Sage Journals: Discover world-class research

Abstract

This article reviews data on sorafenib use in renal cell carcinoma. Mechanisms of actions and pharmacokinetics are briefly described. Major clinical trials are presented, summarizing efficacy and safety of sorafenib. Its place in current treatment of renal cell carcinoma is discussed. Sorafenib is likely to remain one of the mainstays of RCC treatment in coming years.

Keywords

sorafenib renal-cell carcinoma review

Introduction

The medical treatment of metastatic renal cell carcinoma (RCC) has been revolutionized in recent years with the approval of several drugs. Previously, only immunotherapy had shown even limited efficacy in a minority of patients. Such revolutionary improvements resulted from advances in the knowledge of RCC's carcinogenesis.¹ Recent research has focused on the importance of two pathways involved in the development and prognosis of clear-cell RCC: the VEGF/VHL/HIF pathway and the PI3K/Akt/mTOR pathway.^2,3 At least two thirds of clear-cell RCC exhibit inactivation of the VHL gene, either by mutation or loss of expression (Fig. 1).⁴ This inactivation results in a deregulation of the expression of a wide range of genes, including Vascular Endothelial Growth Factor (VEGF). VEGF is the main growth factor involved in angiogenesis. Thus, the development of VEGF inhibitors was successful in many tumor types, including breast, colorectal, lung carcinomas.⁵ In fact, RCC shows the greatest expression of VEGF in solid tumors, and the importance of its vascularization is a characteristic that has been recognized by clinicians for decades. In addition, VEGF expression was shown to be an adverse prognosis factor, either in localized tumors or in the metastatic setting.⁶ Therefore, this axis was a preferred target for the development of targeted therapies in RCC. Five targeted therapies inhibiting the VEGF axis have already gained regulatory approval due to positive phase 3 clinical studies: sorafenib, sunitinib, bevacizumab, pazopanib and axitinib.^7–11 In addition, others are still in development. Sorafenib, sunitinib, pazopanib and axitinib are multi-target tyrosine kinase (TKI) inhibitors that inhibit the VEGF Receptor, as well as other tyrosine kinases. Bevacizumab is a monoclonal antibody that target VEGF specifically. One other class of targeted therapies, mTOR inhibitors, was approved for metastatic RCC, including temsirolimus and everolimus.^12,13 Among these treatments, sorafenib was the first TKI to gain approval by regulatory agencies concerned with RCC and is the focus of this review.¹⁴

Figure 1

The VHL/HIF/VEGF Pathway.

Mechanism of Action, Metabolism and Pharmacokinetic Profile

Sorafenib is a multi-target TKI.¹⁵ Like most TKI, it binds to the kinase at the ATP-binding site and inhibits the phosphorylation induced by the catalytic site. Sorafenib inhibits a wide range of tyrosine kinases, including BRAF (as well as mutant V600E BRAF), VEGFR-2, VEGFR-3, PDGFRβ, FLT3 and KIT. The concentrations inhibiting 50% (IC50) of activity of these tyrosine kinase are 6 nmol/L for RAF, 22 nmol/L for V600E BRAF, 90 nmol/L for VEGFR-2, 20 nmol/L for VEGFR-3, 57 nmol/L for PDGFRβ,58 nmol/L for FLT3 and 58 nmol/L for KIT.¹⁶ Sorafenib inhibits phosphorylation and activity of the receptors and consecutively inhibits the activity of downstream signaling via the MAPKinase-pathway, as assessed by the inhibition of ERK signaling.¹⁷ It should be noted that sorafenib was first developed as a RAF inhibitor, and was then recognized as a potent VEGFR inhibitor. This inhibitory profile could raise the possibility of a dual action in both endothelial and tumoral cells (Fig. 2). This was shown in cell lines model, but the effect in animal models and in human is more difficult to analyze.^18,19 However, most data support a predominant effect as an antiangiogenic agent rather than a direct effect on tumoral cells.¹⁸

Figure 2

Potential mechanisms of action of Sorafenib in RCC.

Sorafenib is administrated as oral tablets. The bioavailability is about 38% to 49%.²⁰ This may be reduced by food ingestion and therefore the Food and Drug Administration (FDA) recommends avoiding ingestion concomitantly with a meal.²¹ Sorafenib shows a large interpatient variability in pharmacokinetics.²² However, this variability was not correlated with toxicities in phase 1 studies. Sorafenib is also highly protein-bound (99.5%). Its half-life is between 24 hours to 48 hours. Steady-state concentrations are reached after 7 days of dosing. Metabolism involves two pathways: sorafenib is a substrate of cytochrome P450 CYP3A4 and is also glucorono-conjugated by UDP glucuronosyltransferase (UGT) 1A9.^23–25 However, around 50% of sorafenib is eliminated in its unchanged form. Two weeks after a single oral administration, 96% of the dose is eliminated, 77% in the feces and 19% in the urine. It is noteworthy that sorafenib seems to be neither an inducer nor an inhibitor of CYP3A4. However, other drugs can affect the activity of CYP3A4 (Table 1). Such treatments should be avoided during sorafenib treatment.

Table 1

List of modifiers of CYP3A4.

Inhibitors	Inducers
Protease inhibitors	Anticonvulsants
Ritonavir	Carbamazepine
Indinavir	Phenytoin
Nelfinavir	Oxcarbazepine
Saquinavir	Phenobarbital
Anti-infective	Antibitics
Clarithromycin	Rifampicin
Telithromycin	Rifabutin
Erythromycin (moderate)
Chloramphenicol
Ketoconazole
Itraconazole
Fluconazole (moderate)
Aprepitant (moderate)	St. John's wort
Verapamil	Non-nucleoside reverse
Diltiazem	transcriptase inhibitors
	Efavirenz
	Nevirapine
Bergamottin (constituent of grapefruit juice) (moderate)	Hypoglycemics
	Pioglitazone
	Troglitazone

Clinical Studies

Major clinical studies of sorafenib are summarized in Table 2

Sorafenib was studied in 4 phase 1 studies, exploring different schedules: 7 days on, 7 days off;²⁶ 21 days on, 7 days off;²⁷ 28 days on, 7 days off;²⁰ and continuous dosing.²² These 4 phase 1 studies were reviewed by Strumberg in 2007.²⁸ Due to the half-life of 24 to 48 hours, most administration schemes involved twice-a-day administration. The maximum doses studied were 800 mg bid. Dose-limiting toxicities were consistent across the 4 studies, and dose-limiting toxicities were usually seen at 600 mg bid or higher.²⁸ In these 4 phase 1 studies, a total of 137 patients were evaluable for response and two responses were seen in this heavily pre-treated population.²⁸ However, in the continuous dosing study, 1 RCC patient had disease stabilization lasting more than 2 years, and 50% of patients with Hepatocellular Carcinoma were stable for more than 6 months, already showing interesting activity in the 2 settings with subsequent positive phase 3 studies. Some signs of activity were also seen in colorectal cancer patients. Detailed results of toxicity are reported in the corresponding section of this article.

Table 2

Sorafenib's clinical studies.

Reference	Type of study	Administration schemes	Setting	Number of patients included	Major results
Clark et al²⁵	Phase 1	7 days on, 7 days off	All tumor types	19	Recommended phase 2 dose: 600 mg bid
Awada et al²⁶	Phase 1	21 days on, 7 days off	All tumor types	44	Recommended phase 2 dose: 400 mg bid
Moore et al¹⁹	Phase 1	28 days on, 7 days off	All tumor types	42	Recommended phase 2 dose: 400 mg bid
Stumberg et al²¹	Phase 1	Continuous	All tumor types	69	Recommended phase 2 dose: 400 mg bid
Ratain et al²⁸	Phase 2 Randomized discontinuation trial	400 mg bid continuous	All tumor types, Publication on RCC patients	502 patients, 202 RCC patients	In RCC patients, time to progression after randomization was increased by sorafenib vs placebo
Escudier et al²⁹	Randomized phase 2	400 mg bid continuous	RCC first line, vs. interferon	189	Higher disease control rate, better quality of life, but no difference in progression-free survival
Escudier et al⁷	Phase 3, TARGET trial	400 mg bid continuous	RCC second line, vs. placebo	903	Sorafenib increased progression-free survival
Beck et al³¹	European Expanded-access study	400 mg bid continuous	RCC	1 159	Confirmation of TARGET results; subgroup analysis
Stadler et al³²	American Expanded-access study	400 mg bid continuous	RCC	2 504	Confirmation of TARGET results; subgroup analysis
Rini et al¹¹	Phase 3, AXIS trial	400 mg bid continuous	RCC second line, vs. axitinib	723	Axitinib increased progression-free survival
Motzer et al, ASCO 2012, abstract 4501	Phase 3	400 mg bid continuous	RCC first line, vs tivozanib	517	Tivozanib increased progression-free survival

Sorafenib was studied as monotherapy in a phase 2 study.²⁹ Interestingly, the design of this phase 2 was innovative: a randomized discontinuation trial. Patients included were initially treated with sorafenib open-label in a 12 week runin period at 400 mg bid. Disease was evaluated at 12 weeks using unusual criteria of response: bidimensional tumor measurements of responses were compared with baseline measurements, shrinkage of ≥25% was considered a response, ≥25% tumor growth or new lesions were considered progression. Patients with response continued open-label sorafenib, patients with progressive disease discontinued treatment. Patients without either response or progression were randomized to either sorafenib or placebo in a double-blind fashion. The primary endpoint was the percentage of patients randomly assigned who remained progression-free 12 weeks after randomization (24 weeks after study entry). In total, 502 patients were enrolled, but the publication focused on the 202 RCC patients. It should be noted that randomized discontinuation trials were developed to ensure rapid accrual–-patients are prone to accept the trial because they are sure to receive the studied drug–-but that in this particular case an important number of patients had to be included before completion of the study. At the end of the run-in phase, according to the study criteria, 36% were responders, 34% were stable, and 25% were progressive. The objective response rate using modified WHO criteria was 4%. Sixty-five patients were randomized, and progression occurred at a median of 6 weeks after randomization in the placebo arm, as compared with 24 weeks after randomization in the sorafenib arm (P = 0.0087). For the whole cohort of patients receiving sorafenib (either continuing open-label due to tumor shrinkage or randomized due to stabilization), the median progression-free survival (PFS) was 29 weeks. This trial illustrates that response rate may not be an appropriate surrogate marker for activity of some targeted therapies and that alternative endpoints such as time to progression (TTP) or PFS may be more relevant. In this view, using randomized discontinuation trial provides a clear advantage. However, another potential advantage of randomized discontinuation trials is not evident in this example due to a high number of patients who had to be included to complete the trial.

Results of other studies are described in the safety and efficacy section of this article.^7,11,30–33 After results of the pivotal TARGET trial, and before approval by regulatory agencies, two expended-access studies were launched, one in Europe and another in the United States and Canada: the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS)³¹ and the US-ARCCS studies.³²

Sorafenib is studied in the adjuvant setting in 2 trials:³³ the SORCE trial (clinicaltrial.gov identifier NCT00492258), sponsored by the UK Medical Research Council, which compared 2 durations of sorafenib (1 year and 3 years) to placebo in patients at risk for relapse; and the ASSURE trial (NCT00326898), sponsored by the ECOG, in collaboration with the CALGB, SWOG, NCI and NCIC, which randomized patients at risk for relapse either to placebo, sorafenib, or sunitinib during a 1 year period. Results of these trials should be available in the next few years.

Safety

Specific side effects

The major side effects of sorafenib reported in published studies are summarized on Table 3.^7,22,29–32 The US-ARCCS study reported only grade 2 or grade ≥ 3, but not all grade toxicities.³² Most frequent toxicities are consistent between studies, with small differences in reported incidences. In the TARGET trial, the incidences of side effect are compared between sorafenib and placebo for grade 2 and grade ≥ 3 respectively, but not for all-grades toxicities.³⁰ Grade 2 toxicities significantly more present in the sorafenib group were diarrhea (incidence ranging between 43% and 58% across studies), rash (26% to 66%), hand-foot skin reactions (HFSR) (23% to 62%), hypertension (17% to 43%), alopecia (16% to 53%), weight loss (10% to 33%), pruritus (11% to 19%) and headache (6%).

Table 3

Toxicities reported in clinical trials of continuous dosing of sorafenib.

	Phase 1	Phase 2-RDT	Phase 2 first-line	Phase 3 (TARGET), all grades		Phase 3 (TARGET), grades 3–4		EU-ARCCS	US-ARCCS, grade 3
				Sorafenib	Placebo	Sorafenib	Placebo
Hypertension*	NR	43%	23%	17%	4%	2%	<1%	20%	5%
Hemorrhage	NR	22%	NR	15%	8%	3%	2%	NR	NR
Fatigue	39%	73%	43%	37%	28%	5%	4%	34%	5%
weight loss*	NR	33%	14%	10%	6%	<1%	0%	11%	<1%
Rash*	26%	66%	41%	40%	16%	1%	<1%	33%	5%
Hand-foot skin reactions*	23%	62%	60%	30%	7%	6%	0%	56%	10%
Alopecia*	16%	53%	41%	27%	3%	<1%	0%	33%	<1%
Pruritus*	NR	NR	13%	19%	6%	<1%	0%	11%
Diarrhea*	55%	58%	55%	43%	13%	2%	1%	55%	2%
Nausea	30%	30%	19%	23%	19%	<1%	1%	17%	1%
Anorexia	42%	47%	30%	16%	13%	<1%	1%	22%	1%
Headache*	NR	NR	NR	10%	6%	<1%	<1%	NR	NR
Sensory neuropathy	NR	NR	NR	13%	6%	<1%	1%	NR	NR
Voice changes	NR	NR	6%	NR	NR	NR	NR	NR	NR
Stomatitis	7%	35%	11%	NR	NR	NR	NR	28%	NR

Abbreviations: NR, Not reported; RDT, Randomized Discontinuation Trial.

Most deceivingly, precise descriptions of hemorrhage are frequently lacking in the report of those trials. A meta-analysis was recently published on fatal adverse events in studies involving VEGFR TKIs, including studies of sorafenib in RCC and other tumoral types.³⁴ Fatal adverse events were more frequent in the treatment arm than in the comparator arm of these studies. For sorafenib, the risk of fatal adverse events was 1.4% (95% CI, 0.6% to 3.2%), not different from others VEGFR TKIs. The relative risk was 2.68 (95% CI, 1.11 to 6.45; P = 0.028), showing significant increase in fatal adverse events; however, the 1.4% incidence could be considered as low. Hemorrhage was the most frequent fatal adverse event. No significant difference was seen between RCC and other tumor types, but confidence intervals were wide. In some retrospective studies, hypertension was associated with clinical benefit of antiangiogenics, but this notion is debated.³⁵

Other toxicities described in subsequent studies were hypothyroidism^36,37 (incidence of 18% in one study, 67% in another), hypophosphatemia, and cardiac dysfunction. Drops in left ventricular ejection fraction were reported under sorafenib and other TKIs.^38–40 However, these cardiac dysfunctions rarely have clinical consequences.⁴¹ Long-term toxicities were reported for the TARGET trial, in patients treated ≫ 1 year.⁴² There was no new toxicity reported, but incidence of side effects seemed higher than those reported for the whole population, with diarrhea in 74% of patients, rash in 51%, HFSR in 49%, alopecia in 39% and fatigue in 38%. However, grade ≥ 3 adverse events were rare, the most frequent being HFSR (7%) and hypertension (5%). Cardiac ischemia was reported in 2%, left ventricular dysfunction in 1%.

Safety in different populations

Safety in elderly patients was addressed in the US-ARCCS study.^32,43 Incidence of reported adverse events were not increased in patients aged more than 70 years. In the EU-ARCCS study, the same conclusion can be drawn, with the exception of fatigue, which was reported in 31% of patients aged < 70 year but in 44% of patients aged ≥ 70 years.³¹ Results of the TARGET trials were comparable in the young and elderly populations.⁴⁴ The safety of sorafenib in patients with brain metastases seemed acceptable in the US-ARCCS and the EU-ARCCS studies, as well as other specific studies, with no increase of bleeding reported.^31,32,45

Sorafenib was studied by the CALGB group in a phase 1 trial that included patients with renal or hepatic dysfunction.⁴⁶ This study involved patients with different abnormalities and was able to include 138 patients. In case of hepatic dysfunction, the recommended dosage was 400 mg bid for patients with bilirubin ≫ upper limit of normal (ULN) but ≤1.5x ULN and/or AST ≫ ULN, 200 mg bid for patients with bilirubin between 1.5 and 3x ULN, but not even 200 mg every third day was tolerable if bilirubin was >3x ULN. When albumin was below 2.5 mg/dL, recommended dosage was 200 mg each day. In case of renal dysfunction, recommended dosage was 400 mg bid if creatinine clearance was ≤40 mL/min, 200 mg bid if creatinine clearance was between 20 mL/min and 39 mL/min, could not be defined if creatinine clearance was below 20 mL/min without dialysis and was 200 mg each day in case of dialysis.

Management of toxicity

The peculiar toxicity profile of sorafenib (as well as those of other TKIs), prompted the need for proper management. Most side effects appear soon after the beginning of treatment, in the first two months, and many appear in the first 4 weeks. This timeframe emphasized the need for early visit of patients, possibly with the help of trained nurses.⁴⁷ Some side effects could be prevented by appropriate measures. Hypertension should be controlled before initiation of treatment.⁴⁸ Development of hypertension may require use of combination of antihypertensive drugs, with the help of a cardiologist if needed. However, sorafenib may, with proper management, be continued in the case of hypertension. HFSR could be prevented by proper counseling, urea-based topics, use of emollient and prompt intervention when symptoms appear.⁴⁹ Treatment of HFSR involves anti-inflammatory and keratolytics topics. No specific recommendations could be made about treatment of sorafenib-induced diarrhea.

Efficacy

First-line metastatic setting

Sorafenib was compared to interferon alpha-2a in untreated patients with metastatic RCC in a randomized phase 2 trial including 189 patients.³⁰ The primary endpoint was PFS. In this trial, patients progressing while receiving sorafenib had a dose-escalation to 600 mg bid and patients progressing while receiving interferon crossed over to sorafenib 400 mg bid. The PFS was not different between sorafenib and interferon: median PFS 5.7 months vs. 5.6 months, respectively, Hazard ratio (HR) = 0.88 (P = 0.50). Response rates were 5.2% for sorafenib and 8.7% for interferon. However, some signs of tumor shrinkage were seen in 68% of patients treated with sorafenib, compared with 39% of patients treated with interferon, and the disease control rate was significantly higher for sorafenib (79% vs. 64%, P = 0.006). The quality of life, assessed by the FKSI-15 and FACT-BRM scores, was also significantly better in the sorafenib arm of this trial.

The TARGET trial included 161 patients who were not previously treated by cytokines.⁷ In these patients sorafenib achieved similar results to patients pretreated with cytokines, with a significant improvement in PFS, suggesting that sorafenib benefit over placebo is independent of the previous treatment with cytokines. In addition, in the EU-ARCCS and US-ARCCS studies, PFS was similar in patients pretreated by cytokines and patients not previously treated.^31,32 Median PFS of non-previously treated patients was 24 weeks in the US-ARCCS study, close to results of the TARGET trial, again suggesting sorafenib's efficacy is independent of line of treatment.

The combination of sorafenib with interleukin-2 (IL2) was tested in a randomized phase 2 study comparing it to sorafenib alone.⁵⁰ Median PFS was 33 weeks with the combination vs. 30 weeks for sorafenib alone. Grade 3–4 adverse events were reported more frequently in the combination arm. Thus, the combination of IL2 with sorafenib did not show improvement in PFS and was associated with more severe adverse events. Other studies of the combination of sorafenib with interferon did not provide evidence of benefit in adding cytokine to sorafenib.^51–54

Results of a phase 3 study comparing sorafenib to tivozanib in the first-line setting were recently presented at the 2012 ASCO annual meeting (Motzer et al, abstract 5401). Tivozanib is a potent inhibitor of VEGFR 1, 2 and 3. The results were in favor of tivozanib, with a median PFS of 12.7 months compared with 9.1 months for sorafenib. The toxicity profile also appeared to be better in the tivozanib arm.

Sorafenib in patients pretreated with cytokines

The TARGET trial included 903 patients pretreated for metastatic RCC, 82% of them being pretreated with cytokines.⁷ Fifty-one percent of patients were classified as low-risk by the Memorial Sloan Kettering Cancer Center (MSKCC) classification, 49% as intermediate risk, and 94% were previously treated by nephrectomy. In this trial, sorafenib demonstrated superiority over placebo. The trial was designed to detect a difference of overall survival (OS). However, an interim analysis showed a significant improvement in PFS; consequently, the trial was prematurely stopped and cross-over was allowed for patients in the placebo arm. In the initial publication in 2007, OS was higher in the sorafenib arm, with a Hazard Ratio of 0.77 (95% CI, 0.63 to 0.95), but the P value of 0.02 was considered not significant as this was an interim analysis. Median OS was 19.3 months in the sorafenib arm vs. 15.9 months in the placebo arm. In the publication of the final analysis in 2009,⁵⁵ OS was not statistically different in the intent-to-treat population, with a median of 17.8 months in the sorafenib arm vs. 15.2 months in the placebo arm, HR = 0.88, and P = 0.146. However, when cross-over was taken into account and patients were censored at the time of their cross-over, the difference became significant, with a median of 17.8 months in the sorafenib arm vs. 14.3 months, HR = 0.78, P = 0.029.

Other efficacy endpoints were in favor of sorafenib: median PFS was 5.5 months for the sorafenib arm vs. 2.8 months in the placebo arm, HR = 0.44 (95% CI, 0.35 to 0.55, P < 0.001). The difference was seen in the investigators’ assessment as well as in the independent radiologic review. In addition, complete response was seen in 1 patient (<1%) treated by sorafenib, partial response in 10% treated by sorafenib vs. 2% treated by placebo, stable disease in 74% vs. 53% and progressive disease in 12% vs. 37%. Disease control rate for at least two cycles was 62% in the sorafenib arm vs. 37% in the placebo arm. Furthermore, data about quality of life were reported in a separate publication, favoring the sorafenib arm.⁵⁶ Sorafenib was also shown to be cost-effective in the second-line treatment of RCC.⁵⁷

Sorafenib in patients pretreated with targeted therapy

The approval of sorafenib was close to those of bevacizumab and sunitinib in RCC. Soon after came the approval of temsirolimus, then everolimus and pazopanib. Despite the lack of proof of efficacy in randomized trials, clinicians were prone to offer access to sorafenib after progression under other targeted therapies. In fact, data from retrospective studies tends to support the use of second-line anti-VEGF treatment after prior antiangiogenic agents. Tamaskar et al studied 14 patients treated with sorafenib (as well as 16 patients treated with sunitinib) after receiving prior antiangiogenic treatment.⁵⁸ Ten out of 14 patients treated with sorafenib experienced some degree of shrinkage, including a partial response. Median time to progression was 10.4 months, with no evidence of difference between sorafenib and sunitinib. Di Lorenzo et al studied 34 patients treated by sorafenib after previous treatment with sunitinib and everolimus.⁵⁹ Median PFS was 4 months and median OS was 7 months. Partial responses were seen in 23.5% of patients. Vickers et al analyzed data of 216 patients receiving second-line treatments after first-line anti-VEGF therapy.⁶⁰ These patients showed better baseline Karnofsky performance status than patients not receiving second-line treatments. Median time to treatment failure after second-line anti-VEGF therapy was 4.9 months, compared with 2.5 months for patients receiving anti-mTOR therapy (P = 0.014). Taken together, these retrospective data suggest a clinical benefit of using second-line sorafenib after progression under antiangiogenic therapy. However, the retrospective nature of these studies leads to many biases, the more obvious being that only a fraction of patients progressing after first-line are able to receive second-line. Thus, patients in these studies are selected for their good prognosis, which leads to difficulty in interpretation of the results. This point is clearly illustrated by the Vickers et al study, in which only 216 patients received second-line treatment out of 645 patients treated by antiangiogenic agents in first-line.⁶⁰

On the basis of these data, sorafenib is frequently proposed after progression under sunitinib. A phase 3 study compared sorafenib to axitinib in second-line treatment.¹¹ The AXIS trial randomized 723 patients between the two anti-VEGFR TKIs. Fifty-four percent of patients included were previously treated with sunitinib, 35% with cytokines, 8% with bevacizumab and 3% with temsirolimus. The results were in favor of axitinib, with a median PFS of 6.7 months in patients receiving axitinib vs. 4.7 months in patients receiving sorafenib (HR = 0.67; 95% CI 0.54 to 0.81, P < 0.001). However, the difference was less obvious in the population of patients pre-treated with sunitinib, with a median PFS of 4.8 months for axitinib vs. 3.4 months for sorafenib, HR = 0.74, P = 0.011. Response rate was 19% for axitinib vs. 9% for sorafenib (P = 0.001). Eight percent of patients discontinued sorafenib due to adverse events, compared with 4% in the axitinib arm. Axitinib was associated with more hypertension, nausea, voice changes and hypothyroidism, while sorafenib was associated with more HFSR, rash and alopecia. Thus, axitinib is an option for second-line treatment. However, approval was granted by the American FDA only in January 2012 and approval by the European EMEA is still pending.

Sorafenib was studied in a retrospective analysis in the third-line setting, after previous treatment with sunitinib and mTOR inhibitor.⁶¹ Thirty-four patients were analyzed, showing median PFS of 4 months and median OS of 7 months in this heavily pretreated population, suggesting activity of sorafenib. However, the retrospective nature of the study and the likely highly selected nature of the population leads to difficulty in drawing firm conclusions.

Sorafenib use in different histological subtypes

Patients included in the TARGET trial had exclusively clear-cell RCC.⁷ However, due to a lack of effective treatment in other histological subtypes, sorafenib was used for patients with different types of RCC. Choueiri et al were the first to describe efficacy of TKIs in other histological subtypes.⁶² They studied 53 patients (41 with papillary RCC, 12 with chromophobe RCC), of whom 33 were treated with sorafenib. Their study tends to show some efficacy of TKIs, with a median PFS of 10.6 months for the chromophobe RCC, and 7.6 months for the papillary RCC. Median PFS was significantly higher in papillary RCC treated with sunitinib vs. those treated with sorafenib (11.9 vs. 5.1 months, P < 0.001). However, the retrospective nature of the study should prompt caution on definitive conclusions. Another small study involving tumors with sarcomatoid features (but with a small median percentage of 14% of tumoral cells) showed some signs of activity of anti-VEGF agents.⁶³ Conversely, the EU-ARCCS study showed a median PFS that is somewhat lower in non-clear-cell histologies and in the case of sarcomatoid features.³¹ However, sarcomatoid differentiation and type 2 papillary RCC had a worse prognosis than pure clear-cell RCC, making it difficult to conclude. Indeed, in the EU-ARCCS study, papillary RCC showed a high rate of non-progressive patients at 8 weeks (near 80%), suggesting some efficacy of sorafenib in this population.

Difficulties in evaluation of response

The emergence of targeted therapies in RCC has raised questions about the proper endpoints of clinical trials. For instance, the Response Criteria in Solid Tumors (RECIST) were criticized as potentially underestimating the true efficacy of the treatment. Sorafenib is a good illustration of this point, with a modest response rate of 10% in the TARGET trial contrasting with a significant improvement in PFS and arguments of efficacy in terms of OS.⁷ Indeed, if response evaluated by RECIST had been used in the phase 2 setting, sorafenib development could have been stopped in RCC. However, the phase 2 was designed as a randomized discontinuation trial, with time-to-progression as the primary objective.²⁹

Alternatives to RECIST were tested in RCC. Dynamic-contrast enhanced CTscan, MRI or UltraSound could help to better evaluate the effect of treatment on tumoral vascularization.^64–69 Criteria using density were also proposed, as well as FDG-PET.^64,70 All these methodologies report increase in the proportion of responding patients. However, data are still lacking about the clinical benefit of such evaluation criteria, and the consensus remains on using RECIST for better inter-trial comparisons. This area will certainly progress in the next few years.

Prediction of response

With the development of targeted therapies comes the hope of a “tailored treatment”.⁷¹ Indeed, these therapies are associated with a high economic burden and significant toxicity. Selection of patients most likely to benefit from treatment would clearly be interesting. Prognostic factors included in the MSKCC classification are still valuable in the area of targeted therapies.⁷² However, despite intensive research in the field, no predictive factor of response to antiangiogenic treatment has emerged. In the final report of the TARGET trial, Escudier et al reported that patients with high baseline plasma VEGF tended to derive more benefit from sorafenib, but even patients with the lowest level of VEGF still derive some benefit from sorafenib over placebo.⁵⁵ Thus, VEGF could not serve as a predictive factor. Pena et al published the complete analysis of biomarkers from the TARGET trial.⁷³ They found that some biomarkers were prognostic on univariate analysis, but that only TIMP-1 remained significant in multivariate analysis, together with the ECOG performance status and MSKCC score. However, no biomarker was found to be predictive of benefit from sorafenib. VHL gene inactivation was studied as a predictive factor of response, but in a cohort of patients mostly treated with sunitinib, and results were not reproduced by other groups.⁷⁴ A recent study provided evidence of a “cytokine and angiogenic factor signature” which could be predictive of benefit in a randomized phase 2 study comparing sorafenib alone vs. sorafenib and interferon.⁷⁵ However, these results could only predict the benefit of adding interferon to sorafenib and should be confirmed in a prospective study.

Patient Preference

Patient-reported outcomes are increasingly considered of first importance for the evaluation of benefit from anticancer therapies. However, data on patient-reported outcomes or quality of life continue to be frequently missing in the literature. Concerning sorafenib, the TARGET trial and the phase 2 randomized trial of first-line sorafenib vs. interferon alpha 2a reported such results.^30,56 In the TARGET trial, quality of life and symptoms were significantly improved in the sorafenib arm when compared with placebo.⁵⁶ In the phase 2 of sorafenib vs. interferon alpha 2a, a statistically and clinically significant difference of 5.9 points in the FKSI-15 scales, as well as an 11 point difference in the FACT-BRM scale, were shown in favor of sorafenib.³⁰ This data suggest that sorafenib was better than interferon in preserving quality of life. The authors also report a greater satisfaction in the convenience of treatment.

Patient preference between different targeted therapies used in RCC is more difficult to analyze. In a collaborative work, Bellmunt et al tried to select the patients’ characteristics that could benefit from sorafenib treatment.⁷⁶ However, they did not discuss patients’ preferences, as data are clearly lacking. Very few head-to-head comparisons in a clinical trial were performed. In the publication of the AXIS trial, no data on quality of life under axitinib or sorafenib were presented.¹¹ However, the authors proposed a composite endpoint including progression, death and deterioration of symptoms, which favored the axitinib arm. The results of the phase 3 study comparing sorafenib to tivozanib were recently presented, with a toxicity profile apparently favorable to tivaozanib over sorafenib. However, this should be taken with caution, as no results on quality of life or patient preference were reported. In the TARGET trial, quality of life was improved as compared with placebo, but comparison with other trials of targeted therapies would be questionable, as the populations included differ greatly. Thus, no conclusion can be drawn about patient preference for the selection between sorafenib and others targeted therapies in RCC. Appropriately on this matter, the PISCES trial compared sunitinib to pazopanib in the first-line setting, the primary objective being patient-reported preference between the two treatments. The results were presented at the 2012 ASCO annual meeting and were in favor of pazopanib. Such data are still lacking for sorafenib, but would be of great interest.

Place in Therapy

Guidelines

There are different guidelines for treatment of metastatic RCC. They are all based on the results of large trials, but differ somewhat on the interpretation of data concerning sorafenib use. While the National Comprehensive Cancer Network (NCCN)⁷⁷ guidelines recommend use of sorafenib in the first-line setting, the European Society of Medical Oncology (ESMO)⁷⁸ and the European Association of Urology (EAU)⁷⁹ guidelines do not. However, all guidelines agree in recommending the use of sorafenib in the second-line setting after treatment by cytokines (which is the main population included in the TARGET trial but a waning practice in current clinical methods), and agree in considering sorafenib as an option for treatment for non-clear-cell RCC.

Sequential or combination treatment

With the clinical use of targeted agents, other practices have emerged, even if strong evidence does not exist supporting them. Sorafenib is commonly used after pretreatment with sunitinib or mTOR inhibitors.⁸⁰ Questions were raised whether targeted therapies should be used in combination or in sequence. Indeed, mTOR acts downstream of VEGFR signaling, and mTOR inhibitors could increase the effects of VEGF-targeting agents. Moreover, mTOR induced stabilization of HIFα protein, increasing its pathway and VEGF secretion. Preclinical data suggest synergism between VEGFR TKIs and mTOR inhibitors.¹⁹ Sorafenib was also tested in combination with chemotherapy.⁸¹ However, most phase 1 trials of combination showed excessive toxicity, with the exception of the sorafenib-everolimus combination.^82–86 Moreover, sequential treatments appear feasible in clinical practice, and data on efficacy in the clinics have emerged, albeit partial and prone to biases. Reintroduction of sorafenib after previous failure was also associated with efficacy in some cases, as well as dose escalation.^87,88

Some studies raised the possibility of better efficacy in the sorafenib-sunitinib sequence when compared to the sunitinib-sorafenib sequence.^89–95 However, additional studies did not report the same results. Another debate was the best sequence after failure of a VEGFR TKI–-should the patient be treated with an mTOR inhibitor, then another VEGFR TKI, or in the reverse sequence? Once again, conflicting results were published.^60,80 To date, no recommendations can be on best sequence of treatment. Only trials of different strategies may help answer the question, such as the SWITCH trial (NCT01481870), which compares the sunitinib-sorafenib sequence with the sorafenib-sunitinib sequence.

A final setting where the use of targeted therapies is debated is the neoadjuvant setting.⁹⁶ One phase 2 trial discussed the opportunity to use sorafenib before surgery.⁹⁷ However, other VEGFR TKIs associated with higher response rates would probably become the treatment of choice in the rare indications where downstaging of locally advanced RCC is needed.

Conclusions

Sorafenib was the first VEGFR-TKI to be approved for treatment of RCC. Its efficacy was demonstrated in metastatic clear-cell RCC refractory to cytokines, but its clinical use exceeds this indication. Sorafenib is currently used as second-line or third-line treatment of metastatic clear-cell RCC, as well as in the treatment of non-clear-cell metastatic RCC. Questions remain about the best sequences of therapies in RCC, as well as about the development of predictive factor for benefit and appropriate evaluation of response. However, sorafenib will likely remain as one of the mainstays of RCC treatment over the next few years. Results on efficacy in the adjuvant setting are eagerly awaited.

Author Contributions

Wrote the first draft of the manuscript: JE. Contributed to the writing of the manuscript: JE, EV, NRL, CP, CV, KB, BL. Agree with manuscript results and conclusions: JE, EV, NRL, CP, CV, KB, BL. Jointly developed the structure and arguments for the paper: JE, EV, BL. Made critical revisions and approved final version: JE, EV, NRL, CP, CV, KB, BL. All authors reviewed and approved of the final manuscript.

Funding

Author(s) disclose no funding sources.

Competing Interests

CV has received payment from Roche for board membership and lectures, from Novartis for board membership and consultancy, and from Amgen for consultancy. All other authors disclose no competing interests.

Disclosures and Ethics

As a requirement of publication author(s) have provided to the publisher signed confirmation of compliance with legal and ethical obligations including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality and (where applicable) protection of human and animal research subjects. The authors have read and confirmed their agreement with the ICMJE authorship and conflict of interest criteria. The authors have also confirmed that this article is unique and not under consideration or published in any other publication, and that they have permission from rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest. Provenance: the authors were invited to submit this paper.

References

Iliopoulos

Molecular biology of renal cell cancer and the identification of therapeutic targets. J Clin Oncol. Dec 10, 2006; 24(35): 5593–600.

Ferrara

, Gerber

H-P

, LeCouter

The biology of VEGF and its receptors. Nat Med. Jun 2003; 9(6): 669–76.

Sabatini

D.M.

Mtor and cancer: insights into a complex relationship. Nat Rev Cancer. Sep 2006; 6(9): 729–34. Epub Aug 17, 2006.

Foster

, Prowse

, van den Berg

. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. Dec 1994; 3(12): 2169–73.

Cook

K.M.

, Figg

W.D.

Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. Jul-Aug 2010; 60(4): 222–43. Epub Jun 16, 2010.

Patard

J-J

, Rioux-Leclercq

, Masson

. Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma. Br J Cancer. Oct 20, 2009; 101(8): 1417–24. Epub Sep 15, 2009.

Escudier

, Eisen

, Stadler

W.M.

. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356: 125–13.

Motzer

R.J.

, Hutson

, Pharm

. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. N Engl J Med. Jan 11, 2007; 356(2): 115–24.

Escudier

, Pluzanska

, Koralewski

. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. Dec 22, 2007; 370(9605): 2103–11.

10.

Sternberg

C.N.

, Davis

I.D.

, Mardiak

. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. Feb 20, 2010; 28(6): 1061–8. Epub Jan 25, 2010.

11.

Rini

B.I.

, Escudier

, Tomczak

. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (axis): a randomised phase 3 trial. Lancet. Dec 3, 2011; 378(9807): 1931–9. Epub Nov 4, 2011.

12.

Hudes

, Carducci

, Tomczak

. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. May 31, 2007; 356(22): 2271–81.

13.

Motzer

R.J.

, Escudier

, Oudard

. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. Aug 9, 2008; 372(9637): 449–56. Epub Jul 22, 2008.

14.

Kane

R.C.

, Farrell

A.T.

, Saber

. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006: 7271–8.

15.

Negrier

, Raymond

Antiangiogenic treatments and mechanisms of action in renal cell carcinoma. Invest New Drugs. Aug 2012; 30(4): 1791–801. Epub May 15, 2011.

16.

Wilhelm

S.M.

, Carter

, Tang

. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. Oct 1, 2004; 64(19): 7099–109.

17.

Murphy

D.A.

, Makonnen

, Lassoued

. Inhibition of tumor endothelial erk activation, angiogenesis, and tumor growth by sorafenib (bay43-9006). Am J Pathol. Nov 2006; 169(5): 1875–85.

18.

Chang

Y.S.

, Adnane

, Trail

P.A.

. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. Apr 2007; 59(5): 561–74. Epub Dec 8, 2006.

19.

Martin

, Edeline

, Patard

J.J.

. Combination of temsirolimus and tyrosine kinase inhibitors in renal carcinoma and endothelial cell lines. J Cancer Res Clin Oncol. Jun 2012; 138(6): 907–16. Epub Feb 10, 2012.

20.

Moore

, Hirte

H.W.

, Siu

. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol. Oct 2005; 16(10): 1688–94. Epub Jul 8, 2005.

21.

van Erp

N.P.

, Gelderblom

, Guchelaar

H.J.

Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. Dec 2009; 35(8): 692–706. Epub Sep 5, 2009.

22.

Strumberg

, Richly

, Hilger

R.A.

. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. Feb 10, 2005; 23(5): 965–72. Epub Dec 21, 2004.

23.

Lathia

, Lettieri

, Cihon

. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol. May 2006; 57(5): 685–92. Epub Aug 25, 2005.

24.

Flaherty

K.T.

, Lathia

, Frye

R.F.

. Interaction of sorafenib and cytochrome p450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. Nov 2011; 68(5): 1111–8. Epub Feb 25, 2011.

25.

Peer

C.J.

, Sissung

T.M.

, Kim

. Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia. Clin Cancer Res. Apr 1, 2012; 18(7): 2099–107. Epub Feb 3, 2012.

26.

Clark

J.W.

, Eder

J.P.

, Ryan

. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. Aug 1, 2005; 11(15): 5472–80.

27.

Awada

, Hendlisz

, Gil

. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer. May 23, 2005; 92(10): 1855–61.

28.

Strumberg

, Clark

J.W.

, Awada

. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist. Apr 2007; 12(4): 426–37.

29.

Ratain

M.J.

, Eisen

, Stadler

W.M.

. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. Jun 1, 2006; 24(16): 2505–12. Epub Apr 24, 2006.

30.

Escudier

, Szczylik

, Hutson

T.E.

. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. Mar 10, 2009; 27(8): 1280–9. Epub Jan 26, 2009.

31.

Beck

, Procopio

, Bajetta

. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. Aug 2011; 22(8): 1812–23. Epub Feb 15, 2011.

32.

Stadler

W.M.

, Figlin

R.A.

, McDermott

D.F.

. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. Mar 1, 2010; 116(5): 1272–80.

33.

Eisen

Adjuvant therapy in renal cell carcinoma: where are we?

European Urology Supplements. Mar 6, 2007: 492–8.

34.

Schutz

F.A.B.

, Je

, Richards

C.J.

. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol. Mar 10, 2012; 30(8): 871–7. Epub Feb 6, 2012.

35.

Ravaud

, Sire

Arterial hypertension and clinical benefit of sunitinib, sorafenib and bevacizumab in first and second-line treatment of metastatic renal cell cancer. Ann Oncol. May 2009; 20(5): 966–7; author reply 967.

36.

Tamaskar

, Bukowski

, Elson

. Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol. Feb 2008; 19(2): 265–8. Epub Oct 24, 2007.

37.

Miyake

, Kurahashi

, Yamanaka

. Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation. Urol Oncol. Sep-Oct 2010; 28(5): 515–9. Epub Nov 13, 2009.

38.

Chu

T.F.

, Rupnick

M.A.

, Kerkela

. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. Dec 15, 2007; 370(9604): 2011–9.

39.

Orphanos

G.S.

, Ioannidis

G.N.

, Ardavanis

A.G.

Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol. 2009; 48(7): 964–70.

40.

Schmidinger

, Zielinski

C.C.

, Vogl

U.M.

. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. Nov 10, 2008; 26(32): 5204–12. Epub Oct 6, 2008.

41.

Tolcher

A.W.

, Appleman

L.J.

, Shapiro

G.I.

. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol. Apr 2011; 67(4): 751–64. Epub Jun 3, 2010.

42.

Hutson

T.E.

, Bellmunt

, Porta

. Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III target. Eur J Cancer. Sep 2010; 46(13): 2432–40. Epub Jul 23, 2010.

43.

Bukowski

R.M.

, Stadler

W.M.

, McDermott

D.F.

. Safety and efficacy of sorafenib in elderly patients treated in the North American advanced renal cell carcinoma sorafenib expanded access program. Oncology. 2010; 78(5-6): 340–7. Epub Aug 20, 2010.

44.

Eisen

, Oudard

, Szczylik

. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. Oct 15, 2008; 100(20): 1454–63. Epub Oct 7, 2008.

45.

Massard

, Zonierek

, Gross-Goupil

. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol. May 2010; 21(5): 1027–31. Epub Oct 22, 2009.

46.

Miller

A.A.

, Murry

D.J.

, Owzar

. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. Apr 10, 2009; 27(11): 1800–5. Epub Mar 2, 2009.

47.

Edmonds

, Hull

, Spencer-Shaw

. Strategies for assessing and managing the adverse events of sorafenib and other targeted therapies in the treatment of renal cell and hepatocellular carcinoma: recommendations from a European nursing task group. Eur J Oncol Nurs. Apr 2012; 16(2): 172–84. Epub Jun 8, 2011.

48.

Izzedine

, Ederhy

, Goldwasser

. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. May 2009; 20(5): 807–15. Epub Jan 15, 2009.

49.

Chu

, Lacouture

M.E.

, Fillos

, Wu

Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 2008; 47(2): 176–86.

50.

Procopio

, Verzoni

, Bracarda

. Sorafenib with interleukin-2 vs. sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial. Br J Cancer. Apr 12, 2011; 104(8): 1256–61. Epub Mar 29, 2011.

51.

Gollob

J.A.

, Rathmell

W.K.

, Richmond

T.M.

. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol. Aug 1, 2007; 25(22): 3288–95.

52.

Escudier

, Lassau

, Angevin

. Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res. Mar 15, 2007; 13(6): 1801–9.

53.

Ryan

C.W.

, Goldman

B.H.

, Lara

P.N.

Jr. . Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol. Aug 1, 2007; 25(22): 3296–301.

54.

Jonasch

, Corn

, Pagliaro

L.C.

. Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis. Cancer. Jan 1, 2010; 116(1): 57–65.

55.

Escudier

, Eisen

, Stadler

W.M.

. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. Jul 10, 2009; 27(20): 3312–8. Epub May 18, 2009.

56.

Bukowski

, Cella

, Gondek

. Effects of sorafenib on symptoms and quality of life: results from a large randomized placebo-controlled study in renal cancer. Am J Clin Oncol. Jun 2007; 30(3): 220–7.

57.

Hoyle

, Green

, Thompson-Coon

. Cost-effectiveness of sorafenib for second-line treatment of advanced renal cell carcinoma. Value Health. Jan-Feb 2010; 13(1): 55–60. Epub Sep 25, 2009.

58.

Tamaskar

, Garcia

J.A.

, Elson

. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol. Jan 2008; 179(1): 81–6; discussion 86. Epub Nov 12, 2007.

59.

Di Lorenzo

, Carteni

, Autorino

. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. Sep 20, 2009; 27(27): 4469–74. Epub Aug 3, 2009.

60.

Vickers

M.M.

, Choueiri

T.K.

, Rogers

. Clinical outcome in metastatic renal cell carcinoma patients after failure of initial vascular endothelial growth factor-targeted therapy. Urology. Aug 2010; 76(2): 430–4. Epub Mar 12, 2010.

61.

Di Lorenzo

, Buonerba

, Federico

. Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma. Eur Urol. Dec 2010; 58(6): 906–11. Epub Sep 24, 2010.

62.

Choueiri

T.K.

, Plantade

, Elson

. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. Jan 1, 2008; 26(1): 127–31.

63.

Golshayan

A.R.

, George

, Heng

D.Y.

. Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. J Clin Oncol. Jan 10, 2009; 27(2): 235–41. Epub Dec 8, 2008.

64.

Smith

A.D.

, Shah

S.N.

, Rini

B.I.

, Lieber

M.L.

, Remer

E.M.

Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR Am J Roentgenol. Jun 2010; 194(6): 1470–8.

65.

Fournier

L.S.

, Oudard

, Thiam

. Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT. Radiology. Aug 2010; 256(2): 511–8. Epub Jun 15, 2010.

66.

Hahn

O.M.

, Yang

, Medved

. Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol. Oct 1, 2008; 26(28): 4572–8.

67.

Flaherty

K.T.

, Rosen

M.A.

, Heitjan

D.F.

. Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol Ther. Apr 2008; 7(4): 496–501. Epub Jan 22, 2008.

68.

Krajewski

K.M.

, Guo

, Van den Abbeele

A.D.

. Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma. Eur Urol. May 2011; 59(5): 856–62. Epub Feb 1, 2011.

69.

Lamuraglia

, Escudier

, Chami

. To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer. Oct 2006; 42(15): 2472–9. Epub Sep 11, 2006.

70.

Ueno

, Yao

, Tateishi

. Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course. BMC Cancer. May 2, 2012; 12(1): 162.

71.

Tonini

, Fratto

M.E.

, Imperatori

. Predictive factors of response to treatment in patients with metastatic renal cell carcinoma: new evidence. Expert Rev Anticancer Ther. Jun 2011; 11(6): 921–30.

72.

Choueiri

T.K.

, Garcia

J.A.

, Elson

. Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. Cancer. Aug 1, 2007; 110(3): 543–50.

73.

Pena

, Lathia

, Shan

. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: Results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res. Oct 1, 2010; 16(19): 4853–63. Epub Jul 22, 2010.

74.

Choueiri

T.K.

, Vaziri

S.A.J.

, Jaeger

. von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol. Sep 2008; 180(3): 860–5; discussion 865–6. Epub Jul 17, 2008.

75.

Zurita

A.J.

, Jonasch

, Wang

. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol. Jan 2012; 23(1): 46–52. Epub Apr 4, 2011.

76.

Bellmunt

, Eisen

, Szczylik

, Mulders

, Porta

A new patient-focused approach to the treatment of metastatic renal cell carcinoma: establishing customized treatment options. BJU Int. Apr 2011; 107(8): 1190–9. doi: 10.1111/j.1464-410X.2010.09829.x. Epub Nov 15, 2010.

77.

Saylor

P.J.

, Michaelson

M.D.

New treatments for renal cell carcinoma: targeted therapies. J Natl Compr Canc Netw. Jun 2009; 7(6): 645–56.

78.

Escudier

, Kataja

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. May 2010; 21 Suppl 5: v137–9.

79.

Ljungberg

, Cowan

N.C.

, Hanbury

D.C.

. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. Sep 2010; 58(3): 398–406. Epub Jul 12, 2010.

80.

Porta

, Szczylik

, Escudier

Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: a critical review. Crit Rev Oncol Hematol. Jun 2012; 82(3): 323–7. Epub Jul 5, 2011.

81.

Bellmunt

, Trigo

J.M.

, Calvo

. Activity of a multitargeted chemo switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-6). Lancet Oncol. Apr 2010; 11(4): 350–7. Epub Feb 15, 2010.

82.

Patel

P.H.

, Senico

P.L.

, Curiel

R.E.

. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. Jan 2009; 7(1): 24–7.

83.

Patnaik

A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies. [abstract]. J Clin Oncol. 2007; 25: 3512.

84.

Soria

J.C.

, Massard

, Izzedine

From theoretical synergy to clinical supra-additive toxicity. J Clin Oncol. Mar 20, 2009; 27(9): 1359–61. Epub Feb 17, 2009.

85.

Negrier

, Gravis

, Perol

. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. Jul 2011; 12(7): 673–80. Epub Jun 12, 2011.

86.

Harzstark

A.L.

, Small

E.J.

, Weinberg

V.K.

. A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer. Sep 15, 2011; 117(18): 4194–200. doi: 10.1002/cncr.25931. Epub Mar 8, 2011.

87.

Nozawa

, Yamamoto

, Minami

. Sorafenib rechallenge in patients with metastatic renal cell carcinoma. BJU Int. Feb 14, 2012. doi: 10.1111/j.1464-410X.2011.10905.x. [Epub ahead of print.]

88.

Amato

, Zhai

, Willis

. A phase II trial of intrapatient dose-escalated sorafenib in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. Sep 2012; 10(3): 15315–8. Epub May 1, 2012.

89.

Sablin

M.P.

, Negrier

, Ravaud

. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. Jul 2009; 182(1): 29–34; discussion 34. Epub May 17, 2009.

90.

Porta

, Procopio

, Carteni

. Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma (RCC): an Italian multicentre retrospective analysis of 189 patient cases. BJU Int. Oct 2011; 108(8 Pt 2): E250–7. doi: 10.1111/j.1464-410X.2011.10186.x. Epub May 23, 2011.

91.

Calvani

, Morelli

, Leo

. Sequential use of sorafenib and sunitinib in advanced renal cell carcinoma: does the order of sequencing matter? Med Oncol. Aug 20, 2011. [Epub ahead of print.]

92.

Buchler

, Klapka

, Melichar

. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma—data from the Czech registry. Ann Oncol. Feb 2012; 23(2): 395–401. Epub May 2, 2011.

93.

Dudek

A.Z.

, Zolnierek

, Dham

. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. Jan 1, 2009; 115(1): 61–7.

94.

Eichelberg

, Heuer

, Chun

F.K.

. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis. Eur Urol. Dec 2008; 54(6): 1373–8. Epub Aug 8, 2008.

95.

Herrmann

, Marschner

, Grimm

M.O.

. Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma. World J Urol. Jun 2011; 29(3): 361–6. Epub Apr 3, 2011.

96.

Ficarra

, Novara

Kidney cancer: neoadjuvant targeted therapies in renal cell carcinoma. Nature reviews. Urol Oncol. Jan-Feb 2010; 28(1): 69–73.

97.

Cowey

C.L.

, Amin

, Pruthi

R.S.

. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol. Mar 20, 2010; 28(9): 1502–7. Epub Feb 16, 2010.