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Molecularly targeted therapy for advanced renal cell carcinoma

Last literature review version 18.2: May 2010 | This topic last updated: June 16, 2010 (More)

INTRODUCTION — Surgical resection of localized renal cell cancer (RCC) can be curative for localized disease, but many patients recur after surgery. In addition, many RCCs are clinically silent for much of their course, and the initial diagnosis is often delayed until disease is either locally advanced and unresectable or metastatic. The prognosis for advanced RCC is generally poor, although patient selection has a major impact on survival in different series. (See "Overview of the prognosis and treatment of renal cell carcinoma".)

RCCs evoke an immune response, which has occasionally resulted in spontaneous and dramatic remissions. In an attempt to reproduce or accentuate this response, various immunotherapeutic strategies have been used. High-dose bolus interleukin-2 (IL-2) is the most widely used and has been associated with durable complete remissions in about 10 percent of patients. However, the widespread use of high-dose IL-2 is limited by severe toxicity and the need for specialized care during treatment. (See "Immunotherapy of renal cell carcinoma".)

An understanding of the pathogenesis RCC at the molecular level has resulted in the identification of specific targets for therapeutic intervention (figure 1 and figure 2). This has led to the development of "molecularly targeted therapies" that are rapidly being integrated into the management of patients with advanced RCC.

These molecularly targeted agents and their application in patients with advanced RCC will be reviewed here. Other aspects of the prognosis and management of RCC are discussed separately. (See "Overview of the prognosis and treatment of renal cell carcinoma".)

MOLECULAR PATHOGENESIS — Approximately 65 to 75 percent of renal epithelial tumors are of the conventional or clear cell type, while the remainder consist of papillary (chromophilic), chromophobe, collecting duct, and medullary carcinomas, as well as oncocytomas. The different RCC subtypes are increasingly being characterized by unique genetic abnormalities and associated gene expression patterns [1,2]. The pathogenesis of clear cell carcinoma is the best understood. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)

The initial insights into the molecular pathogenesis of clear cell RCC came from studies in patients with von Hippel-Lindau (VHL) disease, a familial cancer syndrome. VHL, an autosomal dominantly inherited syndrome, is characterized by the development of cerebellar and spinal hemangioblastomas, retinal angiomas, pheochromocytomas, and renal cysts and tumors. Clear cell RCCs develop in 40 to 60 percent of patients; these tend to be multicentric and bilateral with an unusually early age of onset. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Genetic analyses of VHL-associated RCCs showed loss of heterozygosity at the VHL locus on chromosome 3p25, and the same abnormality is present in 75 to 80 percent of sporadic clear cell RCCs. These findings implicated the VHL gene in the pathogenesis of clear cell RCCs. The molecular consequences of this abnormality result in the overproduction of vascular endothelial growth factor (VEGF) and the activation of a number of signaling pathways (figure 1 and figure 2). (See "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

VEGF is probably the most important growth factor that is involved in tumor angiogenesis, and it plays a significant role in the growth and progression of many types of human cancer, including RCC. Elucidation of the downstream pathways from the VEGF receptor has defined a number of targets for interruption of the signaling pathways resulting in angiogenesis. The most promising results have been seen with small molecules that inhibit signaling through the VEGF receptor pathway and with monoclonal antibodies (MoAbs) that neutralize circulating VEGF. (See "Overview of angiogenesis inhibitors", section on 'VEGF receptors'.)

An alternative pathway is mediated by the mammalian target of rapamycin (mTOR), which is downstream of the phosphoinositide 3-kinase and Akt (figure 1) and is regulated by the PTEN tumor suppressor gene. Inhibition of this pathway by agents such as temsirolimus leads to decreased protein translation and can thereby inhibit both angiogenesis and tumor cell proliferation.

VEGF PATHWAY INHIBITION — Two different approaches have clinical activity in blocking the VEGF pathway (figure 1 and figure 2): the use of small molecule tyrosine kinase (TK) inhibitors (sunitinib, sorafenib, pazopanib) to block the intracellular domain of the VEGF receptor and a monoclonal antibody (eg, bevacizumab) to bind circulating VEGF and prevent its activating the VEGF receptor [3].

Most clinical data with these agents are derived from studies in patients with typical clear cell RCC. In retrospective analyses, VEGF pathway inhibition has had some activity in patients with a sarcomatoid component in their RCC, although the prognosis is less favorable [4].

Sunitinib — Sunitinib inhibits the VEGF receptor TK, as well as other TKs associated with the platelet-derived growth factor (PDGF) receptor and c-kit oncogene. Sunitinib has an important role in the initial management of patients with advanced RCC who are not candidates for treatment with high-dose IL-2.

Phase II studies — Antitumor activity and safety were demonstrated in two phase II trials that included 169 patients with measurable advanced RCC who had failed one prior cytokine-based therapy [5,6].

The activity of sunitinib in this setting was illustrated by the results of a phase II study, in which there were 25 partial responders (40 percent) among the 63 enrolled patients, eight of whom remained progression-free for 21+ to 24+ months [5]. Twenty-four of the 25 responders had clear cell histology. The median time to tumor progression and median survival durations for the entire group were 8.7 and 16.4 months, respectively. In the other trial, results were similar with an overall response rate of 34 percent and a median time to progression of 8.3 months [6].

The toxicity observed with sunitinib and other VEGF TK inhibitors is discussed below. (See 'Toxicity of VEGF TK inhibitors' below.)

First-line therapy — Sunitinib was evaluated in a phase III trial of 750 patients with largely good- or intermediate-prognosis metastatic clear cell RCC who had not received prior systemic treatment [7]. Patients were randomly assigned to six-week cycles of sunitinib (50 mg daily for four weeks, followed by two weeks off) or interferon alfa (IFNa 9 million units three times per week). Results were updated at the ASCO meetings in June 2007 and June 2008 [8,9].

Key observations include the following:

• The objective response rate was significantly increased with sunitinib (39 versus 8 percent with IFNa) [8].
• Median progression-free survival was significantly prolonged (11 versus 5 months, hazard ratio [HR] 0.54) [8]. This benefit included patients at good, intermediate, and poor risk (progression-free survival 14.5 versus 7.9, 10.6 versus 3.8, and 3.7 versus 1.2 months, respectively).
• The final analysis of the trial showed that overall survival was prolonged with sunitinib (median 26.4 versus 21.8 months, hazard ratio [HR] 0.82, 95% CI 0.67-1.00, p=0.051) [9]. The analysis of overall survival was complicated by post protocol treatment of over one-half of all patients on both arms with VEGF pathway inhibitors. Overall, 33 percent of patients assigned to IFN subsequently were treated with sunitinib, and approximately one-third of patients on both arms received treatment with another VEGF TK inhibitor after completing the protocol. Multivariate analysis of survival based upon the pretreatment stratification parameters and treatment assignment found that initial treatment with sunitinib was a statistically significant predictor of prolonged survival.

Sorafenib — Sorafenib is a potent small molecule inhibitor of multiple TKs including VEGF receptor 2, FLT3, platelet derived growth factor (PDGF) receptor, and fibroblast growth factor receptor-1 (FGFR1) (figure 1 and figure 2). It also inhibits C-raf and both mutant and wild-type B-raf. Raf kinase is an important mediator of the Ras/Raf/MEK pathway. Although activating mutations in B-raf (BRAF) have not been identified in RCC, constitutive activation in the B-raf pathway (Raf, MEK, and ERK) has been observed in approximately 50 percent of tumors [10].

Previously treated patients — The activity of sorafenib in advanced RCC was demonstrated in two placebo-controlled trials in previously treated patients [11-13].

In the phase III TARGET trial, 903 patients with advanced RCC who had failed prior standard therapy were randomly assigned to sorafenib (400 mg orally twice daily) or placebo [12]. Based upon results at the first planned interim analysis, the study was amended to allow those patients originally assigned to placebo to cross over and receive sorafenib, potentially obscuring differences in survival due to treatment.

Key findings included:

• Based upon a protocol-defined independent review of 769 patients, the median progression-free survival was significantly longer in those receiving sorafenib (5.5 versus 2.8 months with placebo, HR for progression 0.44, 95% CI 0.35-0.55).
• In the final intention-to-treat analysis of all patients enrolled in this trial [13], overall survival with sorafenib was not significantly prolonged compared to placebo (median 17.8 versus 15.2 months, HR 0.88, 95% CI 0.74-1.04) [13].
• In a secondary analysis [13], sorafenib significantly improved survival when patients who had received sorafenib after progressing on placebo were censored (median 17.8 versus 14.3 months, HR 0.78, 95% CI 0.62-0.97).
• In another analysis from this trial, sorafenib appeared to be effective in carefully selected older patients [14]. Older patients (≥70 years) treated with sorafenib had a significant improvement in progression-free survival (26 versus 14 weeks with placebo), without an apparent increase in toxicity.

The toxicity observed with sorafenib and other VEGF TK inhibitors is discussed below. (See 'Toxicity of VEGF TK inhibitors' below.)

Untreated patients — The role of sorafenib compared to IFNa and other targeted agents in previously untreated patients is less clear.

Sorafenib was compared to IFNa in a randomized phase II trial in good- and intermediate-risk patients with previously untreated advanced RCC [15]. Patients were randomly assigned to sorafenib (400 mg by mouth twice a day) or IFNa (9 million units three times per week). At progression, patients originally assigned to sorafenib were allowed to dose escalate to sorafenib 600 mg by mouth twice a day, while those who had been assigned to IFNa could be crossed over to sorafenib (400 mg twice a day).

Key results included the following:

• During the initial treatment phase, quality of life and percentage of patients achieving tumor shrinkage were greater with sorafenib than IFNa.
• However, there was no increase in progression-free survival with sorafenib (5.7 versus 5.6 months with IFNa, HR 1.14, 95% CI 0.61-1.27) during the initial phase of the trial.
• Dose escalation to 600 mg twice a day was well tolerated in patients who were tolerating 400 mg twice a day and associated with an additional period of progression-free survival of four months.

Dose escalation — The original trials with sorafenib indicated that a dose of 400 mg twice a day was well tolerated and associated with antitumor activity. Subsequent clinical trials have indicated that dose escalation is feasible and may be associated with increased antitumor activity [15,16].

The possible utility of dose escalation was illustrated by a phase II study in 44 patients with advanced RCC presented at ASCO in June 2007 [16]. Each patient was initially treated with sorafenib 800 mg/day (400 mg twice a day) for 28 days. If this was well tolerated, the dose was escalated to 1200 mg/day for another 28 days and then to 1600 mg/day. Overall 41 of 44 patients (93 percent) were able to escalate to 1200 mg/day, and 32 were treated at 1600 mg/day. Treatment at the higher doses was well tolerated, with a similar toxicity profile. Overall, objective responses were observed in 55 percent of patients, including seven complete and 17 partial responses. Although median PFS was 8.4 months, median overall survival was surprisingly short (11 months).

Additional clinical trials will be required to determine the role of sorafenib dose escalation in the management of patients with advanced RCC.

Pazopanib — Pazopanib is an oral agent that targets the tyrosine kinases associated with the VEGFR, PDGFR, and Kit receptor.

In a phase III trial, 435 patients, who were previously untreated or had received only cytokine therapy, were randomly assigned to pazopanib or placebo [17]. Almost all patients were good or intermediate risk.

There was a significant increase in progression-free survival with pazopanib (median 9.2 versus 4.2 months with placebo, hazard ratio [HR] 0.46, 95% CI 0.34-0.62), with significant increases both in those previously untreated and in those who had received cytokine therapy [17]. In a preliminary report, there was a nonsignificant improvement in overall survival at the interim analysis (median 21.1 versus 18.7 months, HR 0.73), even though patients were allowed to cross over to pazopanib when they progressed on active treatment [18].

Treatment was generally well tolerated. The most frequent toxicities were consistent with other agents in this class, and included diarrhea, hypertension, changes in hair color, nausea, anorexia, and vomiting, all of which were observed in 20 percent or more of patients.

Clinically significant abnormalities in liver function tests were observed in approximately 10 percent of patients, and these may require dose reduction in patients with abnormal liver function tests. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Pazopanib'.)

Polymorphisms in the uridine diphosphoglucuronosyltransferase 1A1 (UGT 1A1) enzyme that cause Gilbert's syndrome (the UGT1A1*28 allele) may be associated with pazopanib-induced hyperbilirubinemia [19]. Isolated hyperbilirubinemia in these patients may represent a benign manifestation of Gilbert's syndrome, and continuation of pazopanib monotherapy is reasonable in this setting. (See "Gilbert's syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

Hemorrhagic complications were more frequent with pazopanib than with placebo (13 versus 5 percent). There was a notable absence of myelosuppression, with severe neutropenia and/or thrombocytopenia present in about 1 percent of cases.

Pazopanib (Votrient) was approved by the United States Food and Administration in October 2009, based upon the results of this phase III trial.

Brain metastases — Regression of RCC brain metastases has been documented in case reports following treatment with both sunitinib and sorafenib [20-24]. Possible additional evidence of central nervous system activity comes from an analysis of 139 patients treated at two centers in the TARGET trial, in which previously treated patients with advanced RCC were randomly assigned to sorafenib or placebo [25]. Patients treated with sorafenib had a statistically significant decrease in the risk of developing brain metastases compared to those given placebo (3 versus 12 percent).

However, these agents may have deleterious effects, particularly when treatment is first started. In an observational study of 67 patients who were treated with either sunitinib or sorafenib, five patients died of an intracerebral hemorrhage within two weeks after initiating therapy [26]. Four of these five had known brain metastases and, among all seven patients with known brain metastases, four had a fatal intracerebral hemorrhage.

Until additional information on the risk of intracerebral hemorrhage is available, it is reasonable to consider imaging the head with MRI or CT prior to starting treatment with a TK inhibitor. Metastases should be treated prior to initiating therapy when possible. (See "Treatment of brain metastases in favorable prognosis patients".)

Novel TK inhibitors — Other small molecule TK inhibitors that block the intracellular domain of the VEGF receptor and other receptor tyrosine kinases are being developed to treat patients with metastatic RCC. These include axitinib, cediranib, AV-951, and BAY 73-4506 [27-32].

The development of these agents will require randomized clinical trials to assess their efficacy compared to other agents.

Toxicity of VEGF TK inhibitors — Although there are differences among these agents, some toxicities are common to this class.

Hypertension and renal toxicity — Both sunitinib and sorafenib are associated with hypertension and less commonly, renal disease.

• A systematic review analyzed the incidence of hypertension in 4599 patients treated with sorafenib in nine prospective studies [33]. These reports included patients with RCC as well as other malignancies. New onset hypertension was reported in 23 percent of cases (relative risk 6.1 compared to controls), and was severe or life-threatening in 6 percent.
• Almost identical findings were noted in a meta-analysis that analyzed the incidence of hypertension in 13 prospective studies with 4999 patients who were treated with sunitinib for RCC or other malignancies [34]. The overall incidence of developing hypertension was 22 percent, and severe hypertension was present in 7 percent. A statistically significant increase in the incidence of renal dysfunction was also observed (relative risk [RR] 1.36).
• A syndrome of reversible hypertension, proteinuria, and hypoalbuminemia has been described in seven patients treated with sunitinib or sorafenib [35].

Based upon these observations, patients treated with sunitinib or sorafenib should be monitored for the development or worsening of hypertension which, if present, should be treated appropriately (table 1A-B). Guidelines for risk assessment and management of hypertension have been published [36].

The development of hypertension with sunitinib treatment may be a predictor of an improved response to therapy. In a combined series based upon four prospective trials that included 544 patients, the development of systolic or diastolic hypertension was associated with a statistically significant improvement in progression-free survival and overall survival on multivariate analysis [37].

Arterial thromboembolism — VEGF TK inhibitors are associated with an increased risk of arterial thromboembolic events. In a systematic review and meta-analysis that included 10,255 patients (8886 with RCC) treated with sunitinib or sorafenib in 10 trials, the incidence of arterial thromboembolic events was 1.4 percent (relative risk 3.0 compared to controls) [38]. A similar rate of arterial thromboembolism was reported in the phase III trial with pazopanib [18]. (See "Drug-induced thrombosis and vascular disease in patients with malignancy".)

Cardiotoxicity — Cardiac toxicity, manifested as a decrease in left ventricular ejection fraction, heart failure, or myocardial ischemia or infarction has been reported in patients treated with both of these agents. The cardiac complications of these agents are discussed separately. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Multitargeted tyrosine kinase inhibitors'.)

Thyroid dysfunction — Thyroid dysfunction has frequently been reported in patients with RCC treated with sunitinib. Typically this has been manifested by hypothyroidism, although transient thyrotoxicosis has also been reported.

The high frequency of hypothyroidism with sunitinib is illustrated by a single institution series of 73 patients treated with sunitinib, in which 56 patients (77 percent) had documented abnormalities in thyroid function tests consistent with hypothyroidism, 47 of whom had clinical signs or symptoms possibly related to hypothyroidism [39]. Thyroid hormone replacement was given to 17 patients, nine of whom noted an improvement in symptoms.

At least two reports have associated thyrotoxicosis with sunitinib treatment in patients with metastatic RCC [40,41]. In the larger report, six patients developed thyrotoxicosis after starting treatment with sunitinib, with four later exhibiting hypothyroidism [40]. Although some of these patients appeared to have a destructive thyroiditis, a case of lymphocytic thyroiditis accompanied by transient thyrotoxicosis has also been reported [42].

Thyroid dysfunction has also been reported in patients treated with sorafenib for metastatic RCC, but this appears to be less frequent [43,44]. This was illustrated by an analysis of thyroid function in 39 patients who were treated with sorafenib, in which hypothyroidism was noted in seven, hyperthyroidism in one, and nonthyroidal illness in eight [43]. Two of the hypothyroid patients were symptomatic and were given thyroid replacement therapy.

Because of the high prevalence of hypothyroidism, regular surveillance of TSH levels is warranted during sunitinib therapy. We suggest that thyroid function be evaluated at baseline and monitored at monthly intervals. (See "Diagnosis of and screening for hypothyroidism" and "Treatment of hypothyroidism".)

The mechanism by which hypothyroidism occurs with these agents is discussed separately. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Sunitinib'.)

Cutaneous toxicity — Hand-foot syndrome is a common cutaneous manifestation of toxicity with both sunitinib and sorafenib. Multiple case reports have also identified an association with keratoacanthomas and squamous cell carcinoma. (See "Cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy".)

Pancreatitis — Elevations of the pancreatic enzymes lipase and amylase have been reported with both sorafenib and sunitinib, although overt pancreatitis is rare [7,13].

Glucose metabolism — Blood glucose levels may be reduced in diabetic patients who are treated with sunitinib for metastatic RCC. In a retrospective series of 19 type II diabetic patients whose blood glucose was monitored at baseline and during treatment, blood glucose levels fell from 149 mg/dL at baseline to 117 mg/dL at four weeks (8.3 to 6.5 mmol/L) [45]. In contrast, blood glucose levels fell only minimally in nine nondiabetic patients (106 to 95 mg/dL [5.89 to 5.26 mmol/L]) who were similarly monitored. No serious episodes of hypoglycemia were reported. Blood glucose should be monitored in diabetic patients who are treated with sunitinib and antidiabetic medications adjusted if necessary.

Hepatotoxicity — Severe and occasionally fatal hepatotoxicity has been observed in clinical studies with pazopanib [46]. Patients treated with pazopanib should be monitored for evidence of liver toxicity, and treatment should be interrupted or discontinued is evidence of toxicity is observed. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease".)

Muscle wasting — Skeletal muscle wasting (sarcopenia) is common in patients with advanced cancer, and may also be an adverse effect of treatment. This loss of muscle mass appears to be additive to that due to advanced cancer and may contribute to asthenia and fatigue.

In a subset analysis of 80 patients treated in the Target trial, body weight was measured and skeletal muscle mass was serially assessed by CT [47]. At six months, sorafenib therapy was associated with a statistically significant decrease in total body weight and muscle mass compared to placebo (-2.1 versus +0.8 kg and -7.4 versus -3.1 cm2, respectively). The loss in weight and muscle mass in patients treated with sorafenib was progressive during treatment from 6 to 12 months. (See 'Previously treated patients' above.)

Bevacizumab — Bevacizumab is a monoclonal antibody that exerts its antiangiogenic effect by binding and neutralizing circulating VEGF. The initial evidence supporting the activity of bevacizumab in patients with advanced RCC came from a randomized phase II trial in which placebo or bevacizumab as a single agent was used in patients whose disease had progressed after immunotherapy [48].

Two phase III trials have yielded similar results, demonstrating the improved progression-free survival with bevacizumab plus interferon alfa (IFNa) compared to IFNa alone:

• In the AVOREN trial, 649 patients previously untreated patients were randomly assigned to interferon alfa (IFNa, 9 million units three times/week for one year) plus either bevacizumab (10 mg/kg every two weeks) or placebo [49-53]. The bevacizumab or placebo was continued until there was evidence of progressive disease.

Interferon plus bevacizumab resulted in the following changes compared to interferon plus placebo:

• - A statistically significant prolongation of progression-free survival with the combination (10.2 versus 5.5 months, HR 0.63, 95% CI 0.45-0.72) [50].
• - A significantly increased objective response rate (31 versus 13 percent) [50].
• - A statistically nonsignificant trend toward improved survival (median survival 23.3 versus 21.3 months, hazard ratio [HR] 0.86, 95% CI 0.72-1.04). Overall, more than one-half of patients received second-line therapy, generally with a molecularly targeted agent, thus potentially obscuring a survival difference between the two treatment arms [53].

Reducing the dose of IFNa dose did not reduce the progression-free survival compared to those receiving the full dose according to protocol [51], and it did not adversely affect overall survival (median 26.0 versus 23.3 months in the entire group treated with the combination) [50]. Given the lack of dose response for IFNa in RCC, the significance of this finding is uncertain.

Furthermore, additional analyses presented at the American Society of Clinical Oncology (ASCO) meeting in 2008 suggest that the benefit from adding bevacizumab to interferon was independent of tumor histology and pre-treatment VEGF levels [52].

Serious adverse events were more common in patients treated with bevacizumab plus IFNa (29 versus 16 percent with IFNa plus placebo) [49]. Grade 3 or 4 adverse events that were more common in patients treated with bevacizumab included thromboembolic events and gastrointestinal perforation (10 [3 percent] versus 3 [1 percent] and 4 [1 percent] versus 0 [0 percent], respectively).

• In the Cancer and Leukemia Group B (CALGB) trial 90206, 732 previously untreated patients with metastatic RCC were randomly assigned to either IFNa plus bevacizumab or IFNa plus placebo. Both IFNa and bevacizumab were given on a schedule similar to that used in the AVOREN trial [54].

The final results of this trial found that there was a trend toward improved overall survival (median 18.3 versus 17.4 months, HR 0.86, p= 0.07) [55]. The analysis of survival was complicated by the fact that more than one-half of patients on both arms received second-line therapy, including VEGF-targeted therapy in 46 percent of those originally treated with IFNa alone.

A previously published interim analysis found that progression-free survival was significantly increased in patients treated with the bevacizumab plus IFNa regimen (median 8.5 versus 5.2 months; hazard ratio 0.71, 0.61-0.83). There was also a statistically significant increase in the objective response rate (25.5 versus 13.1 percent).

Both of these phase III trials excluded patients with brain metastases because of the concerns about intracerebral hemorrhage. However, the risk of hemorrhage appears to be small and may not be significantly greater than the risk for patients with brain metastases who are not treated with bevacizumab. (See "Systemic chemotherapy for brain metastases".)

Hypertension is a frequent side effect of bevacizumab. Guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure in patients receiving bevacizumab are available (table 1A-B). This subject is discussed elsewhere. (See "Overview of angiogenesis inhibitors", section on 'Hypertension'.)

Based upon the results of these trials, bevacizumab was approved by the United States Food and Drug Administration for use in combination with interferon alfa for the treatment of patients with metastatic RCC [56].

Sequential inhibition of the VEGF pathway — Although both the TK inhibitors and bevacizumab are thought to act by interrupting the VEGF signaling pathway, tumors do not appear to be totally cross-resistant to sequential therapy with different agents [27,57,58].

As an example, in a phase II study in 52 patients who had progressed on sunitinib demonstrated objective responses to treatment with sorafenib in five cases (10 percent), with a median time to progression of 16 weeks [57]. In a similar phase II study of 62 patients previously treated with sorafenib, treatment with axitinib resulted in an objective response rate of 23 percent [27]. The median time to progression and overall survival were 7 and 14 months, respectively. (See 'Novel TK inhibitors' above.)

Despite the promising results with various VEGF pathway inhibitors in patients with advanced RCC, many questions remain regarding the optimal use of these agents, including which agent to use in a particular patient, when to start treatment, and what is the optimal sequence of available agents and treatment approaches. All of these questions require further study, and thus clinical trials are still important in patients with treatment naive advanced RCC.

TEMSIROLIMUS AND EVEROLIMUS — The mammalian target of rapamycin (mTOR) pathway is downstream of the phosphoinositide 3-kinase and Akt pathway that is regulated by the PTEN tumor suppressor gene (figure 1). Although mutations in PTEN have not been found in RCC, diminished protein expression with increased levels of phospho-Akt has been observed [59]. Activation of mTOR can also upregulate HIF-1 gene expression, which, in patients with VHL mutations, can magnify HIF accumulation and the expression of HIF-inducible genes [10]. Thus, inhibition of the mTOR pathway has the potential to inhibit tumor progression at multiple levels.

Both temsirolimus and everolimus have important clinical activity in patients with clear cell RCC.

Temsirolimus — Temsirolimus is a parenterally administered rapamycin analog that functions as a competitive inhibitor of mTOR kinase. Temsirolimus has important clinical activity in both untreated and previously treated patients with advanced RCC.

Refractory patients — In a randomized phase II trial, 111 patients with advanced RCC who either had received previous interferon or interleukin therapy for advanced disease or were not considered candidates for such therapy were randomly assigned to one of three different dose levels of temsirolimus (25, 75, or 250 mg, each as a 30 minute IV infusion weekly) [60]. The response rate for the total population was 7 percent (one complete and seven partial responses) [60]. Despite the low objective response rate, significant antitumor activity was suggested by the substantial number of patients with minor responses (26 percent) and stable disease for six months or longer (17 percent), as well as the relatively long time to progression (5.8 months) and overall median survival (15 months).

When patients were segregated according to prognostic factors for response to IFN-alfa [61], those with intermediate- and poor-prognosis disease appeared to benefit the most (median survival 19.3 versus 14 and 8.2 versus 5 months, respectively, compared to the MSKCC database) (table 2). This benefit occurred even though the patients were receiving temsirolimus as second- or third-line therapy.

Previously untreated patients — Based upon the phase II results, temsirolimus was evaluated in a phase III trial in which 626 previously untreated poor-prognosis patients with metastatic or recurrent RCC were randomly assigned to temsirolimus (25 mg IV/week), the combination of temsirolimus (15 mg IV/week) plus IFNa (escalated up to 6 million units three times per week as tolerated), or IFNa as monotherapy (escalated up to 18 million units three times per week as tolerated) [62].

Key results from this trial included the following:

• Temsirolimus as a single agent significantly prolonged the median overall survival compared to IFNa as a single agent (10.9 versus 7.3 months; HR for mortality 0.73, 95% CI 0.58-0.92).
• Temsirolimus significantly prolonged the median progression-free survival compared to single agent IFNa according to both the site investigator and independent radiologic assessment (3.8 versus 1.9 months and 5.5 versus 3.1 months, respectively). The independent assessment did not include clinical deterioration as a criterion, which may have accounted for the differences between the two analyses.
• Both overall and progression-free survival for the combination of temsirolimus plus IFNa were not significantly better than with IFNa alone. The inferior results may have been due to the lower dose intensity of temsirolimus in the combination arm (10.9 versus 23.1 mg/week with temsirolimus alone).
• In a subset analysis presented at ASCO in 2007, benefit was particularly noted in patients with non-clear cell histology [63].

Toxicity — Treatment with temsirolimus was generally well tolerated in these trials:

• In refractory patients, the most frequent side effects were maculopapular rash, mucositis, asthenia, and nausea (76, 70, 50, and 43 percent, respectively) [60]. Severe adverse events were uncommon however; the most frequent grade 3 or 4 adverse events were hyperglycemia, hypophosphatemia, anemia, and hypertriglyceridemia (17, 13, 9, and 6 percent, respectively).
• In previously untreated patients, temsirolimus was better tolerated than either IFNa alone or the combination of IFNa plus temsirolimus [62]. The most frequent serious adverse events with temsirolimus were asthenia and anemia (11 and 20 percent, respectively). Less severe adverse events that were more frequent with temsirolimus or the combination compared to IFNa alone included rash, peripheral edema, stomatitis, hyperlipidemia, hyperglycemia, and hypercholesterolemia.

Hypersensitivity reactions have also been reported and may be severe or life threatening [64]. Premedication with diphenhydramine (25 to 50 mg IV prior to each dose of temsirolimus) is recommended. The management of patients with a hypersensitivity reaction to temsirolimus is discussed separately. (See "Infusion reactions to systemic chemotherapy".)

Temsirolimus has been associated with pneumonitis in 0.5 to 5 percent of patients with cancer who were enrolled in clinical studies; severe toxicity, including rare fatalities, was seen in some cases. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Temsirolimus'.)

The chemotherapy administration schedule for temsirolimus is shown in Table 2 (table 3). The toxicities associated with temsirolimus are summarized in Table 3 (table 4).

Everolimus — Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). In phase I and II studies, everolimus activity was observed in patients with clear cell RCC who had failed previous treatment with a VEGF TK inhibitor.

In a phase III trial, 410 patients with metastatic clear cell RCC whose disease had progressed on a VEGF targeted were randomly assigned in a 2:1 ratio to everolimus (10 mg per day) or placebo [65]. All patients had developed progressive disease either while on VEGF TK inhibitors (sunitinib, sorafenib) or within six months after completion of such therapy.

Key observations in this trial included:

• The median progression-free survival with everolimus was significantly prolonged compared to placebo (4.0 versus 1.9 months, hazard ratio [HR] 0.30, 95%CI 0.22-0.40). The benefit extended to all stratification sets (risk group, prior treatment, age, sex, geographic region).
• Objective responses were rare (1 and 0 percent with everolimus and placebo, respectively), although stable disease was more common (63 and 32 percent, respectively).
• There was no significant difference in a preliminary analysis of overall survival (HR 0.83, 95% CI 0.50-1.37). Analysis of overall survival was complicated since patients who had been assigned to placebo were eligible for crossover to everolimus when progressive disease developed, and 81 percent of placebo patients received everolimus.
• The most frequent severe laboratory abnormalities in patients treated with everolimus were lymphopenia and hyperglycemia (15 versus 5 percent and 12 versus 1 percent, respectively, compared to placebo). Grade 3 or 4 adverse events increased with everolimus included stomatitis and pneumonitis (3 versus 0 percent and 3 versus 0 percent, respectively).

Based upon these results, everolimus should be considered a standard treatment for patients with metastatic clear cell RCC who have failed on VEGF TK inhibitors. Although the benefit associated with everolimus is significant in comparison to placebo, its value relative to either continuing sunitinib or sorafenib or crossing over to the alternative VEGFR TK inhibitor remains to be determined.

Like temsirolimus, everolimus has been associated with pulmonary toxicity. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Temsirolimus'.)

In the United States, everolimus was approved by the Food and Drug Administration for use after progression on sunitinib, sorafenib, or both. Everolimus is approved in Europe as an immunosuppressant for use in the prevention of rejection of solid organ transplants.

OTHER TARGETED APPROACHES

Inhibition of EGFR pathway — Despite a high rate of epidermal growth factor receptor (EGFR) expression on RCCs, there does not appear to be a clinical role for inhibition of the EGFR pathway in patients with advanced RCC.

Small molecules targeting the EGFR TK (gefitinib [66], lapatinib [67]) and monoclonal antibodies directed against the extracellular domain of the EGFR (cetuximab [68] or panitumumab [69]) have not demonstrated significant clinical activity in multiple clinical studies. Similarly, attempts to combine an inhibitor of the EGFR pathway (erlotinib) with blockade of the VEGF pathway using bevacizumab have not resulted in improved survival compared to bevacizumab alone [70,71].

Carbonic anhydrase IX inhibition — Carbonic anhydrase IX (CAIX) is a member of the carbonic anhydrase family of proteins that is thought to play a role in the regulation of cellular proliferation in response to hypoxia. It is expressed in the majority of RCCs, and high levels of expression are associated with a more favorable prognosis and a greater likelihood of a response to immunotherapy. (See "Immunotherapy of renal cell carcinoma", section on 'Carbonic anhydrase IX'.)

CAIX may also represent a useful therapeutic target in RCC, and studies with agents targeting CAIX are in progress. As an example, a chimeric monoclonal antibody against CAIX (WX-G250) appears to have some activity against RCC [72].

In vitro studies showed that WX-G250 can elicit antibody-dependent cellular cytotoxicity (ADCC), which could be upregulated by IL-2 [73-75]. This provided the rationale for the study of combined therapy with low-dose IL-2 and WX-G250. In an early report of 35 patients with progressive metastatic clear cell RCC who received weekly infusions of WX-G250 combined with daily low-dose IL-2, three had a partial response and five had stable disease for six months or longer [76]. Median survival was 22 months. The contribution of WX-G250 to the apparently beneficial response could not be determined.

Given that CAIX expression has been found to diminish with more advanced disease, WX-G250 may be more appropriate to study in the adjuvant setting. An international trial of comparing WX-G250 to placebo in patients with resected high-risk RCC is currently underway.

NONCLEAR CELL CARCINOMA — Molecularly targeted agents have not been studied as extensively in patients with nonclear cell carcinoma as in those with clear cell tumors. However, subset analyses from larger studies, as well as data from expanded access programs, suggest that sorafenib, sunitinib, and temsirolimus may have activity in patients with papillary and chromophobic RCCs and in translocation carcinomas [63,77-79]. Additional studies will be required to clarify the role of these agents in nonclear cell carcinoma.

In addition, cytotoxic chemotherapy may be useful in this setting although data are limited. (See "Overview of the prognosis and treatment of renal cell carcinoma", section on 'Chemotherapy'.)

FUTURE DIRECTIONS — There are a number of areas for which there are inadequate data to guide therapy with molecularly targeted therapy:

• Combination regimens — The understanding of the molecular pathogenesis of RCC might make it possible to further improve the efficacy of treatment by blocking multiple steps in the same pathway ("vertical blockade") or by simultaneously inhibiting more than one pathway ("horizontal blockade"). As an example, a study combining everolimus plus bevacizumab suggested that the combination had more activity than everolimus alone in patients previously treated with a VEGF TK inhibitor [80]. However, there is currently no evidence that this is superior to sequential use of agents with different mechanisms. It may also be possible to combine a molecularly targeted approach with immunotherapy, although at least one trial has indicated that such a combination may be detrimental if it involves decreasing the dose of a targeted agent. (See 'Molecular pathogenesis' above and 'Temsirolimus' above.)
• Cross resistance — The development of resistance to one molecularly targeted agent does not mean that inhibition elsewhere within that pathway may not remain a useful approach. For instance, patients with progressive disease following bevacizumab treatment may still respond to a TK inhibitor. (See 'Sequential inhibition of the VEGF pathway' above.)

Cytoreductive nephrectomy — Cytoreductive nephrectomy has been shown to increase survival in patients who are subsequently treated with immunotherapy. Whether it will have similar value in patients who are then treated with molecularly targeted agents has not been evaluated. (See "Immunotherapy of renal cell carcinoma", section on Cytoreductive (debulking nephrectomy).)

• Adjuvant therapy — Adjuvant immunotherapy has not been effective in improving long-term survival following nephrectomy. However, molecularly targeted agents are being evaluated in this setting because of the increased response rates and improved survival observed in patients with metastatic disease. (See "Immunotherapy of renal cell carcinoma", section on 'Adjuvant immunotherapy'.)
• Biomarkers — The role of various biomarkers in predicting responsiveness to molecularly targeted agents remains unknown. Measurements of VEGF and the soluble VEGF receptor do change in response to treatment but whether such alterations can be used as a surrogate for tumor responsiveness remains unknown [81]. Analysis of data collected from the TARGET trial showed that high VEGF levels were independently associated with poorer progression-free survival and overall survival, reflecting an aggressive tumor biology [13]. Data from the TARGET trial also suggested that patients with a high VEGF level derived more benefit from sorafenib that those who had a low VEGF level.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. We encourage you to print or e-mail this topic review, or to refer patients to our public Web site, www.uptodate.com/patients, which includes this and other topics. (See "Patient information: Renal cell carcinoma (kidney cancer)".)

SUMMARY AND RECOMMENDATIONS — The rapid development of agents blocking the vascular endothelial growth factor (VEGF) pathway (sunitinib, sorafenib, bevacizumab) or the mTOR pathway (temsirolimus) has established molecularly targeted therapy as the preferred treatment approach for most patients with advanced clear cell RCC.

Currently there are no trials that provide data comparing different molecularly targeted agents, and each of the drugs has been evaluated in a somewhat different clinical setting. Despite this, there is no reason to assume that a given agent will not be active in other settings.

Previously untreated patients

• For good-risk patients who are able to tolerate the toxicity associated with high-dose interleukin-2 (IL-2) and who have access to this treatment, we suggest treatment with this approach because of its ability to induce durable long-term remissions in approximately 10 percent of patients (Grade 2B). (See "Immunotherapy of renal cell carcinoma", section on 'Interleukin-2'.)
• For previously untreated patients with advanced clear cell RCC who are not candidates for high-dose IL-2, we recommend the use of either a the tyrosine kinase (TK) inhibitor (sunitinib, pazopanib), the mTOR inhibitor temsirolimus , or the combination of bevacizumab plus interferon-alfa (Grade 1B). Results in previously untreated patients do not support the use of the TK inhibitor sorafenib in previously untreated patients. (See 'First-line therapy' above and 'Temsirolimus' above and 'Untreated patients' above.)

    - For previously untreated good- and intermediate-risk patients, sunitinib, pazopanib, or the combination of bevacizumab plus interferon-alfa significantly increase progression-free survival. Additional follow-up information from the comparative phase III trial is required to assess the significance and magnitude of the improvement in overall survival observed in the interim analyses. (See 'First-line therapy' above.)

    - For previously untreated poor-prognosis patients, temsirolimus as a single agent (25 mg IV weekly) significantly increases survival (table 3). Sunitinib has not been as extensively evaluated in this patient subset, but has shown a similar level of activity relative to IFNa in the subset of patients with poor risk features who were enrolled in a large phase III trial. (See 'Temsirolimus' above and 'First-line therapy' above.)

    - Bevacizumab has activity in advanced, previously untreated RCC. The combination of bevacizumab plus interferon alfa (IFNa) improves progression-free survival and overall survival compared to IFNa as a single agent. However, the design of the phase III trial leaves it unclear how active bevacizumab is as a single agent or the contribution of IFNa to the observed results. (See 'Bevacizumab' above.)

Previously treated patients

• For patients with advanced clear cell RCC who have failed prior immunotherapy with IL-2 or interferon-alfa, we recommend treatment with a molecularly targeted agent (Grade 1A).

• - Sorafenib is the most extensively evaluated agent in patients who have previously received cytokines. A large randomized trial comparing sorafenib to placebo demonstrated a significant increase in progression-free survival. (See 'Previously treated patients' above.)
• - Sunitinib, pazopanib, temsirolimus, and bevacizumab are also active in patients with advanced RCC who have received prior cytokines, although data for second-line therapy are more limited than for sorafenib. (See 'Phase II studies' above and 'Refractory patients' above and 'Bevacizumab' above.)

• For patients whose disease has progressed on VEGF pathway inhibitors, we recommend treatment with everolimus (Grade 1A). There currently are no clinical data available for patients whose disease has progressed following therapy with an mTor inhibitor. (See 'Everolimus' above.)
• For patients with progressive disease refractory to a VEGF pathway inhibitor, use of an alternative agent targeting the VEGF pathway may offer clinical benefit in terms of tumor shrinkage, although outcome has never been compared to best supportive care. Whenever possible, such patients should be enrolled on clinical trials. (See 'VEGF pathway inhibition' above and 'Temsirolimus and everolimus' above.)

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