Novel Targets and Therapies for Metastatic Renal Cell Carcinoma

December 1, 2006

For the past 20 years, the systemic treatment of metastatic renal cell carcinoma (RCC) has been limited primarily to cytokines, with few patients showing benefit. However, recent advances in understanding the pathobiology of RCC have led to the identification of novel therapeutic targets for this disease. Drugs specifically designed to inhibit these targets have been developed, with several showing superior efficacy over traditional cytokine therapy. Moreover, these agents are well tolerated and have improved the span of progression-free, and in some cases, overall survival. As a result, between December 2005 and January 2006, two of these targeted therapies—sunitinib (Sutent) and sorafenib (Nexavar)—were approved by the US Food and Drug Administration for the treatment of advanced RCC. The authors review the clinical trials that have focused on these two drugs as well as those concentrating on two other promising agents, bevacizumab (Avastin) and temsirolimus. The ways in which these novel drugs are changing the standard of care for metastatic RCC and the future directions of RCC clinical trials are also discussed.

For the past 20 years, the systemic treatment of metastatic renal cell carcinoma (RCC) has been limited primarily to cytokines, with few patients showing benefit. However, recent advances in understanding the pathobiology of RCC have led to the identification of novel therapeutic targets for this disease. Drugs specifically designed to inhibit these targets have been developed, with several showing superior efficacy over traditional cytokine therapy. Moreover, these agents are well tolerated and have improved the span of progression-free, and in some cases, overall survival. As a result, between December 2005 and January 2006, two of these targeted therapies-sunitinib (Sutent) and sorafenib (Nexavar)-were approved by the US Food and Drug Administration for the treatment of advanced RCC. The authors review the clinical trials that have focused on these two drugs as well as those concentrating on two other promising agents, bevacizumab (Avastin) and temsirolimus. The ways in which these novel drugs are changing the standard of care for metastatic RCC and the future directions of RCC clinical trials are also discussed.

Renal cell carcinoma (RCC) has historically been regarded as highly resistant to systemic therapy-indeed, it has been considered among the most resistant of all neoplasms. A review of the state of affairs in the treatment of metastatic RCC 20 years ago provides important insight into the formidable difficulty in developing active agents for this disease. In a lecture at the Memorial Sloan-Kettering Cancer Center (MSKCC) in 1984, Dr. Alan Yagoda summarized the almost nonexistent status of systemic therapy for metastatic RCC, noting, "At this time, there appears to be no single agent, hormonal manipulation or combination drug regimen which is useful in controlling disseminated renal cancer..."[1] This statement was based on the results of multiple trials demonstrating the relative futility of both cytotoxic and hormonal therapies. More than 20 agents had already been studied at that time, with some of the more notable ineffective therapeutics including vinblastine, the nitrosoureas, dactinomycin (Cosmegen), etoposide, lomustine (CeeNU), flutamide, and progesterone agonists.[1]

Over the past 20 years, substantial progress has been made in both understanding and treating metastatic RCC. This paper will discuss the most important of these advances, including a brief focus on the evolution of cytokine treatment in the late 1980s and early 1990s and a comprehensive review of the more recent development of novel targeted therapies. In addition, we will review some of the important basic science discoveries that have provided insight into the pathogenesis of RCC and led to the identification of the targets of these new drugs.

Introduction and Epidemiology

It is estimated that in the year 2006, nearly 39,000 new cases of renal cell carcinoma (RCC) will be diagnosed in the United States. With a 1.6:1.0 male-to-female ratio, RCC ranks 7th in cancer incidence among American men and 12th among American women, comprising 2% to 3% of all cancer cases diagnosed in the United States each year.[2] In addition, RCC contributes annually to over 13,000 American[2] and 100,000 worldwide deaths.[3] Furthermore, there has been a steady 3% annual rise in the incidence of RCC in both the United States and Europe over the past 3 decades.[4] This trend cannot be entirely explained by the shift toward earlier diagnoses with the increasing use of radiographic diagnostic testing.[4]

There are several distinct histologic types of RCC, each originating from different locations within the renal epithelia. The majority (≥ 75%) of cases are of the clear cell (conventional) type; other renal cell histologies include type I (5%) and type II (10%) papillary (chromophilic), chromophobic (5%), oncocytoma (< 5%), and collecting duct (Bellini's duct) tumors (< 1%).[5,6] As is the case with many malignancies, each histologic subtype exhibits a different clinical behavior and is associated with distinct mutations.

Despite the earlier detection of renal cell malignancies by imaging studies performed for the work-up of unrelated complaints, approximately 30% of patients will still have metastatic disease at diagnosis. Of the remaining 70% who present with localized disease, up to one-third will go on to develop metastases. For patients with metastatic disease, the median survival is approximately 1 year from diagnosis, and only 10% will survive 5 years.[7,8] Such statistics reflect the aggressive nature of metastatic RCC, and underscore the historical lack of effective treatments.

To improve outcomes for advanced RCC, many different treatment approaches have been investigated. While cytoreductive radical nephrectomy[9,10] and metastasectomy[11,12] are an important part of management and can even prolong patients' lives, these procedures are rarely curative.[11] Furthermore, patients with widespread disease are often not candidates for these surgical options. Ideally, an effective systemic therapy is needed to provide long-term disease control for metastatic RCC.

Unfortunately, in contrast to other aggressive malignancies, RCC is highly resistant to cytotoxic chemotherapy. Many such agents have been explored in clinical trials but none has demonstrated sufficient efficacy to justify the associated toxicities.[5] Hormonal therapies have been similarly ineffective,[5] and no member of either of these two classes has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic renal carcinomas. Until recently, the mainstay of treatment for patients with metastatic disease has consisted of immune modifying agents, such as interleukin (IL)-2 (Proleukin) and interferon (IFN)-alpha.

Cytokine Therapy

The initial use of cytokine therapy for metastatic RCC was based on several findings that suggested an ability of the immune system to regulate renal tumor growth. Such evidence included observations of patients with long disease-free intervals following nephrectomy,[13] disease stabilization for 1 to 2 years without any treatment,[14] and spontaneous tumor regression in a minority of patients.[15,16]

In general, the response rates to IL-2 and IFN-alpha range from 10% to 20%, with a median survival of approximately 12 months.[5] Although complete responses (CR) are rare with IFN-alpha, at least two studies have shown this cytokine to provide a survival advantage compared with either placebo or cytotoxic chemotherapy.[17,18] Unlike IFN-alpha, high-dose IL-2 can induce a durable CR in about 5% of patients.[19] For those who achieve a CR, the median duration of response is about 40 months, with some responses lasting up to 6 years.[20] On the basis of these results, high-dose IL-2 was approved in the United States, and IFN-alpha in parts of Europe, for the treatment of advanced RCC.

Unfortunately, these immunomodulating agents are not without toxicities, and high-dose IL-2 is generally administered with intensive-care unit support. In addition, the clinical benefit of both agents, particularly IL-2, is restricted to a relatively small group of highly selected patients. Furthermore, randomized trials have failed to demonstrate a superior median survival or progression-free survival with high-dose therapy, compared with low-dose or combination cytokine treatment.[21,22] Attempts to improve upon the modest response rates afforded by cytokine therapy by adding cytotoxic chemotherapy or combining IFN with IL-2 have also been disappointing. These strategies generally lead to increased toxicity and do not improve outcomes.[23] Finally, until recently, effective treatment options were lacking for cytokine-refractory patients, since switching to an alternate cytokine therapy was shown to provide no benefit.[24]

Pathobiology and Identification of Therapeutic Targets

Association of VHL Disease With Clear Cell RCC

As part of his two-hit hypothesis regarding tumor-suppressor genes, Knudson theorized that sporadic cases of a particular type of cancer should involve the same gene as those associated with a hereditary syndrome.[25] With the genetic syndrome, patients are borrn with a germ-line mutation or deletion in one allele and then acquire the second "hit" (usually) early in life. Sporadic tumors occur at older ages because sufficient time is required for both alleles to become mutated.

Von-Hippel-Lindau (VHL) disease is an inherited, autosomal, dominant syndrome characterized by a variety of benign and malignant tumors, most notably retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytomas, renal and pancreatic cysts, and clear cell RCC. In the early 1990s, the VHL gene was successfully cloned, and in accordance with Knudson's theory, alterations in this gene were found in many cases of sporadic clear cell RCC in addition to patients with VHL disease.[26] In particular, somatic mutations occur in about 50% and hypermethylation in an additional 10% to 20% of clear cell RCC cases.[27]

VHL Protein Function

The protein product of the VHL gene is a polyubiquitin complex (pVHL) responsible under normoxic conditions for ubiquitinating the transcription factor, hypoxia-inducible factor (HIF)-1-alpha, which marks it for proteasomal degradation.[27] This process depends upon oxygenated conditions, because pVHL can only bind to HIF-1 after hydroxylation of one of its prolyl residues. Under hypoxic conditions, hydroxylation of HIF-1-alpha does not occur, prohibiting pVHL from binding. Instead of being degraded, HIF-1-alpha can then translocate to the nucleus and attach to HIF-1-beta to form the active HIF-1 complex.

In the nucleus, active HIF-1 acts as a transcription factor for several hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), the epidermal growth factor receptor (EGFR), glucose transporters (eg, GLUT-1), transforming growth factor-alpha (TGF-alpha, ligand for EGFR), and erythropoietin.[27] Many of these proteins are involved in angiogenesis, survival, pH regulation, and glucose metabolism. The absence of a functional VHL protein in the inherited and sporadic forms of clear cell carcinoma simulates hypoxia with resultant constitutive upregulation of these genes.

In addition to regulation by pVHL, recent studies have shown that HIF-1 activity is also affected by the EGFR-phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway. Binding of TGF-alpha to EGFR results in stimulation of the PI3K-AKT-mTOR pathway, leading to increased translation of HIF-1.[28] Since EGFR and TGF-alpha are also under transcriptional regulation by HIF-1-alpha, such integration creates a positive feedback loop, ensuring an adequate response to hypoxic conditions. Furthermore, signaling through EGFR-PI3K-AKT-mTOR can also result in increased VEGF levels through a mechanism independent of HIF [29].

The Ras-Raf-MEK-ERK pathway may also regulate HIF-1-alpha.[30] Thus, in clear cell RCC, mutations in VHL and genes of distinct but interrelated pathways results in upregulation of proteins integral to tumor growth and angiogenesis. Dissection of the complex relationships between these pathways has led to the identification of new targets for RCC treatment. Based on such advances, drugs that attack these targets have been developed. These agents have recently demonstrated efficacy in clinical trials and are beginning to change the standard of care for metastatic RCC.

Targeted Therapies

Sorafenib

Although the bisaryl urea sorafenib (BAY 43-9006, Nexavar) was first designed as an in vitro inhibitor of the RAF-1 protein, it was subsequently found to inhibit VEGF receptor (VEGFR) and PDGF receptor (PDGFR) as well. Phase I trials determined the safety and dosing of sorafenib, with the most common side effects being hand-foot syndrome, rash, fatigue, diarrhea, and hypertension.[31] The dose level recommended for phase II trials was 400 mg twice daily.[31] The one patient with RCC treated in this initial study had prolonged disease stabilization for over 2 years.[31]

 

Phase II Trial-Subsequently, a large phase II trial was performed with an innovative "randomized discontinuation" design.[32] Over 500 patients with advanced solid tumors were enrolled, of which 202 (40%) had RCC. All patients received sorafenib for a 12-week "run-in period," at the end of which they were stratified based on their response. In an analysis of only RCC patients, response assessment was available in 193 cases. Of these, 73 (36%) achieved a partial response (PR) and were assigned to continue sorafenib, while 51 (25%) had disease progression and were removed from the study. Of the remaining 69 (34%) patients who were considered to have stable disease (SD), 65 were randomized to either 12 more weeks of sorafenib treatment or placebo.

The primary endpoint of the trial was the effect of the drug in preventing tumor growth (rather than causing tumor regression) in these randomized patients, and the secondary endpoint was progression-free survival. At the end of this additional treatment period, 50% of patients receiving sorafenib were progression-free compared with only 18% of those receiving placebo (P = .0077). Median progression-free survival was 24 weeks from randomization for the sorafenib group vs 6 weeks for the placebo group (P=.0087). The most common toxicities were skin rash, hand-foot syndrome, and fatigue.[32]

 

Phase III Trial-Based on these results, the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs) study was initiated. This multicenter, randomized phase III trial compared sorafenib to placebo in patients with previously treated RCC. A total of 903 patients were randomized, with a planned interim data analysis presented after 353 events (progression or death) encompassing the first 769 patients.[33] The primary endpoint was overall survival, and secondary endpoints included progression-free survival and quality of life. The median progression-free survival was 24 weeks in sorafenib-treated patients, compared with 12 weeks in the placebo group (P < .000001, hazard ratio = 0.44).

Independent review of responses as assessed by RECIST criteria, demonstrated that 80% of patients were progression-free in the sorafenib arm (2% PR, 78% SD) compared with 55% in the placebo arm (0% PR, 55% SD).[33] The major side effects, which occurred more frequently with sorafenib, were rash/desquamation (31% vs 11%), diarrhea (30% vs 7%), hand-foot skin reaction (26% vs 5%), alopecia (23% vs 3%), neuropathy (9% vs 2%), and hypertension (8% vs 1%). However, grade 3 and 4 side effects were rare, and only 13 patients discontinued sorafenib due to adverse events. Fatigue (18% vs 14%) and nausea (14% vs 11%) were common in both groups.[33] These data demonstrated sorafenib to be safe and effective, and led to the FDA approval of sorafenib for advanced RCC in December 2005.

The impact of sorafenib on overall survival was recently reported.[34] As of November 2005, 367 deaths had occurred, with a median survival of 19.3 months for sorafenib-treated patients compared with 15.9 months for those receiving placebo. Although this difference did not reach statistical significance, a trend in survival benefit was observed. In addition, 202 (45%) patients in the placebo arm crossed over to treatment with sorafenib, estimated to improve survival in the placebo group by 30% and causing the survival difference to be underestimated.

 

Ongoing Trials-Studies are under way evaluating sorafenib in the first-line setting, as adjuvant treatment following nephrectomy, and in combination with either cytokines or additional targeted therapies. A randomized phase II trial comparing first-line treatment with sorafenib vs IFN-alpha conducted in 188 patients showed a favorable safety profile for sorafenib.[35] However, progression-free and overall survival data have not yet matured.

Sunitinib

Sunitinib malate (SU11248, Sutent) is a multitargeted inhibitor of receptor tyrosine kinases including VEGFR and PDGFR. In preclinical studies, sunitinib induced marked tumor regression and had antiangiogenic effects on various tumor cell lines and xenograft models.[36-38] Various schedules were evaluated in phase I trials, with the optimal dosing plan for phase II studies determined to be 50 mg for 4 weeks on and 2 weeks off (4/2).

 

Phase II Studies-RCC was chosen as the optimal malignancy for phase II testing of sunitinib because three out of four patients (75%) with RCC treated on the phase I trial had objective partial responses [39] and because the upregulation of PDGF and VEGF pathways in this malignancy provide a rational basis for its efficacy. Two sequentially conducted single-arm multi-institutional phase II trials were subsequently performed in RCC patients previously treated with cytokines. Of 63 patients treated in the first trial, 25 (40%) achieved a PR and an additional 17 (27%) had SD for at least 3 months. The median time to progression was 8.7 months, and the median overall survival was 16.4 months.[40]

The second trial[41] included 106 patients, of which 105 were evaluable. The PR rates as assessed by the investigators and an independent third-party review were 43% and 34%, respectively, and SD rates were 22% and 29%, respectively. The median progression-free survival was 8.3 months, based on independent review, and the median duration of response was 10 months. The most common adverse effects (most of which were grades 1 and 2) in both trials were fatigue, diarrhea, nausea, and stomatitis. The most frequently occurring grade 3/4 adverse events included lymphopenia (30%), elevated lipase (21%) and amylase (8%) without clinical signs of pancreatitis, and fatigue (8%). Serial measurements of left-ventricular ejection fractions also demonstrated asymptomatic declines of > 20% in five patients (5%), who were removed from the study.[41] The pooled results of these two trials were superior to historical outcomes with cytokines and led to the rapid FDA approval of sunitinib for advanced RCC in January 2006.

 

Phase III Trial-Based on the above results, a phase III trial was initiated, randomizing previously untreated patients with advanced RCC to either sunitinib (50 mg, 4/2 schedule) or IFN-alpha. At the first interim analysis, sunitinib demonstrated superior progression-free survival compared with IFN-alpha (47.3 vs 24.9 weeks, P < .000001, hazard ratio [HR] = 0.394, 95% confidence interval [CI] = 0.297-0.521). In addition, objective response rates by an independent third-party review were 24.8% for sunitinib vs 4.9% for IFN-alpha (P < .000001).[42] The toxicity profile was similar to that reported in second-line studies. As a result of this interim analysis, sunitinib has become the new standard for the first-line treatment for metastatic RCC.

 

Ongoing Trials-Current studies are evaluating the combination of sunitinib with cytokines, cytotoxic chemotherapy, or other targeted agents, as well as a new monotherapy dosing schedule. In the latter study,[43] sunitinib has been administered to 88 RCC patients at a dose of 37.5 mg daily on a continuous basis (eg, no rest period). Thus far, this regimen seems to be well tolerated, with only a few patients requiring dose interruptions or reductions.[43] It will be interesting to see if patients continue to tolerate long-term administration of sunitinib on this schedule, and how efficacy will compare to that of standard dosing.

Temsirolimus

Temsirolimus, also known as cell-cycle inhibitor-779 (CCI-779), is a soluble ester analog of the macrolide antibiotic sirolimus, a drug with antifungal activity and immunosuppressive properties approved by the FDA to prevent organ rejection in renal and liver transplant recipients. Sirolimus also exerts antitumor effects by inhibiting the mammalian target of rapamycin (mTOR), a large polypeptide kinase involved in the regulation of cell growth and proliferation.[44] mTOR is activated via the PI3K-Akt pathway, and appears to be essential for the initiation of protein translation and cell-cycle progression from G1 to S phase.[44] There is also evidence that this pathway is important to angiogenesis, since activation leads to increased VEGF production and prevents HIF-1 degradation.[44] Furthermore, the role of mTOR in tumorigenesis is underscored by the high frequency of mutations in the EGFR-PI3K-AKT pathway in a variety of malignancies.[44]

 

Phase I/II Studies-In a phase I study of 24 patients with advanced refractory solid tumors, temsirolimus was found to be safe and demonstrated activity in 3 out of 6 patients with RCC (1 PR and 2 minor responses by World Health Organization [WHO] criteria).[45] An optimal dose was not defined, since activity was seen across a wide range. These results led to the initiation of a randomized phase II study[46] in 111 patients with advanced treatment-refractory RCC, designed to determine the efficacy and optimal dosing of temsirolimus. Patients randomly received 25, 75, or 250 mg of temsirolimus by intravenous infusion once weekly; responses were evaluated by WHO criteria.

Objective responses were seen in 7% of patients (1 CR, 7 PR) with minor responses in an additional 26% of patients and stable disease lasting greater than 24 weeks in 17%, for a total of 51% patients considered to benefit from therapy. The median time to progression was 5.8 months, with a median overall survival of 15 months. These results were felt to be especially encouraging, because a retrospective review revealed that 49 (44%) patients had "MSKCC poor-risk" disease, and this subset achieved a significantly longer survival than a historical group of poor-risk patients treated with IFN-alpha.[8] The most common grade 1 or 2 adverse events included rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). Grade 3 and 4 toxicities primarily included hyperglycemia (17%) and hypophosphatemia (13%). Since side effects were more common and more severe in the two higher-dose groups with no difference in efficacy, the 25-mg regimen was concluded optimal for further testing.

Phase III Study-In a phase I/II clinical trial of 71 patients, temsirolimus was combined with IFN-alpha; 11% of patients achieved PRs and a median time to progression of 9.1 months.[47] Based on the prolonged time to progression in this study, which included patients treated previously with IFN, a large, three-arm, randomized controlled trial[48] was initiated comparing this combination regimen with each agent alone. The study was specifically designed for poor-risk patients because of the particular benefit for this group of patients shown in the phase II trial with temsirolimus.[46] In addition, other studies with targeted agents had included few if any patients with MSKCC poor-risk disease.

A total of 626 patients were randomized (n = 207 for IFN, n = 209 for temsirolimus, and n = 210 for the combination). Single-agent temsirolimus resulted in a significantly longer median overall survival (the primary endpoint) than IFN (10.9 vs 7.3 months, P = .0069; HR = 0.73, 95% CI = 0.57-0.92), whereas a statistically significant benefit was not achieved for the combination arm (8.4 months).[48] The reason for the nonsuperiority of the combination regimen could be the lower dose of temsirolimus (15 mg) administered to these patients compared with the single-agent arm (25 mg), or an inhibitory effect of interferon on temsirolimus.

Based on this trial, some experts are proposing temsirolimus as the new standard of care for poor-risk patients. Further studies are needed to determine the role of temsirolimus as first-line therapy for patients with good- and intermediate-risk disease, as sequential therapy following progression on sunitinib or sorafenib, and in combination with these or other targeted agents.

Bevacizumab

Bevacizumab (Avastin) is a humanized monoclonal antibody that binds to all major isoforms of VEGF-A, preventing attachment to VEGFR and subsequent downstream events that promote angiogenesis. Bevacizumab has activity in a wide variety of malignancies, and is approved by the FDA for use in combination with chemotherapy for the treatment of colorectal cancer.

 

Phase II Study-The first trial to explore the role of bevacizumab in RCC was a randomized, double-blind trial in which 116 patients were allocated to receive placebo, low-dose bevacizumab (3 mg/kg), or high-dose bevacizumab (10 mg/kg) every 2 weeks. All patients had clear cell RCC histology and had previously received IL-2 or had a contraindication to treatment with IL-2. Patients in the placebo group whose disease progressed were allowed to cross over to either the low-dose bevacizumab arm or a combination of low-dose bevacizumab and thalidomide (Thalomid).

Four patients (10%)-all in the high-dose bevacizumab group-achieved PRs. Median time to progression (the primary endpoint of the study) at a planned interim analysis was significantly longer for the high-dose bevacizumab group compared with the placebo group (4.8 vs 2.5 months, P < .001). A comparison of median time to progression between the low-dose bevacizumab group and the placebo group was of borderline significance (3.0 vs 2.5 months, P = .041). Based on the differences between the high-dose and placebo groups, the study closed early. Neither bevacizumab group demonstrated a survival benefit compared with placebo, but this might reflect the crossover design of the study.

 

Current Studies-Currently, two large randomized trials are comparing bevacizumab plus IFN-alpha with IFN-alpha alone. These trials are powered to detect an improvement in median overall and progression-free survival, and have already completed accrual. Since neither trial includes a bevacizumab monotherapy arm, it is unclear whether an observed benefit with the combination regimen would justify the use of single-agent bevacizumab for the first-line treatment of metastatic RCC. Investigations of combinations of bevacizumab with other targeted agents (sunitinib, sorafenib) are also being explored.

Other Promising Agents and Combinations of Targeted Therapies

In addition to the four drugs reviewed above, several other targeted agents are in clinical trials. Those with the most promise include RAD001 and AG013736. RAD001 (everolimus) is an mTOR inhibitor similar to temsirolimus, but with the advantage of oral administration. In a single-arm phase II trial of mostly pretreated patients, RAD001 demonstrated significant activity, with a 36% PR rate and prolonged time to progression (≥ 3 months in 86% of patients).[49] Like sunitinib and sorafenib, AG013736 is a small-molecule inhibitor of multiple receptor tyrosine kinases including VEGFR-1, -2, and -3, PDGFR- beta, and c-Kit. AG013736 produced a 40% response rate in a phase II trial conducted in 52 patients with cytokine-refractory metastatic RCC.[50] Based on these studies, separate phase II trials are already under way for RAD001 and AG013736 in patients who develop progressive disease following therapy with sunitinib or sorafenib.

Combinations of various targeted therapies are the current focus of many phase I and II RCC trials. Examples include the combination of an mTOR inhibitor (temsirolimus, RAD001) with a VEGFR inhibitor (sorafenib, sunitinib) or the use of bevacizumab with either drug class. An additional approach would include combining one of these agents with drugs targeting important pathogenic molecular mechanisms in RCC that are not related to the VHL-HIF pathway. While many combination trials are under way or in planning stages, two completed studies provide insight into the issues that will be important in the development of this approach.

A phase II study evaluated the combination of bevacizumab and erlotinib (Tarceva) in previously untreated patients with advanced RCC, and demonstrated 15 responses in 59 evaluable patients (25%) and a median progression-free survival of 11 months. A randomized phase II trial [51] then compared this same combination with bevacizumab plus placebo in patients whose disease had progressed on prior therapy. In this trial, there was no significant difference in response or progression-free survival between the two arms.[51] A multicenter, single-arm phase II trial also evaluated the safety and efficacy of the bevacizumab/erlotinib combination with the addition of imatinib (Gleevec).[52] Compared with the prior two trials, there was no improvement in efficacy, and toxicity was substantially worse.[52] These trials underscore the importance of patient selection for the testing of combination programs, and serve as a reminder that until safety and efficacy have been proven, such approaches should remain purely investigational.

Treatment Recommendations and Future Directions

We now have sufficient phase III evidence to support the use of sunitinib rather than cytokines for the first-line treatment of metastatic RCC (Table 1). In addition, multiple phase II studies support the use of either sunitinib or sorafenib for patients who have progressed on cytokine therapy (Table 2).

Despite the current lack of efficacy data for sorafenib in the first-line setting, such use is also reasonable, especially for patients who are not eligible for sunitinib therapy. For those who progress on sunitinib or sorafenib, a trial of the other drug is appropriate despite the lack of data for this approach. Anecdotally, we have seen patients achieve durable stable disease and minor responses with this strategy. Cytokine therapy and single-agent bevacizumab represent other options following progression on sunitinib or sorafenib. Temsirolimus has not yet been approved by the FDA, but may be especially beneficial for patients with poor-risk disease for first- or second-line treatment. Clinical trials should also be discussed with patients at all treatment stages.

Over the past 10 years, the identification of novel therapeutic targets and their inhibitors has led to improvements in response rates and progression-free survival for patients with metastatic RCC. Future efforts will concentrate on determining the most effective dosing schemes, the optimal sequencing and combination of these agents, and the identification of new targets and drugs. In addition, studies will need to define the role of targeted therapies in non-clear cell RCC and to develop methods for selecting patients most likely to respond to particular agents. Since progression on targeted treatment eventually occurs, mechanisms of resistance need to be elucidated, and strategies to overcome this problem must be developed. Finally, large trials will be required to define the role of targeted therapies for the adjuvant treatment of patients following nephrectomy and for head-to-head comparisons of targeted therapies (eg, sorafenib vs sunitinib) in the metastatic setting.

For patients, medical oncologists, and researchers alike, advances in understanding and treating RCC over the past several years have provided a new level of excitement and optimism. It is hoped that progress will continue at the current pace, and that eventually metastatic renal cell carcinoma can be changed from a life-threatening illness to a manageable chronic disease or curable malignancy.

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