Systemic Therapy for Metastatic Renal Cell Carcinoma: A Review and Update

Management Update

ManageMent Update Systemic Therapy for Metastatic Renal Cell Carcinoma: A Review and Update Joshua E. Logan, MD, Edward N. Rampersaud, MD, Geoffrey A. Sonn, MD, Karim Chamie, MD, MSHS, Arie S. Belldegrun, MD, FACS, Allan J. Pantuck, MD, MS, FACS, Dennis J. Slamon, MD, PhD, Fairooz F. Kabbinavar, MD Institute of Urologic Oncology, Department of Urology, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA An in-depth understanding of metastatic renal cell carcinoma (mRCC) is important so that practitioners can make informed evidenced-based decisions with patients to optimize not only quantity of life but quality of life as well. Therefore, this review focuses on the biology of mRCC as it relates to targets for therapy, as well as on the small molecules rationally designed with these targets in mind. In addition, anticipated emerging therapies are highlighted, including the new tyrosine kinase inhibitors axitinib and tivozanib, as well as new immune-based therapies such as dendritic cell-based vaccines and antibodies. We also briefly review recent reports from the emerging field of predicting drug response based on molecular markers. And finally, management of metastatic non-clear cell RCC histologies are discussed focusing on available evidence to direct decision making when assessing therapeutic options. [ Rev Urol. 2012;14(3/4):65-78 doi: 10.3909/riu0562] ® © 2013 MedReviews , LLC Key words Metastatic renal cell carcinoma • Tyrosine kinase inhibitors • Dendritic cell-based vaccines • Non-clear cell renal cell carcinoma T he treatment of metastatic renal cell carcinoma (mRCC) has progressed toward the goal of transforming cancer to a chronic rather than a lethal disease. This has been particularly highlighted with the advances in systemic therapy that have come forward in the past decade. Prior to these advances, patients with mRCC were left with relatively few options, as mRCC is known to have low response rates to traditional cytotoxic therapy, with . 70 agents being tested and response rates , 10%.1,2 In its most recent annual report, the American Cancer Society stated kidney cancer Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 65 40041700002_RIU0562.indd 65 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued comprises approximately 3% to 5% of adult malignancies in the United States with approximately 61,000 new cases diagnosed and over 13,000 deaths reported in 2011.3 Unfortunately, data suggest that the rates of RCC are rising, but what is the most alarming epidemiologic aspect of this disease is that 25% to 30% of these patients will present with metastatic disease and an additional 25% to 30% who initially presented with localized disease will progress at sometime following the diagnosis.4-6 By these estimates, at least one-half of patients diagnosed with RCC will ultimately require additional therapy and, for most of these patients, cure will no longer be an option. Until the middle of this past decade, immunotherapy with interleukin-2 (IL-2) or interferon-a (IFNa) was considered to be the standard of care for mRCC despite modest improvements in survival. However, in a small minority of patients, it has lead to tumor regression and longterm survival. Response rates with high-dose IL-2 have been reported at 20%, and complete responses at 7% with a minority of patients achieving a durable response.7,8 With regard to IFN-a, response rates range from 10% to 15%, with a median survival improvement of only 3 to 7 months.9 The toxicity profile associated with these therapies often limits their applicability and patients are therefore often left with no other options. Elucidation of the von HippleLindau (VHL) tumor suppressor and its role in RCC led to the identification of pathways that eventually became targets for therapy.10 Vasoendothelial growth factor (VEGF) and the VEGF receptor (VEGFR) are two targets that have been exploited with results that have revolutionized treatment for mRCC as seen with sorafenib, sunitinib, pazopanib, and bevasizumab. This was followed by identification and manipulation of the mammalian target of rapamycin pathway (mTOR), which offered additional therapeutic options with temsirolimus and everolimus, both of which have demonstrated the potential to provide a survival advantage in mRCC patients.11,12 An in-depth understanding of this disease is important so that the practitioner can make informed evidenced-based decisions with the patient and thereby optimize not only quantity of life but quality of life as well. Therefore, this review focuses on the biology of RCC as it relates to targets for therapy, as well as on the small molecules rationally designed with these targets in mind. In addition, anticipated emerging therapies are highlighted, including the new tyrosine kinase inhibitors (TKIs) axitinib and tivozanib, as well as new immunebased therapies such as dendritic cell-based vaccines and antibodies. We will also briefly review recent reports from the emerging field of predicting drug response based on molecular markers. And finally, management of metastatic nonclear cell RCC (non-ccRCC) histologies are discussed, focusing on available evidence to direct decision making when assessing therapeutic options. Elucidation of the Molecular Biology of RCC To understand the genetic etiology of ccRCC, attention was focused on the familial form of ccRCC associated with the VHL syndrome. VHL is a syndrome characterized by renal cysts, retinal hemangiomas, hemangioblastomas of the cerebellum and spinal cord, pheochromocytomas, pancreatic carcinoma, and RCC. The VHL gene is located on the short arm of chromosome 3 at the 25-26 locus and is a tumor-suppressor gene.13 Patients with VHL are born with a germ-line mutation in one allele and acquire a so-called second hit, either mutation or deletion, in the other allele in accordance with Knudson’s two-hit theory. In patients with sporadic, noninherited RCC, the coding region of VHL has been shown to be inactivated through methylation or deletion in 34% to 60% of cases. The VHL gene product, pVHL, functions in a multiprotein complex with elongin B, elongin C, Cullin-2, and RING-box protein 1, forming an E3 ubiquitin ligase complex called vascular endothelial cadherin (VEC) multiprotein complex. In normoxic conditions, the VEC complex targets a subunits of hypoxia-inducible factor (HIF1a) for ubiquitin-mediated degradation. HIF1a is a transcription factor that permits cell survival and growth under hypoxic conditions.14 When cells lack, or have dysfunctional, pVHL HIFa does not undergo proteasomal degradation; instead, constitutively active HIF1a localizes to the nucleus where it forms a heterodimer with HIF1β.15 The heterodimer complex activates expression of several hypoxia-inducible genes including VEGF, insulin-like growth factor, transforming growth factor (TGF), platelet-derived growth factor (PDGF), glucose transporter-1, and carbonic anhydrase IX (CAIX).16 It is clear from the spectrum of genes upregulated by the HIF pathway that its purpose is to ensure that the cell has a properly regulated environment and nutrients with which to be sustained. To that end, like VEGF, PDGF has demonstrated angiogenic properties, whereas TGF, a ligand for the EGFR, is a mitogen-promoting cell proliferation, and it is also involved in angiogenesis as well.17-19 This redundant system reflects the fact 66 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 66 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update that angiogenesis is essential for tumor growth, and neovascularization is necessary for tumors to grow and metastasize.20 Following the elucidation of these molecular biologic pathways came the understanding of their importance as targets for therapy and much effort has been directed at these targets as evidenced by the revolution seen in the past decade with the development of numerous small molecules in the realm of targeted therapy with many more on the horizon. Targeted Therapy In 2005, the US Food and Drug Administration (FDA) approved sorafenib for the treatment of patients with mRCC. Sorafenib is an orally active multikinase inhibitor, and has demonstrated inhibi- skin reactions; hypertension and cardiac ischemia were rare serious AEs.22 In 2006, sunitinib, also an orally active TKI, received FDA approval for treatment of mRCC. Its inhibitory activity is directed at several tyrosine kinases, including VEGFR, PDGFR, Flt-3, and c-Kit.23,24 Evaluation of sunitinib was carried out in a phase III clinical trial in comparison with IFN-a. The primary endpoint was PFS, and the median was significantly longer in the sunitinib group at 11 months than in the IFN-a group at 5 months (P , .001). Sunitinib showed a higher objective response rate than what was seen in those treated with IFN-a (31% vs 6%; P , .001). A higher rate of grade 3 or 4 treatmentrelated fatigue was experienced in patients treated with IFN-a; however, patients in the sunitinib group In 2005, the US Food and Drug Administration approved sorafenib for the treatment of patients with mRCC. Sorafenib is an orally active multikinase inhibitor, and has demonstrated inhibitory activity on cell proliferation and angiogenesis. tory activity on cell proliferation and angiogenesis. Specific receptors inhibited include VEGFR, PDGF receptor β (PDGFRβ), FMSlike tyrosine kinase 3 (Flt-3); c-Kit protein (c-Kit), and RET receptor tyrosine kinases.21 Escudier and colleagues22 reported the results of a phase III, randomized, controlled trial in which mRCC patients who had failed previous therapy were randomized to sorafenib or placebo; the results showed that patients who received the drug had a median progression-free survival (PFS) of 5.5 months versus 2.8 months in patients who received the placebo. However, the primary endpoint of the study was overall survival (OS), and sorafenib failed to demonstrate superiority. The most common adverse events (AEs) associated with sorafenib include diarrhea, rash, fatigue, and hand-foot experienced more frequent diarrhea (P , .05). Regarding quality of life, patients receiving sunitinib fared better than patients receiving IFN-a (P , .001).23 A follow-up study reporting the long-term outcomes of these patients was published in 2009 showing the median OS was greater in the sunitinib group than in the IFN-a group, 26.4 versus 21.8 months, respectively (P , .051). The median PFS for those treated with sunitinib was 11 months compared with 5 months in those treated with IFN-a (P ,.001). The greatest differential detected was in the objective response rate, which was 47% in the sunitinib group compared with 12% in the IFN-a group (P , .001). The commonly reported grade 3 AEs in the sunitinib group were hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).25 In 2009, the FDA approved pazopanib, another oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit. This targeted-agent demonstrated efficacy in a placebocontrolled, randomized, doubleblind, phase III study in treatment-naive, or cytokine-pretreated populations of mRCC patients. The primary endpoint was PFS, and secondary endpoints included OS, as well as tumor response rate by Response Evaluation Criteria in Solid Tumors (RECIST). PFS was significantly prolonged with pazopanib at 9.2 months compared with placebo at 4.2 months in the overall study population (P , .0001). In the treatment-naive patients, median PFS was 11.1 months compared with 2.8 months in patients receiving placebo (P , .0001), and in cytokine-pretreated patients, the median PFS was 7.4 compared with 4.2 months in patients receiving placebo (P , .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P , .001). The median duration of response was longer than 1 year. The most common AEs were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo.26 The newest available TKI, axitinib, is a selective inhibitor of VEGFR 1, 2, and 3, and lacks substantial inhibition of other tyrosine kinase receptors, unlike previous TKIs, which may provide benefits with reduced toxic effects. This new agent received unanimous recommendation for approval by the Oncologic Drugs Advisory Committee on December 7, 2011 for second-line treatment of patients with mRCC, based on phase III data comparing axitinib and sorafenib, in what was the first phase III head-to-head comparison Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 67 40041700002_RIU0562.indd 67 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued of targeted agents in advanced RCC. The data showed median PFS of 6.7 months in the axitinib group versus 4.7 months in the sorafenib group (P , .0001). In addition, the discontinuation of axitinib for toxic effects was half the rate that was seen in those patients receiving sorafenib.27 In January 2012, the FDA approved axitinib for use in patients with RCC who have failed previous therapy. Tivozanib is the next TKI with a completed phase III clinical trial and recently reported results. This agent is a selective inhibitor of all three VEGFRs that is designed to optimize VEGF blockade while minimizing off-target toxicities. Tivozanib is not yet available commercially, but represents the first TKI studied in mRCC patients, head-to-head with a current FDA-approved TKI in the firstline setting. In a press release dated January 3, 2012, AVEO Pharmaceuticals (Cambridge, MA) announced that tivozanib demonstrated a statistically significant improvement over sorafenib with a median PFS of 12.7 months compared with 9.1 months in treatmentnaive patients, and a median PFS of 11.9 months versus 9.1 months in those who had previously been treated.28 The formal publication of these results is pending. As the VEGF pathway was being manipulated for the clinical benefit of those with mRCC, targets in other pathways were being investigated for their therapeutic efficacy. Most notable is the mTOR pathway. The mTOR kinase is a component of intracellular signaling pathways involved in growth and proliferation of cells, as well as the response of cells to hypoxic stress.29-31 mTOR was initially discovered in the 1990s while studying the mechanism of action of rapamycin (also known as sirolimus), a macrolide originally found as an antifungal and later recognized for having immunosuppressive and anticancer effects.32 Signaling pathways upstream and downstream of mTOR are dysregulated in cancer, demonstrating its essential role in cancer biology and as a target for rapamycins.33,34 Temsirolimus is an mTOR inhibitor with more favorable pharmaceutical properties compared with its parent compound rapamycin.35 Temsirolimus binds to an intracellular protein, FKBP-12, forming a complex which inhibits mTOR signaling.36 The disruption of mTOR signaling suppresses the production of proteins that regulate progression through the cell cycle and angiogenesis.35,37 Temsirolimus was evaluated in a phase III clinical trial with positive results leading to its FDA approval in 2007 for advanced RCC. The clinical trial evaluated temsirolimus alone compared with IFN-a alone, and in combination with IFN-a. The primary endpoint was OS. Patients treated with temsirolimus alone had longer OS (P 5 .008) and PFS (P , .001) than did patients who received IFN-a alone. OS in the combination-therapy group did not differ significantly from that in the IFN-a group (P 5 .70). Median OS times in the temsirolimus, the interferon, and the combination groups were 10.9, 7.3, and 8.4 months, respectively. AEs including rash, peripheral edema, hyperglycemia, and hyperlipidemia were more frequently experienced in the temsirolimus group, whereas asthenia was more commonly experienced in those receiving IFN-a. Overall, fewer patients had serious AEs in the temsirolimus group than in the IFN-a group (P 5 .02).11 Currently, the National Comprehensive Cancer Network (NCCN) recommends the use of temsirolimus in patients with advanced RCC and poor prognosis.38 Everolimus is also an mTOR inhibitor, and is available as an oral tablet, unlike temsirolimus, which requires an infusion. In 2009, the FDA approved everolimus for the treatment of patients with advanced RCC who had previously failed treatment with sunitinib or sorafenib. Everolimus was evaluated in a phase III, randomized, double-blind, placebo-controlled trial in patients with advanced RCC who had failed previous TKI therapy. Prior therapy with bevacizumab, IL-2, or IFN-a was also permitted. The primary endpoint was PFS. The median PFS was 4.9 and 1.9 months in the everolimus and placebo arms, respectively (P , .0001), and treatment effect was similar across prognostic scores and prior treatment status. Median OS was 14.8 months in the everolimus group and 14.4 months in the placebo group; this result was not significant (P 5 .167). As anticipated, AEs were more frequent within the everolimus group compared with the placebo group, and these AEs were mostly grade 1 or 2. The most common AEs were stomatitis, rash, fatigue, and diarrhea. Grade 3 or 4 events were low for both groups, but patients receiving everolimus had higher rates of grade 3 or 4 events than those in the placebo group. One particular high-grade AE that bears mentioning, as it appears to be a class-effect, is noninfectious pneumonitis; clinical evidence of grade 3 pneumonitis was reported for eight patients (3%) receiving everolimus in this study. It has been reported as being associated with rapamycin, as well as its derivatives, including temsirolimus.12,39,40 As previously discussed, for many years the best treatment option for patients with mRCC was immunotherapy. This modality of treatment was broadened in its application as our understanding 68 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 68 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update of RCC tumor biology improved. Because most patients with ccRCC have mutations involving the VHL tumor suppressor gene, with resultant increased transcription of VEGF, it became clear that this ligand was just as viable, and valuable of a target as the corresponding receptor tyrosine kinases.41 Bevacizumab is a humanized monoclonal antibody that inhibits VEGF, and has demonstrated efficacy in phase II studies of mRCC patients showing monotherapy increased the median time to disease progression 4.8 months compared with placebo at 2.5 months (P , .001).42 In a randomized, double-blind, phase III trial in mRCC patients who were previously untreated, patients were randomized to bevacizumab plus IFN-a or placebo plus IFN-a. The primary endpoint was OS with secondary endpoints of PFS and safety. Median OS was 23.3 months with bevacizumab plus IFN-a and 21.3 months with placebo plus IFN-a (unstratified hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76-1.10; P 5 .3360; stratified HR, 0.86; 95% CI, 0.72-1.04; P 5 .1291). These results may be obscured by the fact that patients (. 55%) in both arms received at least one postprotocol therapy, possibly confounding the OS analysis. The median duration of PFS was significantly longer at 10.2 months in the bevacizumab plus IFN-a group compared with placebo plus IFN-a at 5.4 months (P 5 .0001). The most common bevacizumab-related toxicities were bleeding, hypertension, proteinuria, and venous or arterial thromboembolism. Serious AEs were reported in 31% of patients treated with bevacizumab plus IFN-a and in 19% of patients treated with placebo plus (ORR), PFS, and OS, are displayed in Table 1. In addition, the targets for each of these therapies are depicted in Figure 1. Sequence of Therapy Sequencing therapy, dosing, management of side effects, and duration of treatment are all important aspects of management that contribute to optimization of quality and quantity of life. With most mRCC patients who are started on targeted therapy, a decision regarding sequencing of therapy will at With regard to therapy selection after disease progression following cytokine therapy, there are data demonstrating efficacy supporting the use of most targeted agents, including bevacizumab, sorafenib, sunitinib, everolimus, pazopanib, and axitinib. IFN-a.43,44 With an overall tolerable and manageable toxicity profile, as well as a 5-month improvement in PFS, bevacizumab plus IFN-a was granted FDA approval for the treatment of patients with mRCC in 2009. Each of the targeted therapies discussed have been FDA-approved in the past decade, and have subsequently transformed the way mRCC is managed. Their most vital statistics, overall response rate some point occur, as virtually all patients receiving one of these drugs will experience progression of the disease requiring initiation of another agent. With regard to therapy selection after disease progression following cytokine therapy, there are data demonstrating efficacy supporting the use of most targeted agents, including bevacizumab, sorafenib, sunitinib, everolimus, pazopanib, and axitinib.22,26,40,42,45,46 TABLe 1 Characteristics of Available Targeted Therapies for Metastatic RCC Drug Sorafenib22,93 Sunitinib23,25 Pazopanib26,94 Axitinib27 Tivozanib28 Temsirolimus11 Everolimus12,39 Bevacizumab 1 IFN-a43,44 N ORR (%) Median PFS (mo) Median OS (mo) 451 335 290 361 250 209 277 327 5.2 47.0 30.0 19.9 n/a 8.6 1.0 31 5.5 11.0 9.2 6.7 11.9 3.8 4.9 10.2 19.3 26.4 22.9 n/a n/a 10.9 14.8 23.3 IFN-a, interferon a; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma. Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 69 40041700002_RIU0562.indd 69 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued Receptor tyrosine kinase Sunitinib Sorafenib Axitinib Pazopanib Tivozanib Normoxia P13K Growth Factor Hypoxia Bevacizumab Ras PTEN Sorafenib Raf AKT TSC Temsirolimus Everolimus MEK mTOR MAPK HIF-1a E2 E L O B Cul2 E L O C VHL – / – RB OH PRO PRO HIF-1a HIF-1b VHL HIF-1a E2 E L O B Cul2 Hsp90 RB E L O C Proteosomal degradation VEGF-A CAIX CXCR4 EGFR TGF GLUT1 angiogenesis pH regulation metastasis tumor growth tumor growth glucose control Figure 1. The pertinent targets for bevacizumab, sunitinib, sorafenib, axitinib, pazopanib, tivozanib, temsirolimus, and everolimus are depicted in the figure. Bevacizumab binds directly to VEGF to prevent its binding to the VEGF receptor. Sunitinib, sorafenib, axitinib, pazopanib, and tivozanib bind to and inhibit several tyrosine kinase receptors, most importantly the VEGF receptor. Sorafenib is also a Raf inhibitor that blocks several downstream tumor-promoting events. Temsirolimus and everolimus are both mTOR inhibitors resulting in blockade of HIF1-a and its downstream effects. Pathways can vary based upon the oxygen tension in the microenvironment. Given that several targeted agents are now available, and that most patients are initially treated with one of these agents, the majority of the literature and investigation focus has been on these therapies. Because sorafenib and sunitinib were the first of the targeted agents available, much has been written on the sequencing of these options. Superiority of one of these agents over another has not been demonstrated in a randomized trial, but retrospective studies have examined this issue. In a small study, Tamaskar and colleagues showed that, in patients who had previously been treated for mRCC, the magnitude of tumor shrinkage was greater in the patients treated with sunitinib than with those treated with sorafenib.47 Sablin and associates showed that the sequence of sorafenib followed by sunitinib was superior to sunitinib followed by sorafenib. OS was 135 weeks versus 82 weeks (P 5 .04), and with regard to PFS, the median was 28 weeks in the sorafenib followed by sunitinib group versus 17 weeks in the sunitinib followed by sorafenib group; however, this was not statistically significant (P 5 .064).48 In another small study, data from Dudek and colleagues also suggested that the sequence of sorafenib followed by sunitinib was favored over the converse sequence with differences in OS of 102 weeks and 45 weeks (P 5 .061), as well as a PFS of 78 weeks and 37 weeks (P 5 .117).49 The results of these two studies favoring the sorafenib followed by sunitinib sequence are contrasted with a similar, but more robust study, again looking at differences in OS and PFS between the two sequencing options. This study demonstrated no difference in either outcome regardless of the sequence.50 All of these studies are limited by their retrospective nature and therefore are most useful for generating questions and less useful for drawing firm conclusions to guide management of mRCC patients. Evidence to support the use of another TKI, axitinib, following failure of prior sorafenib treatment has also been reported. The median PFS was slightly greater than 7 months, with a response rate of 21% and 56% of patients experiencing tumor regression.51 To date, the only level I evidence to assist in decision making in the clinical scenario of disease progression on a TKI was reported by Motzer and colleagues, showing that patients 70 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 70 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update who had previously been treated with sunitinib or sorafenib, who then progressed and were treated with everolimus, experienced a PFS of 4.9 months compared with 1.9 months for those who were treated with placebo.12,39 Second-line treatment with sunitinib following There are clearly multiple clinical scenarios in which questions remain regarding optimal sequencing of therapy; for instance, as patients are living longer with these therapies, more answers will be needed for the third-line and beyond. Fortunately, data are There are clearly multiple clinical scenarios in which questions remain regarding optimal sequencing of therapy; for instance, as patients are living longer with these therapies, more answers will be needed for the third-line and beyond. primary treatment with bevacizumab has also demonstrated efficacy with a PFS of 29.7 weeks and a response rate of 23%. There are also retrospective data to support the use of a TKI, specifically sorafenib, in the third-line setting following failure of sunitinib in the first-line and mTOR failure in the second-line. DiLorenzo and colleagues demonstrated a 4-month PFS and a 7-month OS in this setting. 52 With several therapy sequences available, the therapeutic options are growing for patients where, less than a decade ago, the field was bleak. The characteristics of the sequences just discussed are outlined in Table 2. now becoming available suggesting efficacy with a rechallenge of a previously effective TKI; this will undoubtedly open further opportunities for patients.53 Clinical trials are needed to answer these pressing sequencing questions. Immunotherapy Despite the rapid changes in the landscape of mRCC treatment over the past decade, improvements in PFS is what emerging therapies have offered; only therapy with IL-2 has produced durable complete responses. The FDA approved IL-2 in 1992 for the treatment of mRCC based on its success in some patients. However, durable complete responses are rare, as approximately 7% of patients will experience freedom from disease, and eligible patients are limited to those with clear cell histology with high carbonic anhydrase 9 expression, free of metastases to the liver, brain, or bone, and good performance status as this therapy is toxic. Finally, few centers offer this therapy due to lack of experience, which limits its use to specialized centers. Despite these limitations, this treatment modality remains the best option for the right patient and should be considered in the treatment algorithm. IFNs were the first biologics to be evaluated in the mRCC setting demonstrating response rates of up to 30%.54 Reports of mRCC responding to IFN-a appeared first in the 1980s.55,56 Studies leading to its adoption as a treatment option showed response rates of 13% to 30% including both partial and complete responses, with remissions of 1 month to more than 12 months in those with partial responses and ≥ 22 months in complete responders.56-59 In a meta-analysis of immunotherapy for mRCC, combined data gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared with 2.5% in 10 nonimmunotherapy TABLe 2 Characteristics of Targeted Therapies in Second- and Third-line Setting First Line Second Line Third Line ORR (%) Median PFS Median OS Bevacizumab Sorafenib Sorafenib Sunitinib Sorafenib/sunitinib Sorafenib or sunitinib Sunitinib95 Axitinib96 sunitinib50 Sorafenib50 Everolimus12 — — — — — — 23.0 22.6 — — 1.8 23.0 30.4 weeks 7.4 months 18.8 months 17.7 months 4.9 months 7.1 months 47.1 weeks 13.6 months 30.0 months 35.4 months 14.8 months 14.5 months Sorafenib52 23.5 4 months 7 months Sunitinib Bevacizumab 1 everolimus74 Everolimus or temsirolimus Median progression-free survival (PFS) and median overall survival (OS) for the sorafenib-sunitinib and the sunitinib-sorafenib sequences represents the total for both drugs, whereas for the others these data only represent either second-line or third-line. ORR, overall response rate. Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 71 40041700002_RIU0562.indd 71 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued control arms, and 4.3% in 2 placebo arms. Median survival averaged 13.3 months (range by arm, 6 to 271 months).60 The authors of the meta-analysis concluded that IFN-a provides a modest survival benefit compared with other commonly used treatments and should be considered for the control arm of future studies of systemic agents, which was done in the sunitinib, temsirolimus, and bevacizumab phase III studies preceding their FDA approval. However, as with IL-2, IFN-a has in large part been supplanted by the emerging targeted therapies and this is most notable in that the newer TKIs in phase III studies are being compared with other TKIs.27,28 The prospective outlook for immunotherapy shows several treatment options emerging. Dendritic cell-based vaccines are a therapeutic approach in which patients undergo leukapheresis to isolate dendritic cells. These cells are then loaded with tumor-specific antigens and reintroduced into the patient to initiate a specific cytotoxic T-cell response directed toward the malignant cells. This approach has already been FDA approved in prostate cancer and several other malignancies have vaccines in various stages of development.61-65 Phase II results of the AGS-003 dendritic cell-based vaccine for RCC were recently reported in which AGS-003 was being evaluated in combination with sunitinib.66 The interest in this particular combination arose from the knowledge that sunitinib has nonspecific immune modulatory effects, including an ability to decrease regulatory T cells, which in effect could result in synergistic effects over what could be achieved with either treatment alone. The study results showed that patients treated concurrently with AGS-003 and sunitinib were able to expand CD281 (one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T-cell activation) memory cytotoxic T lymphocytes (CTL) with a broad range of effector functions. In addition, the study showed that expansion of CD281 CTL revealed a trend with PFS posttreatment. Nine of 11 (82%) subjects with PFS of . 10 months demonstrated CTL population increases whereas only 2 of 4 subjects (50%) with PFS , 10 months showed increases in this specific CTL population. The authors concluded that the combination of AGS-003 and sunitinib can decrease the percentage of T regulatory cells with a concurrent expansion of CD281 CTL, thereby overcoming tumor-induced immunosuppression and potentially improving clinical outcomes in the context of PFS.66 In the authors’ previous study, the preliminary median PFS was 12.5 months in patients who received both AGS-003 and sunitinib, and had intermediate to poor risk factors.62 Further studies allowing for assessment of survival advantage related to AGS-003 are anticipated. Girentuximab is a chimeric monoclonal antibody directed at carbonic anhydrase IX (CAIX), which is expressed on the cell surface of ccRCC, but not on healthy renal tissue. Antibody binding to CAIX antigen on tumor cells triggers an immune reaction, antibody-dependent cellular cytotoxicity. Girentuximab showed positive results in phase I and II trials when administered in combination with cytokine therapy.67,68 It was recently evaluated in a phase III adjuvant therapy trial for patients with nonmetastatic ccRCC who are at high risk of relapse after surgery. Enrollment included 864 patients assessed for disease-free survival and OS. Patients underwent either a radical or partial nephrectomy and had no detectable metastases. During the 6-month treatment phase, patients received weekly injections of girentuximab. No significant safety issues have been reported. In a recent press release, it was reported that the trial failed to meet its primary endpoint and therefore the trial has been terminated, which is unfortunate as to date the FDA has not previously approved any drug for the adjuvant therapy of ccRCC. Girentuximab continues to be evaluated for its role in diagnostics related to RCC. Therapy Selection Although much progress has been made in systemic therapy for patients with metastatic ccRCC over the past decade, as evidenced by the preceding discussion, there are areas in which much work remains to be done. There is a clear need for evidence-based clarification of the management of metastatic clear cell patients with regard to which patients should receive which therapy and in which order it should proceed. To date, the selection of an agent for the treatment of a patient with metastatic ccRCC has, in large part, been determined by one of the TKIs, unless the patient is an optimal candidate to receive IL-2. Unfortunately, the selection of a particular TKI is not data driven, but rather selected, more or less, based on the practitioners’ experience. This is an area in which molecular characterization of patients may allow for making rational decisions when selecting therapy. A recent study has indicated an effort to elucidate a molecular means for therapy selection. The objective of the study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a survival advantage in patients treated for metastatic ccRCC. Genes encoding for efflux transporters, metabolizing enzymes, and drug targets were 72 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 72 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update evaluated for single nucleotide polymorphisms that were associated with PFS and OS in 136 metastatic ccRCC patients treated with sunitinib. Multivariate analysis showed that PFS was significantly improved when particular alleles were present in the cytochrome P450 (CYP450) pathway, in NR1I3, a gene encoding a protein regulating the expression of CYP450 family members, and in ABCB1, a gene encoding a glycoprotein efflux transporter. Carriers with each of these three alleles (n 5 95) were considered to have a favorable genetic profile, and had an improved PFS and OS as compared with noncarriers with a median PFS and OS of 13.1 versus 7.5 months and 19.9 versus 12.3 months, respectively.69 Another study evaluated biomarkers to predict response to with the IL-8 wild-type genotype, the IL-8 2767TT variant genotype showed inferior PFS with a median of 48 weeks versus 27 weeks, respectively (P 5 .009). The HIF1a 1790AG genotype, with a median PFS of 20 weeks, was associated with inferior PFS and reduced RR compared with its wild-type, which had a median PFS of 44 weeks (P 5 .03). Reductions in RR were detected for the NR1I2 25385TT genotype, compared with its wild-type, 37% versus 50% respectively (P 5 .03), and for the VEGFA 1498CC genotype compared with the TT genotypes, 33% versus 51%. The authors concluded that germline variants in genes related to the metabolism and mode of action of pazopanib may predict treatment response in patients with RCC, and may explain why This molecular approach to stratifying responders and nonresponders reflects the paradigm shift that is occurring in medicine as we move from a one-size-fits-all model to a more tailored approach such that patients are treated based on their particular genetic composition. pazopanib. The authors tested the hypothesis that the variable response to pazopanib between patients is partially dependent on germline genetic variants, and if so, is there a genetic association with PFS and ORR. They evaluated 27 functional polymorphisms within 13 genes that were selected based on the following criteria: involvement in angiogenesis (eg, IL-8, HIF1a) or the metabolism (eg, CYP3A4/5), disposition (eg, permeability glycoprotein, breast cancer resistance protein), or mode of action (eg, VEGF, VEGFR) of pazopanib. The study cohort was comprised of 397 patients with RCC. The results showed that three polymorphisms in IL-8 and HIF1a and five polymorphisms in HIF1a, NR1I2, and VEGFA showed nominally significant association (P # .05) with PFS and response rate (RR), respectively. Compared some patients fail anti-angiogenesis therapy, and may support the use of other therapeutic strategies in these patients.70 This molecular approach to stratifying responders and nonresponders reflects the paradigm shift that is occurring in medicine as we move from a one-size-fits-all model to a more tailored approach such that patients are treated based on their particular genetic composition. The previous two studies cited regarding the potential identification of molecular markers to select therapy were published within the last year demonstrating that this approach remains in a developmental stage awaiting validation. Combination Therapy Another strategy that has been employed in treatment of mRCC during the targeted-therapy era is combination therapy. Several combinations have been evaluated. In 2008, Sosman and colleagues reported on the combination of sorafenib and bevacizumab in patients with mRCC. Twenty-one of 46 patients (46%) experienced a partial response by RECIST criteria, including 2 patients with sarcomatoid features. In addition, the median time to progression was 11.2 months with 10 patients (21%) progression-free at 18 months. Toxicities led to a lower dose of each agent, and bevacizumab appeared to significantly increase sorafenibrelated toxicity, especially handfoot syndrome.71 In 2009, Feldman and colleagues reported on combination of bevacizumab and three increasing doses of sunitinib: 25 mg, 37.5 mg, and 50 mg. Twentyfive patients received treatment at one of the three dose levels. Grade 4 hemorrhage, a dose-limiting toxicity, occurred in one patient in the 25-mg cohort and one patient in the 50-mg cohort. The maximally tolerated dose was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of AEs. One complete and 12 partial responses were noted, providing an ORR of 52%. The authors concluded that, in this trial of patients with mRCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension, vascular and hematologic toxicities at the highest dose level, and they did not plan to pursue additional study of this regimen at these doses in patients with mRCC.72 Also in 2009, Patel and colleagues evaluated temsirolimus and sunitinib in patients with mRCC. However, the study was terminated because of dose-limiting toxicity Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 73 40041700002_RIU0562.indd 73 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued observed including grade 3 rash, thrombocytopenia, cellulitis, and gout reported at low starting doses of both agents. This lead the authors to conclude that concomitant use of intravenous temsirolimus, 15 mg weekly, and oral sunitinib, 25 mg daily, is not recommended.73 In 2010, Hainesworth and colleagues evaluated the efficacy and toxicity of bevacizumab combined with everolimus in mRCC patients. Eighty patients (50 untreated, 30 previously treated) entered this trial. The combination of the two drugs showed activity in both groups. Median PFS in previously untreated and previously treated patients were 9.1 and 7.1 months, respectively. The duration of PFS in both groups was greater than the 4.9 month PFS reported in the phase III trial of everolimus, and the 4.8 month PFS reported in the randomized phase II trial of bevacizumab. With regard to the bevacizumab/everolimus combination, ORRs of 30% and 23% were similar in both groups. The regimen was well tolerated by most patients, with a toxicity profile as expected based on the known toxicities of the two drugs. Based on these results, it was concluded that the combination is active and well tolerated in the treatment of mRCC patients, either as firstline or after treatment with a TKI. However, the authors are careful to point out that the benefits of this combination, versus sequential use of these two drugs would require further investigation.39,42,74 The combination of mTOR inhibitor and TKI has been evaluated in three studies reported in the past year. Semrad and colleagues evaluated temsirolimus and pazopanib in combination therapy but did not pursue further evaluation due unacceptable dose limiting toxicity, specifically grade 3 fatigue and electrolyte disturbances.75 Molina and associates evaluated everolimus combined with sunitinib in 20 pretreated patients with mRCC, 7 of whom had non-ccRCC. Patients were divided and placed into five varying dosing regimens. The authors identified a schedule of 20 mg of everolimus weekly and 37.5 mg of sunitinib daily was tolerated as chronic therapy. Five of the subjects (25%) had confirmed partial responses, three of whom had non-ccRCC. The other dosing combinations, namely, the daily dosing, were associated with significant acute and chronic toxicities, which were prohibitive. What is particularly encouraging in this study was that 43% of patients with non-ccRCC experienced a partial response.76 Harzstark and colleagues completed a phase I study of everolimus and sorafenib in 20 mRCC patients in which they compared three dosing regimens, each of which included daily dosing of each drug. Everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily was established as the maximum-tolerated dose. Treatment-related AEs occurring in . 20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved partial responses by RECIST criteria, all occurring in treatment-naive patients. Seven of eight patients treated at maximally multicenter, randomized trial, were recently reported in which patients who had untreated metastatic RCC were randomly assigned (2:1:1) to receive the combination of bevacizumab every 2 weeks and temsirolimus weekly (group A), or a standard treatment: sunitinib daily (group B), or the combination of IFN-a 3 times per week and bevacizumab every 2 weeks (group C). The primary endpoint was PFS at 48 weeks, and was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term OS. During the period of March 2008 to May 2009, 171 patients were randomized: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29.5% (26 of 88 patients) in group A, 35.7% (15 of 42) in group B, and 61.0% (25 of 41) in group C. Median PFS was 8.2 months in group A, 8.2 months in group B, and 16.8 months in group C. Forty-five of 88 patients (51%) in group A stopped treatment for reasons other than progression compared with 5 (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse AEs were reported in 68 of 88 patients (77%) in group A versus 25 (60%) of 42 in group B and 28 of 40 (70%) in group C. The toxicity of the experimental group, temsiroli- Unfortunately, in most instances, combination therapy has resulted in more toxicity than improvement in outcomes and as a result has not become commonplace practice. tolerated dose experienced a partial response or stable disease. The authors concluded that the combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with mRCC.77 Finally, the results from the TORAVA study, a large, phase II, mus and bevacizumab, was much higher than anticipated and limited treatment continuation. The clinical activity observed was low and therefore this regimen is not recommended for first-line treatment in patients with mRCC.78 Unfortunately, in most instances, combination therapy has resulted in more toxicity than improvement 74 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 74 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update in outcomes and as a result has not become commonplace practice. Systemic Therapy for Metastatic non-ccRCC Systemic therapy for patients with metastatic non-ccRCC has not progressed as quickly as therapy for metastatic ccRCC. In a 2002 retrospective review of treatment outcomes and assessment of survival associated with metastatic non-ccRCC, Motzer and colleagues evaluated 64 patients. Twenty-six patients had collecting duct RCC, 12 had chromophobe, 18 had papillary, and 8 patients had tumors that could not be classified for specific tumor histology. Forty-three patients were treated with 86 systemic therapies, including 37 cytokine therapies, and 2 patients (5%) had a partial response. The median OS time was 9.4 months. This short survival period likely reflects the large number of patients included with collecting duct histology, a known aggressive subtype. However, only 5% of patients receiving systemic therapy showed any response highlighting and supporting the authors’ conclusion that treatment with novel agents on clinical trials is warranted.79 With regard to IL-2 therapy, Upton and associates evaluated response based on pathologic subtype of RCC and found response rates of 21% (30/146) for patients with ccRCC versus 6% (1/17) for patients with variant or indeterminate type RCC (P 5 0.20).80 This experience has led to non-ccRCC being labeled a contraindication to treatment with IL-2. With the advent of TKIs and demonstrated efficacy in metastatic ccRCC, they were soon evaluated for the treatment of metastatic nonccRCC, and with good rationale, as both papillary and chromophobe histologies have demonstrated no difference in VEGF expression when compared with ccRCC.81 In 2008, Choueiri and colleagues reported on 41 patients with papillary histology and 12 patients with chromophobe histology treated with sorafenib or sunitinib. The RR, PFS, and OS for the entire cohort was 10%, 8.6 months, and 19.6 months, respectively. Three (25%) chromophobe patients achieved a response, two patients were treated with sorafenib, and one patient was treated with sunitinib. The PFS for the whole chromophobe cohort was 10.6 months. Two (4.8%) papillary patients achieved a response with sunitinib, and PFS for the whole papillary cohort was 7.6 months. The PFS for sunitinibtreated papillary patients was 11.9 months compared with 5.1 months for sorafenib-treated patients (P , .001). However, although there does appear to be some extension of the PFS for patients with chromophobe and papillary RCC, the ORR is low.82 Molina and colleagues also evaluated sunitinib in metastatic non-ccRCC in a phase II trial. Twenty-three patients were enrolled, including eight patients with papillary, two with chromophobe, four with collecting duct, one with medullary, five with unclassified, and three with hereditary leiomyomatosis and renal cell cancer-related RCC. Unfortunately, the trial was stopped early because of slow accrual; of note, no responses were seen in the eight patients with papillary RCC. In the 22 evaluable patients, a partial response was achieved in 1 patient with unclassified RCC, stable disease in 15, and progression in 6. The median PFS was 5.5 months in all 23 patients, and 5.6 months for the 8 papillary patients.83 These data, in addition to the previous study discussed, consistently demonstrates lower RRs of metastatic non-ccRCC compared with RRs in metastatic ccRCC for the most commonly used TKIs. However, a recently published multicenter, phase II trial of sunitinib in 25 patients with metastatic non-ccRCC (22 patients had papillary RCC, and 3 had chromophobe RCC) demonstrated partial responses in 11 patients for an RR of 36% and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months, and median PFS was 6.4 months.84 These data combined suggest that the use of sunitinib in metastatic non-ccRCC patients is a reasonable option. Other TKIs have been evaluated in patients with papillary RCC, erlotinib, an oral EGFR TKI showed an 11% ORR in 45 patients with metastatic papillary RCC and the probability of freedom from treatment failure at 6 months was 29%. The authors concluded that a better molecular understanding of papillary RCC was necessary before moving forward with additional trials of erlotinib or similar agents.85 Regarding mTOR inhibitors, Hudes and colleagues included 124 metastatic non-ccRCC patients in their phase III trial of temsirolimus, which comprised 20% of the total cohort. Although temsirolimus was demonstrated to be superior to combination with IFN-a or IFN-a alone, subset analysis was not completed to evaluate if this effect remained in those patients with non-ccRCC histology. However, a subsequent subset analysis was published showing that based on histology, patients with non-ccRCC who received temsirolimus, like their ccRCC counterparts, did better in terms of tumor reductions, OS, and PFS than those who received IFN-a.11,86 This is currently the only level one evidence available to support the use of an agent in metastatic non-ccRCC and supported the FDA approval of the use of temsirolimus for this indication. This is reflected in the NCCN guidelines Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 75 40041700002_RIU0562.indd 75 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued for the management of metastatic non-ccRCC in which temsirolimus is considered first-line therapy for these patients; however, the authors state that clinical trial is the “preferred” first option.38 The preceding discussion has focused on the more commonly encountered subtypes of metastatic non-ccRCC. Less commonly encountered is the collecting duct histologic subtype, which requires a different approach to therapy. This subtype has been shown to be a more aggressive disease than its clearcell counterpart, and there is a significantly higher likelihood for the patient to present with metastatic disease, and a 3-year disease-specific survival rate of 58% compared with 79% for clear cell.87 Several systemic therapeutic approaches to these patients have been tried, including immunotherapy and chemotherapy, with varying results.80,88 To date, case reports of responses to TKIs, including sorafenib and sunitinib, are reported in the literature but large series are not yet available.89,90 Embryologically, the collecting ducts of the nephron develop from the ureteric bud and therefore are of urothelial origin, providing rationale for treatment with regimens effective against urothelial cell carcinoma. A prospective, phase II study of gemcitabine plus platinum for metastatic collecting duct was completed predicated on this fact. A total of 23 patients who had not received prior systemic therapy were treated with gemcitabine and cisplatin or carboplatin (for patients with renal insufficiency), and objective RR was the primary endpoint. There was one complete response and five partial responses for an objective RR of 26%. The median PFS and OS were 7.1 and 10.5 months, respectively. Toxicity was mainly hematological with grade 3 to 4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The authors concluded that platinumbased combination is an active and safe regimen for first-line treatment of patients with metastatic collecting duct carcinoma, and should be considered the standard regimen in these patients.91 There are other even less commonly experienced histologic subtypes. As a result of their relative infrequent presentation, the experience with treating these patients is minimal and there is no standard therapy. The most virulent of these lesions is medullary RCC with a reported mean survival of 4 months from the time of diagnosis.92 This highlights a desperate need for a molecular understanding of this disease in order to develop rationalbased therapy, but with so few patients, obvious challenges arise. Conclusions This review and update has looked at systemic therapy for mRCC from the first successful therapeutic option in immunotherapy through the current status with numerous targeted agents, including TKIs and mTOR inhibitors. The essential studies leading to their approval by the FDA for their respective indications has been reviewed. A few points emerge from this. First, complete responders remain, for the most part, confined to a small portion of patients receiving immunotherapy, specifically with IL-2. Second, the most realistic expectation that mRCC patients receiving targeted therapies can have is in prolongation of their PFS, as virtually all patients receiving these drugs will experience progression of their disease. Third, although there are some targeted therapies with longer PFSs than others, it remains unclear which patients will have optimal responses to any given drug; therefore, the current state-of-the art is that a patient’s treating oncologist will select a therapy based on their experience and interpretation of the literature. Fourth, because therapy selection remains haphazard, investigation into defining predictive molecular markers is imperative to keep up with the pace at which new therapeutic options are becoming available. Two studies that are attempting to do this at a molecular level were discussed and highlight the fact that this science is in its infancy and will not likely be common practice in the clinic in the next few years. Finally, a review of systemic therapy for metastatic nonccRCC demonstrated that, although there are options for treatment available, they generally do not perform as well in the histologic subtypes when compared with ccRCC. This highlights a need for a deeper molecular understanding of these diseases so that a rationale for therapy can be designed. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Amato RJ. Chemotherapy for renal cell carcinoma. Semin Oncol. 2000;27:177-186. Yagoda A, Petrylak D, Thompson S. Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol Clin North Am. 1993;20:303-321. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212-236. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States. JAMA. 1999;281:1628-1631. Gupta K, Miller JD, Li JZ, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34:193-205. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60:615-621. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271:907-913. Fyfe GA, Fisher RI, Rosenberg SA, et al. Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1996;14:2410-2411. Fosså S. Interferon in metastatic renal cell carcinoma. Semin Oncol. 2000;27:187-193. Gnarra JR, Duan DR, Weng Y, et al. Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochim Biophys Acta. 1996;1242:201-210. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256-4265. 76 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 76 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260:1317-1320. Leung SK, Ohh M. Playing tag with HIF: The VHL story. J Biomed Biotechnol. 2002;2:131-135. Bárdos JI, Ashcroft M. Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays. 2004;26:262-269. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38-47. Ishikawa F, Miyazono K, Hellman U, et al. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 1989;338:557-562. Luetteke NC, Lee DC. Transforming growth factor alpha: expression, regulation and biological action of its integral membrane precursor. Semin Cancer Biol. 1990;1:265-275. Ellis LM. Epidermal growth factor receptor in tumor angiogenesis. Hematol Oncol Clin North Am. 2004;18:1007-1021, viii. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 suppl 16):15-18. Wilhelm SM, Carter C, Tang L, et al. 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. 2004;64:7099-7109. Escudier B, Eisen T, Stadler W, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta 25. 26. 27. 28. 29. 30. 31. 32. 33. in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471-478. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584-3590. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061-1068. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939. TAVEO and Astellas announce tivozanib successfully demonstrated progression-free survival superiority over sorafenib in patients with advanced renal cell cancer in phase 3 TIVO-1 trial. [press release]. Cambridge, MA: AVEO Pharmaceuticals, Inc. and Astellas Pharma Inc.; January 3, 2012. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell. 2000;103:253-262. Fingar DC, Richardson CJ, Tee AR, et al. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004;24:200-216. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1a expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22:7004-7014. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729-734. Bhatta-Dhar N, Reuther A, Zippe C, Klein EA. No difference in six-year biochemical failure rates with or without pelvic lymph node dissection during radi- 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. cal prostatectomy in low-risk patients with localized prostate cancer. Urology. 2004;63:528-531. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004;4:335-348. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 2006;66:5549-5554. Harding MW. Immunophilins, mTOR, and pharmacodynamic strategies for a targeted cancer therapy. Clin Cancer Res. 2003;9:2882-2886. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926-1945. National Comprehensive Cancer Institute. NCCN Guidelines on Kidney Cancer – Version 2. 2012. http://www.nccn.org/professionals/physician_gls/pdf/ kidney.pdf. Accessed November 20, 2012. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor–targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti–vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427-434. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic MAin PoinTs • Available targeted therapies that have been US Food and Drug Administration–approved over the past decade for metastatic renal cell carcinoma (mRCC) include sorafenib, sunitinib, pazopanib, axitinib, tivozanib, temsirolimus, everolimus, and bevacizumab 1 interferon-a. These therapies have subsequently transformed the way mRCC is managed. • Only therapy with interleukin-2 (IL-2) has produced durable complete responses. However, durable complete responses are rare, as approximately 7% of patients will experience freedom from disease. Few centers offer this therapy due to lack of experience, which limits its use to specialized centers, although this treatment modality remains the best option for the right patient and should be considered in the treatment algorithm. • The prospective outlook for immunotherapy shows several treatment options emerging. Dendritic cell-based vaccines are a therapeutic approach in which patients undergo leukapheresis to isolate dendritic cells. Girentuximab is being evaluated in a phase III adjuvant therapy trial for patients with nonmetastatic clear-cell RCC (ccRCC) who are at high risk of relapse after surgery. • Although there are some targeted therapies with longer progression-free survival than others, it remains unclear which patients will have optimal responses to any given drug and therefore the current state-of-the art is that a patient’s treating oncologist will select a therapy based on his or her experience and interpretation of the literature. • Because therapy selection remains haphazard, investigation into defining predictive molecular markers is imperative and necessary to keep up with the pace at which new therapeutic options are becoming available. • A review of systemic therapy for metastatic non–clear-cell RCC demonstrated that, although there are options for treatment available, they do not perform as well in the histologic subtypes when compared with ccRCC. This highlights a need for a deeper molecular understanding into these diseases so that a rationale for therapy can be designed. Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 77 40041700002_RIU0562.indd 77 12/02/13 2:27 PM Systemic Therapy for mRCC: An Update continued 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-2111. Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28: 2144-2150. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16-24. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007;8:975-984. Tamaskar I, Garcia JA, Elson P, et al. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol. 2008;179:81-86; discussion 86. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29-34; discussion 34. Dudek AZ, Zolnierek J, Dham A, et al. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115:61-67. Buchler T, Klapka R, Melichar B, et al. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma—data from the Czech registry. Ann Oncol. 2012;23:395-401. Rini BI, Wilding GT, Hudes G, et al. Axitinib (AG013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib. J Clin Oncol. 2007;25(suppl):5032. Di Lorenzo G, Buonerba C, Federico P, et al. Thirdline sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma. Eur Urol. 2010;58:906-911. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer. 2010;116:5400-5406. Choudhury M, Efros M, Mittelman A. Interferons and interleukins in metastatic renal cell carcinoma. Urology. 1993;41(suppl 1):67-72. Hengst JC, Kempf RA, Kan-Mitchell J, et al. Immunological effects of recombinant interferon-alpha 2 in cancer patients. J Biol Response Mod. 1983;2:516-527. Kuzmits R, Scheithauer W, Ludwig H, Flener R. Interferon (IFN) therapy (recombinant IFN-alpha-2C or recombinant IFN-gamma) in metastasized hypernephroma. [Article in German] Acta Med Austriaca. 1985;12:129-134. Sarna G, Figlin R, de Kernion J. Interferon in renal cell carcinoma. The UCLA experience. Cancer. 1987; 59(suppl 3):610-612. de Mulder PH, Debruyne FM, Franssen MP, et al. Phase I/II study of recombinant interferon alpha and gamma in advanced progressive renal-cell carcinoma. Cancer Immunol Immunother. 1990;31:321-324. de Mulder PH, Oosterhof G, Bouffioux C, et al. EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group. Br J Cancer. 1995;71:371-375. Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005;(1): CD001425. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. Amin A, Dudek A, Logan T, et al. A phase II study testing the safety and activity of AGS-003 as an immunotherapeutic in subjects with newly diagnosed 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. advanced stage renal cell carcinoma in combination with sunitinib. J Clin Oncol. 2010;28(suppl): Abstract 4588. Logan T, Amin A, Cohen V, et al. A phase I/II study of AGS-003, a personalized immunotherapeutic evaluated in newly diagnosed metastatic renal cell carcinoma (mRCC) subjects. J Clin Oncol. 2010;28(suppl): Abstract 379. Phuphanich S, Wheeler CJ, Rudnick J, et al. Gliomaassociated antigens associated with prolonged survival in a phase I study of ICT-107 for patients with newly diagnosed glioblastoma. J Clin Oncol. 2011;29(suppl): Abstract 2042. López MN, Pereda C, Segal G, et al. Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol. 2009;27:945-952. Figlin RA, Nicolette CA, Amin A, et al. Monitoring T-cell responses in a phase II study of AGS-003, an autologous dendritic cell-based therapy in patients with newly diagnosed advanced stage renal cell carcinoma in combination with sunitinib. J Clin Oncol. 2011;29(suppl): Abstract 2532. Bleumer I, Oosterwijk E, Oosterwijk-Wakka JC, et al. A clinical trial with chimeric monoclonal antibody WX-G250 and low dose interleukin-2 pulsing scheme for advanced renal cell carcinoma. J Urol. 2006;175: 57-62. Siebels M, Rohrmann K, Oberneder R, et al. A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX®) and interferon-alpha-2a in metastatic renal cell carcinoma patients. World J Urol. 2011;29:121-126. van der Veldt AA, Eechoute K, Gelderblom H, et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 2011;17:620-629. Xu CF, Bing NX, Ball HA, et al. Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes. J Clin Oncol. 2011;29:2557-2564. Sosman JA, Flaherty KT, Atkins MB, et al. Updated results of phase I trial of sorafenib and bevacizumab in patients with metastatic renal cell cancer (mRCC). J Clin Oncol. 2008;26(suppl): Abstract 5011. Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1432-1439. Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2009;7:24-27. Hainsworth JD, Spigel DR, Burris HA, et al. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol. 2010;28:2131-2136. Semrad TJ, Eddings C, Dutia MP, et al. Phase 1 study of temsirolimus and pazopanib in solid tumors with emphasis on renal cell carcinoma. J Clin Oncol. 2011;29(suppl): Abstract e15113. Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2012;118: 1868-1876. Harzstark AL, Small EJ, Weinberg VK, et al. A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer. 2011;117:4194-4200. Négrier S, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12:673-680. Motzer R, Bacik J, Mariani T, et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non–clear-cell histology. J Clin Oncol. 2002;20: 2376-2381. Upton MP, Parker RA, Youmans A, et al. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother. 2005;28: 488-495. Jacobsen J, Grankvist K, Rasmuson T, et al. Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int. 2004;93: 297-302. Choueiri T, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26:127-131. Molina AM, Feldman DR, Ginsberg MS, et al. Phase II trial of sunitinib in patients with metastatic nonclear cell renal cell carcinoma. Invest New Drugs. 2010;30:335-340. Lee JL, Ahn JH, Lim HY, et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. Ann Oncol. 2012;23:2108-2114. Gordon M, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009;27:5788-5793. Dutcher J, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol. 2009;26:202-209. Wright JL, Risk MC, Hotaling J, Lin DW. Effect of collecting duct histology on renal cell cancer outcome. J Urol. 2009;182:2595-2599. Chao D, Zisman A, Pantuck AJ, et al. Collecting duct renal cell carcinoma: clinical study of a rare tumor. J Urol. 2002;167:71-74. Ansari J, Fatima A, Chaudhri S, et al. Sorafenib induces therapeutic response in a patient with metastatic collecting duct carcinoma of kidney. Onkologie. 2009;32:44-46. Miyake H, Haraguchi T, Takenaka A, Fujisawa M. Metastatic collecting duct carcinoma of the kidney responded to sunitinib. Int J Clin Oncol. 2011;16:153-155. Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales) study. J Urol. 2007;177:1698-1702. Swartz MA, Karth J, Schneider DT, et al. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology. 2002;60:1083-1089. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27: 1280-1289. Sternberg C, Hawkins RE, Szczylik C, et al. Randomized, double-blind phase III study of pazopanib in patients with advanced/metastatic renal cell carcinoma (mRCC): final overall survival (OS) results. Presented at: 35th European Society for Medical Oncology ESMO Congress, October 8-12, 2010; Milan, Italy. Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743-3748. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27:4462-4468. 78 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0562.indd 78 12/02/13 2:27 PM