulation of insulin-like growth factor and increase

Preclinical studies revealed that resistance to VEGF targeted therapies can be reversible. Hammers and colleagues grafted skin metastases of mRCC patient who had become resistant to sunitinib into mice and these xenogafts regained sensitivity and responded to sunitinib. Histology of original skin metastasis and xenograft revealed that a reversible epithelial-tomesenchymal transition could be responsible for acquired resistance to sunitinib. Zhang

resistant tumors [23].

196 Renal Tumor

coverage [23].

tumor [23].

*4.2.2. Down-regulation of angiostatic factors*

resistance to sunitinib and sorafenib [23].

*4.2.3. Recruitment of bone marrow-derived cells*

*4.2.4. Development of invasion without angiogenesis*

in the ERK/MAPK pathway signaling [4,24,25].

*4.2.5. Resistance to m-TOR inhibitors*

*4.2.6. Reversible resistance*

Overcoming the resistance to first line therapy is one of the aims of administering the second line and beyond. Several factors play important role in selection of second line strategy: clinical evidence, toxicity issues and individual patient profile [4,25,26].

Sequential use of targeted agents is currently the standard of care for mRCC patients. This approach enables patients to get most benefit from these agents avoiding the excessive toxicity associated with combination therapy [26-28]. Targeted agent in the second line can have the same or different mechanism of action as first-line one. Limited data suggest that the use of a TKI after the failure of another TKI is reasonable and that there is not complete cross-resistance of these agents. The hypothesis behind this is that although TKIs share the same mechanism of action, their molecular targets are different. Despite this, the evidence of this approach is not strong; prospective, phase III trials are missing. Changing mechanism of action can have several advantages: greater chance of overcoming resistance while decreasing the probability of cumulative toxicity [4,25]. Toxicities of TKI-s and mTOR inhibitors for example, differ considerably. Frequent grade 3 toxicities encountered in patients on TKI-s are hand-foot syndrome, diarrhoea, fatigue, hypertension, neutropenia and leukopenia, while grade 3 toxicities in patients treated with mTOR inhibitors are rash, stomatitis, pneumonitis, anemia and infection [25-30].

### **5.1. TKI-s following cytokine therapy**

The almost historical treatment strategy where changing of mechanism of action proved to be effective was TKI-s following cytokines. Currently this approach is not of clinical use anymore, because most of the patients get molecular targeted agent in the first line; however it is likely that some patients will have been treated with a cytokine previously. Phase III trials demon‐ strated that this approach is effective and safe and become a basis of approval of sunitinib and pazopanib in the first line treatment [3].

sorafenib (p=0,001). Shorter median PFS in both arms receiving first line sunitinib compared to those receiving cytokines (median PFS 12.1 in axitinib and 6.5 moths in sunitinib) suggest

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Reduced clinical efficacy of second line therapy as a result of cross resistance is key concern associated with the sequential administration of agents targeting the same molecular path‐ ways. Two prospective trials showed that because of the cross-resistance, sorafenib had limited

Another concern about using sequential VEGF-TKI therapies is toxicity. Although they may differ in toxicity profiles, all TKI-s share similar targets and exhibit class effect toxicities like hypertension, hand foot syndrome and rash [9]. Current data suggest that Switching to agents with different mechanisms of action in the second line therapy may provide superior efficacy

Very limited data are available on the use of TKI-s after progression on bevacisumab and no clinical trial is currently ongoing to address this issue. Only two minor prospective trials conducted by Garcia and Rini evaluated the use of sunitinib or sorafenib in patients with

In a phase II trial of Garcia, 48 patients were enrolled. After progression on treatment with sunitinib or bevacisumab, patients received twice daily 400 mg of sorafenib. One unconfirmed objective partial response was observed and the tumor burden reduction rate was 30%. The median PFS was 4.4 months. There was no association of PFS and tumor shrinkage with response to prior therapy. Most treatment-related adverse events were of mild-to-moderate intensity, and included fatigue, hypertension, diarrhoea, and hand-foot syndrome [33].

Rini et.al. conducted a phase II multicentric trial in which patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6 week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment). Sixty-one patients were enrolled. The ORR was 23.0%, median PFS was 30.4 weeks and median OS was 47.1 weeks. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome. Results from measuring different VEGF-s in the plasma suggest that sunitinib could inhibit some of the signaling factors

Another approach in patients who progress on first line TKI-s is to switch to a second line therapy with an agent with different mechanism of action like mTOR inhibitor [3,9]. On theoretical basis mTOR inhibitors could overcome the resistance to VEGF-TKIs. VEGF-TKIs increase tumor hypoxia which results in up-regulation of proangiogenic factors and increase potential of metastases. mTor inhibition decreases translation of proangiogenic factors and tumors that have become resistant to VEGF-TKI may respond to treatment with mTOR

that at least partial cross-resistance with sequential TKI-s [3,9,19].

efficacy in patients who progressed on sunitinib or bevacisumab [27].

and reduced cumulative toxicity [27].

bevacisumab-refractory mRCC [3].

involved in bevacisumab resistance [34].

**5.5. mTOR inhibitor after first line VEGF-TKI**

**5.4. VEGF-TKI after first line anti VEGF**

### **5.2. Combinations of targeted agents**

Combinations of targeted agents could be in theory effective mechanism to overcome the resistance because we could combine agents with different mechanisms of action. However combining these therapies may increase the incidence of side effects if the combination drugs are not selected carefully [29]. Most of patients do not tolerate full doses of two VEGF inhibitors at the same time. That is the reason why administering combination therapy long enough to surpass the clinical benefit of subsequent mono-therapy is not possible [25].

Combinations of VEGF-TKI and mTOR inhibitors also lead to unacceptable toxicity. In a trial of Patel et.al, combination of temsirolimus and sunitinib lead to dose limiting toxicity in 2 of 3 patients [31]. Data suggest that the side effects and tolerability of combinations correlate with the total number of inhibited targets. This is the explanation why some combinations with VEGF specific agent bevacisumab may be tolerated (e.g. bevacisumab plus everolimus). At present combination of targeted agents in the treatment of mRCC is not recommended in clinical practice mainly because of excessive toxicity [23,29].

### **5.3. Second VEGF-TKI after the first line VEGF-TKI**

Retrospective and prospective phase II trials showed that treatment with second TKI could be beneficial in patients that progressed on first TKI. At first sight this may seem not logical, but variations in kinase targets and interaction may avoid resistance. However definitive data from phase III trials on this topic are still missing. Benefit of the second TKI after the first TKI may be dependent on its relative potency and selectivity profile [9]. Most of the results from retrospective and small prospective trials suggest that patients with mRCC who progress on sorafenib could benefit from sunitinib. Conversely the use of sorafenib after sunitinib or bevacisumab showed limited efficacy [9,27].

Sabin et.al. evaluated 68 patients treated with sunitinib and sorafenib consequently. ORR was better when the patients received sorafenib first; 15% in the group that received sunitinib followed by sorafnib group and 9% in the group that received sorafenib after sunitinib. Median PFS in the first group was 12.4 months (6 months on sorafenib and 6.4 months on sunitinib) and 8.9 months in the second group (5 months on sunitinib and 3.9 months on sorafenib) [26]. Porta et.al evaluated retrospectively 99 patients treated with sunitinib followed by sorafenib (SuSo) and 90 patients treated with sorafenib followed by sunitnib (SoSu). The median PFS of second line treatment in the first group (SuSo) was 7.9 months and in the second group was 4.2 months (SoSu) [32]. Clinical trial in progress NCT00732914 with the aim to evaluate if total PFS of sorafenib followed by sunitinib is superior compared to sunitinib followed by sorafenib is expected to give some additional light to this issue [3].

AXIS trial directly compared the efficacy and safety of axitinib to sorafenib after progression on sunitinib, bevacisumab, temsirolimus or cytokines. In the subpopulation of patients who previously received sunitinib, median PFS was 4.8 months with axitinib and 3.4 months with sorafenib (p=0,001). Shorter median PFS in both arms receiving first line sunitinib compared to those receiving cytokines (median PFS 12.1 in axitinib and 6.5 moths in sunitinib) suggest that at least partial cross-resistance with sequential TKI-s [3,9,19].

Reduced clinical efficacy of second line therapy as a result of cross resistance is key concern associated with the sequential administration of agents targeting the same molecular path‐ ways. Two prospective trials showed that because of the cross-resistance, sorafenib had limited efficacy in patients who progressed on sunitinib or bevacisumab [27].

Another concern about using sequential VEGF-TKI therapies is toxicity. Although they may differ in toxicity profiles, all TKI-s share similar targets and exhibit class effect toxicities like hypertension, hand foot syndrome and rash [9]. Current data suggest that Switching to agents with different mechanisms of action in the second line therapy may provide superior efficacy and reduced cumulative toxicity [27].

### **5.4. VEGF-TKI after first line anti VEGF**

strated that this approach is effective and safe and become a basis of approval of sunitinib and

Combinations of targeted agents could be in theory effective mechanism to overcome the resistance because we could combine agents with different mechanisms of action. However combining these therapies may increase the incidence of side effects if the combination drugs are not selected carefully [29]. Most of patients do not tolerate full doses of two VEGF inhibitors at the same time. That is the reason why administering combination therapy long enough to

Combinations of VEGF-TKI and mTOR inhibitors also lead to unacceptable toxicity. In a trial of Patel et.al, combination of temsirolimus and sunitinib lead to dose limiting toxicity in 2 of 3 patients [31]. Data suggest that the side effects and tolerability of combinations correlate with the total number of inhibited targets. This is the explanation why some combinations with VEGF specific agent bevacisumab may be tolerated (e.g. bevacisumab plus everolimus). At present combination of targeted agents in the treatment of mRCC is not recommended in

Retrospective and prospective phase II trials showed that treatment with second TKI could be beneficial in patients that progressed on first TKI. At first sight this may seem not logical, but variations in kinase targets and interaction may avoid resistance. However definitive data from phase III trials on this topic are still missing. Benefit of the second TKI after the first TKI may be dependent on its relative potency and selectivity profile [9]. Most of the results from retrospective and small prospective trials suggest that patients with mRCC who progress on sorafenib could benefit from sunitinib. Conversely the use of sorafenib after sunitinib or

Sabin et.al. evaluated 68 patients treated with sunitinib and sorafenib consequently. ORR was better when the patients received sorafenib first; 15% in the group that received sunitinib followed by sorafnib group and 9% in the group that received sorafenib after sunitinib. Median PFS in the first group was 12.4 months (6 months on sorafenib and 6.4 months on sunitinib) and 8.9 months in the second group (5 months on sunitinib and 3.9 months on sorafenib) [26]. Porta et.al evaluated retrospectively 99 patients treated with sunitinib followed by sorafenib (SuSo) and 90 patients treated with sorafenib followed by sunitnib (SoSu). The median PFS of second line treatment in the first group (SuSo) was 7.9 months and in the second group was 4.2 months (SoSu) [32]. Clinical trial in progress NCT00732914 with the aim to evaluate if total PFS of sorafenib followed by sunitinib is superior compared to sunitinib followed by sorafenib

AXIS trial directly compared the efficacy and safety of axitinib to sorafenib after progression on sunitinib, bevacisumab, temsirolimus or cytokines. In the subpopulation of patients who previously received sunitinib, median PFS was 4.8 months with axitinib and 3.4 months with

surpass the clinical benefit of subsequent mono-therapy is not possible [25].

clinical practice mainly because of excessive toxicity [23,29].

**5.3. Second VEGF-TKI after the first line VEGF-TKI**

bevacisumab showed limited efficacy [9,27].

is expected to give some additional light to this issue [3].

pazopanib in the first line treatment [3].

198 Renal Tumor

**5.2. Combinations of targeted agents**

Very limited data are available on the use of TKI-s after progression on bevacisumab and no clinical trial is currently ongoing to address this issue. Only two minor prospective trials conducted by Garcia and Rini evaluated the use of sunitinib or sorafenib in patients with bevacisumab-refractory mRCC [3].

In a phase II trial of Garcia, 48 patients were enrolled. After progression on treatment with sunitinib or bevacisumab, patients received twice daily 400 mg of sorafenib. One unconfirmed objective partial response was observed and the tumor burden reduction rate was 30%. The median PFS was 4.4 months. There was no association of PFS and tumor shrinkage with response to prior therapy. Most treatment-related adverse events were of mild-to-moderate intensity, and included fatigue, hypertension, diarrhoea, and hand-foot syndrome [33].

Rini et.al. conducted a phase II multicentric trial in which patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6 week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment). Sixty-one patients were enrolled. The ORR was 23.0%, median PFS was 30.4 weeks and median OS was 47.1 weeks. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome. Results from measuring different VEGF-s in the plasma suggest that sunitinib could inhibit some of the signaling factors involved in bevacisumab resistance [34].

### **5.5. mTOR inhibitor after first line VEGF-TKI**

Another approach in patients who progress on first line TKI-s is to switch to a second line therapy with an agent with different mechanism of action like mTOR inhibitor [3,9]. On theoretical basis mTOR inhibitors could overcome the resistance to VEGF-TKIs. VEGF-TKIs increase tumor hypoxia which results in up-regulation of proangiogenic factors and increase potential of metastases. mTor inhibition decreases translation of proangiogenic factors and tumors that have become resistant to VEGF-TKI may respond to treatment with mTOR inhibitor [27]. The evidence of effectiveness of this approach comes from preclinical data. Trial conducted by Larkin and colleagues compared treatment with sunitinib, sunitinib followed by sorafenib or sunitinib followed by everolimus in mice implanted with murine RCC. Sunitinib followed by everolimus was associated with reduced primary tumor weight and volume in a greater extend compared to tumors treated with sunitinib and sunitinib followed by sorafenib. The conclusion was that sequential therapy with sunitinib followed by everoli‐ mus is associated with significant anti-tumor and anti-metastatic effect [35].

a feasible treatment option in first and second line of treatment [37,38]. Comparison between the two scheduling is currently not very well determined, but clinical and toxicological differences may in future be important issue in treatment individualization. Another option is re-challenge with the same drug after discontinuation period on disease progression. The basis for this approach comes from pre-clinical data that indicate that resistance to sorafenib

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The question of optimal treatment dosage becomes particularly relevant on disease progres‐ sion. Meta-analysis of patients with solid tumors receiving sunitinib revealed that patients receiving higher dose, had longer time to progression compared to patients who received less sunitinib. Additionally patient receiving higher dose had more complete or partial remissions and greater decrease in tumor size. In the trial comparing sorafenib with IFN-α, patients in the sorafenib group received higher dose of sorafenib (600 mg BID) after progression on 400 mg BID. Reduction of tumor size was observed. Suggested clinical benefit of increased dose after progression is outweighed by increased toxicity. Most of patients do not tolerate dosage

Prognosis of patients who progress early in the course of first line therapy VEGF targeted therapy is poor. No available agents seem to alter the course of their disease and give them clinical benefit. 86 patients with rapid progression after first line therapy were evaluated in a retrospective trial. PFS after second line therapy with treatment with different VEGF-TKI was 2 months and after second line therapy with mTOR 0.9 months (p=0.536). Larger retrospective trial in which 272 patients were included showed similar results. All patients had rapid disease progression after first line VEGF-TKIs. The response rates, PFS and OS of those receiving second-line VEGF-targeted therapy compared with mTOR inhibitors were 10 vs 6%, 2.8 vs.2

Small prospective and retrospective trials suggest that changing the mechanism of action in the third line may restore the sensitivity to the initial treatment [3,9,27,32,39,40]. In the ASCO meeting in 2010 Ferrari presented the results of a prospective trial that compared the admin‐ istration of everolimus or temsirolimus as third line therapy to good performance status patients resistant to TKI-s. Median PFS was 6 months and disease control was achieved in 39% of patients. These results suggest that treatment with mTOR inhibitor in the third line and

Another trial conducted by Di Lorenzo et.al. evaluated sorafenib treatment in the third line after treatment with sunitinib and mTor inhibitor. Of the 34 patients eligible, 23.5% responded to third line sorafenib. Desease control was 44%, median PFS was 4 and median OS was 6 months. 47% of patients that responded to first line therapy, responded to third-line sorafenib while of patients who did not respond to first-line, did not respond also to third-line sorafenib.

months and 7.9 vs. 4.7 months. Differences were not statistically significant [9].

further than, could be a potential promising treatment option [40].

is reversed by re-implantation of resistant tumors in untreated mice [23].

increase [22].

**5.7. Intrinsic resistance**

**6. Third line and beyond**

Everolimus was approved in the second line therapy on results of RECORD-1 trial. In this double blind, phase III trial, patients who had progressed on first line sunitinib, sorafenib or both were randomized to everolimus or placebo. Patients receiving everolimus had longer PFS compared to placebo (4.9 vs. 1.9 months, p<0.001). The clinical benefit of everolimus was observed regardless if the patients received previously one or two consequent TKI-s. In the subgroup of patients who received one TKI, median PFS in everolimus group was 5.4 months, and in group who received two TKI-s 4 months. This was statistically significant longer than in placebo groups, where PFS was 1.9 and 1.8 months respectively [8,20,36-38].

Prospective head to head trials to compare mTOR inhibitors and VEGF-TKI-s in the second line of treatment in patients who progressed on the first line VEGF-TKI-s have not been done. Di Lorenzo and colleagues indirectly compared survival benefit in patients on everolimus or sorafenib in the second line. Median overall survival was 81.5 weeks for patients receiving everolimus and 32.0 weeks for sorafenib [37].

The optimal sequencing of sunitinib and everolimus is currently being evaluated in the RECORD-3 trial and furthermore the everolimus plus bevacisumab in the second line after progression on TKI-s is currently being compared to everolimus plus placebo in the NCT01198158 trial [3].

The efficacy and safety of temsirolimus after progression on TKI-s are expected to be revealed in an ongoing trial NCT00474786, a phase III trial comparing temsirolimus vs. sorafenib in the second line treatment in patients who have failed on first-line sunitinib. Results from small population in retrospective and prospective phase II trial presented on ASCO 2010 suggest, that temsirolimus is safe and effective in pretreated patients, especially those with good performance status and good prognostic factors [3].

Regarding toxicity mTOR inhibitors and VEGF-TKIs block different molecular mechanisms, the toxicity profiles are usually not overlapping. In the RECORD-1 trial patients could tolerate treatment with everolimus after progression on VEGF-TKIs. Stomatitis, infection, asthenia and fatigue were the most common side effects reported on everolimus therapy. Common toxicities encountered in the treatment with VEGF-TKIs such as hypertension or hand-foot syndrome, were not frequent [3,19].

### **5.6. Alternative scheduling and dosage**

A different approach to overcome the resistance can potentially be the change in scheduling and/or dosage of the targeted agent in usage. Sunitinib is approved in intermittent schedule of 4 weeks on drug and 2 weeks off drug. Continuous low-dose therapy has been shown to be a feasible treatment option in first and second line of treatment [37,38]. Comparison between the two scheduling is currently not very well determined, but clinical and toxicological differences may in future be important issue in treatment individualization. Another option is re-challenge with the same drug after discontinuation period on disease progression. The basis for this approach comes from pre-clinical data that indicate that resistance to sorafenib is reversed by re-implantation of resistant tumors in untreated mice [23].

The question of optimal treatment dosage becomes particularly relevant on disease progres‐ sion. Meta-analysis of patients with solid tumors receiving sunitinib revealed that patients receiving higher dose, had longer time to progression compared to patients who received less sunitinib. Additionally patient receiving higher dose had more complete or partial remissions and greater decrease in tumor size. In the trial comparing sorafenib with IFN-α, patients in the sorafenib group received higher dose of sorafenib (600 mg BID) after progression on 400 mg BID. Reduction of tumor size was observed. Suggested clinical benefit of increased dose after progression is outweighed by increased toxicity. Most of patients do not tolerate dosage increase [22].

### **5.7. Intrinsic resistance**

inhibitor [27]. The evidence of effectiveness of this approach comes from preclinical data. Trial conducted by Larkin and colleagues compared treatment with sunitinib, sunitinib followed by sorafenib or sunitinib followed by everolimus in mice implanted with murine RCC. Sunitinib followed by everolimus was associated with reduced primary tumor weight and volume in a greater extend compared to tumors treated with sunitinib and sunitinib followed by sorafenib. The conclusion was that sequential therapy with sunitinib followed by everoli‐

Everolimus was approved in the second line therapy on results of RECORD-1 trial. In this double blind, phase III trial, patients who had progressed on first line sunitinib, sorafenib or both were randomized to everolimus or placebo. Patients receiving everolimus had longer PFS compared to placebo (4.9 vs. 1.9 months, p<0.001). The clinical benefit of everolimus was observed regardless if the patients received previously one or two consequent TKI-s. In the subgroup of patients who received one TKI, median PFS in everolimus group was 5.4 months, and in group who received two TKI-s 4 months. This was statistically significant longer than

Prospective head to head trials to compare mTOR inhibitors and VEGF-TKI-s in the second line of treatment in patients who progressed on the first line VEGF-TKI-s have not been done. Di Lorenzo and colleagues indirectly compared survival benefit in patients on everolimus or sorafenib in the second line. Median overall survival was 81.5 weeks for patients receiving

The optimal sequencing of sunitinib and everolimus is currently being evaluated in the RECORD-3 trial and furthermore the everolimus plus bevacisumab in the second line after progression on TKI-s is currently being compared to everolimus plus placebo in the

The efficacy and safety of temsirolimus after progression on TKI-s are expected to be revealed in an ongoing trial NCT00474786, a phase III trial comparing temsirolimus vs. sorafenib in the second line treatment in patients who have failed on first-line sunitinib. Results from small population in retrospective and prospective phase II trial presented on ASCO 2010 suggest, that temsirolimus is safe and effective in pretreated patients, especially those with good

Regarding toxicity mTOR inhibitors and VEGF-TKIs block different molecular mechanisms, the toxicity profiles are usually not overlapping. In the RECORD-1 trial patients could tolerate treatment with everolimus after progression on VEGF-TKIs. Stomatitis, infection, asthenia and fatigue were the most common side effects reported on everolimus therapy. Common toxicities encountered in the treatment with VEGF-TKIs such as hypertension or hand-foot syndrome,

A different approach to overcome the resistance can potentially be the change in scheduling and/or dosage of the targeted agent in usage. Sunitinib is approved in intermittent schedule of 4 weeks on drug and 2 weeks off drug. Continuous low-dose therapy has been shown to be

mus is associated with significant anti-tumor and anti-metastatic effect [35].

in placebo groups, where PFS was 1.9 and 1.8 months respectively [8,20,36-38].

everolimus and 32.0 weeks for sorafenib [37].

performance status and good prognostic factors [3].

NCT01198158 trial [3].

200 Renal Tumor

were not frequent [3,19].

**5.6. Alternative scheduling and dosage**

Prognosis of patients who progress early in the course of first line therapy VEGF targeted therapy is poor. No available agents seem to alter the course of their disease and give them clinical benefit. 86 patients with rapid progression after first line therapy were evaluated in a retrospective trial. PFS after second line therapy with treatment with different VEGF-TKI was 2 months and after second line therapy with mTOR 0.9 months (p=0.536). Larger retrospective trial in which 272 patients were included showed similar results. All patients had rapid disease progression after first line VEGF-TKIs. The response rates, PFS and OS of those receiving second-line VEGF-targeted therapy compared with mTOR inhibitors were 10 vs 6%, 2.8 vs.2 months and 7.9 vs. 4.7 months. Differences were not statistically significant [9].
