New therapeutic developments in renal cell cancer

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1 Critical Reviews in Oncology/Hematology 69 (2009) New therapeutic developments in renal cell cancer Hans Prenen a,b,, Thierry Gil b, Ahmad Awada b a Department of General Medical Oncology, University Hospital Gasthuisberg, Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium b Department of Medicine, Medical Oncology Clinic, Jules Bordet Institute, Rue Heger-Bordet 1, 1000 Brussels, Belgium Accepted 10 July 2008 Contents 1. Introduction Immunotherapy in RCC Interleukin-2 (IL-2) Interferon-alpha (IFN- ) Vaccine therapy Cytoreductive nephrectomy for metastatic RCC Pathogenesis and genomics of RCC Molecular pathways and targeted therapies in RCC Vascular endothelial growth factor (VEGF) pathway Sunitinib Sorafenib Bevacizumab Axitinib (AG ) Pazopanib The mtor pathway Conclusion Conflict of interest statement Reviewers References Biography Abstract Metastatic renal cell cancer is associated with a poor prognosis and is very resistant to conventional cytotoxic chemotherapy. Progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The recent approval of sunitinib, sorafenib, temsirolimus and bevacizumab in combination with IFN- has revolutionized the management of renal cell carcinoma. In this review, we describe the status of current treatment strategies for metastatic renal cell cancer and we focus on the new compounds including targeted therapy such as new anti-angiogenic and mtor inhibitors Elsevier Ireland Ltd. All rights reserved. Keywords: Renal cell cancer; Molecular targeted therapy; Angiogenesis; Sunitinib; Sorafenib; Temsirolimus 1. Introduction Corresponding author at: Department of General Medical Oncology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: ; fax: address: hans.prenen@uz.kuleuven.be (H. Prenen). Renal cell cancer (RCC) accounts for about 2 3% of all adult malignancies and is the third most frequent urological malignancy after prostate and bladder cancer. Worldwide, the /$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) mortality from RCC exceeds 100,000 per year [1]. Smoking, obesity, end-stage renal disease, exposure to asbestos and petroleum are important risk factors. It is thought that 20 30% of all RCC is due to smoking [2]. RCC comprises a histologically diverse group of tumors and five distinct subtypes have been identified: clear cell (75%), chromophilic (papillary) (10 15%), chromophobic (5 10%), oncocytoma (uncommon) and collecting duct (Bellini s duct) tumors (very rare) [3]. In addition, some RCCs (<3%) are unclassified. The histology of RCC is important in predicting the biological characteristics and clinical behavior. The pathogenesis of clear cell carcinoma is the best understood. An early event during the evolution of clear cell RCC is loss of function of the von Hippel-Lindau (VHL) gene, which is a tumor suppressor gene. This loss of function occurs in approximately 70% of sporadic clear cell RCC. If the disease is detected at an early stage, curative surgery can be performed. Surgery is highly effective for treating localized RCC in an early stage. Nephrectomy is appropriate for patients with stage I and II disease and a part of stage III disease. However, approximately 30% of patients present with metastatic disease and about 30% of initially organconfined cases develop metastases during follow-up [4]. The prognosis for patients with advanced or metastatic RCC is generally poor. Metastatic RCC poses a therapeutic problem because the tumor is highly resistant to conventional cytotoxic chemotherapy and 5-year survival rates are less than 2% [5]. RCC is one of the most immunoresponsive of human malignancies. As immune mechanisms are thought to be important in regulating tumor growth in metastatic RCC, immunotherapeutic agents such as interleukin-2 (IL-2) and Interferon-alpha (IFN- ) have been evaluated with limited success. The field of RCC is undergoing a revolution during the past 10 years. An improved understanding of the genetic and molecular abnormalities in RCC have led to interest in vascular endothelial growth factor receptor (VEGFR) and its pathway as a possible target for the treatment of RCC. Several important questions have risen by the development of active molecular therapies in RCC. In this review we will discuss the new therapeutic developments in the era of targeted therapies. 2. Immunotherapy in RCC RCC can evoke an immune response that occasionally results in spontaneous remissions [6]. Therefore, various immunotherapeutic strategies have been used to increase the anti-tumor immunity, such as the administration of cytokines, stimulators of the immune system or specific anti-tumor immunotherapy Interleukin-2 (IL-2) Interleukin-2 belongs to the family of cytokines and is an immune system signaling molecule that mediates its effects by binding to IL-2 receptors which are expressed by lymphocytes. IL-2 is normally produced during an immune response. The initial use of IL-2 in RCC combines high-dose bolus therapy with lymphokine-activated killer (LAK) cells which showed durable responses in some patients [7]. Subsequently, studies showed that high dose IL-2 alone was as effective as the combination of IL-2 and LAK [8]. Responses to immunotherapy are most frequent in patients with clear cell RCC. In most studies a dose of 600, ,000 IU/kg was administered as an IV infusion every 8 h over 5 consecutive days (up to 14 consecutive doses), yielding response rates of 10 23% with a median duration of response of 54 months [7 9]. The initial IV use of IL-2 was associated with severe toxicity and thus, this protocol was restricted to selected patients with excellent organ function. Alternative schedules have been evaluated to increase the anti-tumor activity of IL-2 or to decrease its toxicity while maintaining activity. However, the response rate and duration seemed to be longer with high dose IL-2 in comparison with low dose [10]. Unfortunately, IL-2 induces tumor regression in only a minority of patients. Given the tremendous toxicity and limited efficacy several clinical factors were suggested to select those patients with a higher likelihood of response including a good performance status, more than 1 year since nephrectomy, a limited number of sites of metastatic disease and the absence of liver and/or bone metastases [11]. Recently the presence of a positive staining of the RCC for carbonic anhydrase IX (CA-IX) has been associated with good outcome in patients that received IL-2 [12]. Until recently, high-dose IL-2 was the only treatment approved by the US Food and Drug Administration for the treatment of RCC. It should be emphasized that a recent phase III study showed no significant improvement in median progression-free survival or overall survival with the use of IL-2 [13] Interferon-alpha (IFN-α) Recombinant IFN has been developed in the beginning of the 1980s and its activity as a monotherapy in metastatic RCC has been extensively evaluated. The overall response rate is as high as 15% and most responses are partial and rarely persist beyond 1 year. Doses ranging from 5 to 10 MU appear to have the most favorable therapeutic index. Combining the cytokines IL-2 and IFN-yielded higher response rates than monotherapy, but survival rate was not significantly improved [14]. Treatment-related toxicity with IFN- includes flu-like symptoms, weight loss, bone marrow suppression and abnormal liver function tests. Randomized trials combining IFN- with chemotherapy have not demonstrated increased survival when compared to IFN- monotherapy [15]. There is no evidence to support a benefit for adjuvant immunotherapy in patients who have undergone potentially curative surgery [16]. In the era of the development of agents targeting the vascular endothelial growth factor (VEGF) and mtor pathway,

3 58 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) which are more active and potentially less toxic than IFN-, the question to be asked is whether there is still a place for a treatment with cytokines for metastatic RCC. We think it is likely that immunotherapy such as IL-2 or IFN- will continue to be a treatment in selected patients with metastatic RCC with good or intermediate prognosis who are able to tolerate the toxicity of this treatment, since durable long remissions occur in about 5 10% of patients. Moreover, combining immunotherapy with tyrosine kinase inhibitors could be a way forward in achieving higher response rates in this immunoresponsive disease Vaccine therapy Although RCC represents one of the most receptive cancers to immunotherapy, the clinical response is limited, mostly due to tumor-induced immune suppression. While cytokine therapy activates the immune system, vaccine therapy seeks to direct the immune system specifically to the tumor cell targets. The purpose of vaccines is to stimulate a specific immune response against tumor cells. They can stimulate both antibody and cellular response against the tumor. Clinical trials have shown that vaccines against renal cell cancer are safe to use and can be clinically effective although in a minority of patients [17]. The total number of patients included in these trials has been small though. Autologous tumor cell vaccines have been used as an adjuvant in high-risk patients. A German phase III trial randomly assigned 558 patients with resected pt2-3b,pn0-3,m0 to 6 months injections of the vaccine or no adjuvant therapy [18]. Vaccine therapy was associated with significant better 5 years PFS (77% vs. 68%). The benefit was mainly seen in patients with T3 tumors. Additional studies with dendritic cell-based vaccines are ongoing, particularly in combination with cytokine such as IL-12 and GM-CSF, which are used as vaccine adjuvants to improve the immune response. A major problem with vaccination is the fact that even if sufficient numbers of anti-tumor effector cells are generated, these cells may not be able to enter tumor stroma. Moreover, as discussed below, metastatic RCC are associated with overproduction of vascular endothelial growth factor (VEGF). Tumor-derived VEGF also affects the function of the immune system. It has been established that VEGF is involved in tumor-induced abnormalities of dendritic cell (DC) differentiation. Therefore a combination with anti-angiogenic agents might overcome this problem. Another approach is to use heat shock proteins (HSP) which are intra- and extracellular chaperones associated with stress response. Exogenous antigens chaperoned by a HSP can be channeled into the endogenous pathway and recognized by CD8+ T-lymphocytes. Vitespen (formerly HSPPC-96; Oncophage) is an autologous, tumor-derived HSP gp96-peptide complex. A recent phase II study in combination with tumor specific antigens did not result in a clear benefit in patients with metastatic RCC [19]. 3. Cytoreductive nephrectomy for metastatic RCC It has been almost 40 years since the radical nephrectomy was suggested as standard treatment by the work of Robson et al. [20]. The principle behind cytoreductive nephrectomy as a treatment for metastatic RCC was based on the immunologic phenomenon of spontaneous regression of metastasis after nephrectomy. However, this occurred in only less than 1% of patients [21]. A higher rate of complete regression of all metastatic disease (4%) has been reported by Marcus et al. in RCC patients with lung metastasis only [22]. Another accepted indication for nephrectomy for metastatic RCC has been to improve quality of life especially when for example the patient is having pain related to the kidney mass or chronic hematuria. Two randomized trials have studied the role of cytoreductive surgery in conjunction with immunotherapy (IFN- ). In the two prospective trials, the survival of patients who underwent cytoreductive nephrectomy before IFN was significantly better than those treated with IFN alone [23,24]. Both studies did not stratify the number of metastatic sites or overall tumor burden, which could be important since Han et al. showed in a retrospective study that patients with more than one metastatic site had a lower response rate to immunotherapy after nephrectomy of the primary tumor and also a significantly shorter survival [25]. No benefit has been established for cytoreductive nephrectomy in patients with non-clear cell tumors. Although cytoreductive surgery followed by systemic therapy is the standard of care in this disease, the question of the best timing of nephrectomy remains. Another unresolved question is the contribution of cytoreductive nephrectomy in the era of molecular targeted agents. A study to compare the survival of patients treated by nephrectomy plus targeted therapy with the survival of patients with targeted therapy alone should be performed to answer this question. These trials are being conducted in France and planned in the EORTC. Until these questions are resolved cytoreductive nephrectomy should be used in selected patients with metastatic RCC receiving post-surgical systemic therapies. 4. Pathogenesis and genomics of RCC The development of most of the new targeted therapies is based on the precise biological pathways deregulated in RCC patients due to genetic and epigenetic abnormalities. Several genes or proteins have been identified that are repeatedly expressed in RCC: VEGF, insulin-like growth factor-binding protein 3, endothelin 1, solute carrier family 2, alpha-methyl- CoA racemase or KIT. This finding provides opportunities for targeted therapies against validated targets. Inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) plays an important role in hereditary and sporadic clear cell RCC and is an early event during the evolution of clear cell RCC. A defective copy of the VHL gene leads to VHL disease and

4 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) is the most common cause for inherited RCC. Moreover, up to 75% of patients with sporadic clear cell RCC have aberrant VHL [26]. Inactivation of the VHL gene leads to activation of the hypoxia pathway via hypoxia-inducible factor-1 (HIF-1 ) and hypoxia-inducible factor-2, which activates expression of genes involved in hypoxia response, angiogenesis and other signaling pathways (VEGF, TGF-, GLUT1, CXCR4 and HIG2) [27 29]. The VHL gene functions in several pathways linked with carcinogenesis. Activations of these genes create a vasculogenic environment that favors tumor growth. In RCC, growth factor signaling pathways are often turned on such as VEGF-R and EGFR and their ligands, which suggest potential therapeutic interference with VEGFR and EGFR inhibitors [30]. To date there is no evidence for gainof-function receptor tyrosine kinase (RTK) mutations or overexpression of RTKs in RCC. Presumably, the activation of the RTK is causes by elevated levels of the ligands. Because angiogenesis is infrequent in the adult, there is a potential to use angiogenesis inhibitors as a specific therapy with potentially minimal toxicity. 5. Molecular pathways and targeted therapies in RCC 5.1. Vascular endothelial growth factor (VEGF) pathway VEGF is the most important growth factor involved in tumor angiogenesis and plays a significant role in the development of many types of human cancer, including RCC. In the clinic two different approaches are being used to block the VEGF pathway: the use of tyrosine kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib) to block the intracellular domain of the VEGF receptor and the use of monoclonal antibodies that neutralize circulating VEGF (bevacizumab) and prevent its activating the VEGF receptor Sunitinib Sunitinib (SU11248, Sutent, Pfizer, New York) is an orally bioavailable small molecule that inhibits multiple receptor tyrosine kinases (RTK) including VEGFR 1, 2 and 3, PDGFR and, KIT receptor and FLT3 receptor [31]. Activated RTKs initiate downstream signaling that ultimately blocks apoptosis, enhances angiogenesis and promotes metastasis and cell proliferation. Sunitinib potentially inhibits several targets that contribute to the pathogenesis of RCC including VEGF and PDGF. A phase I trial conducted in the Gustave Roussy Institute with sunitinib showed responses in 3 out of 5 patients with metastatic RCC [32]. Based on this phase I study and a solid biological background, anti-tumor activity and safety were demonstrated in two phase II trials that included 169 patients with advanced RCC who had failed on prior cytokine therapy [33,34]. In the first study [33], 63 patients with advanced RCC were enrolled; the majority had clear cell carcinoma (87%). Using RECIST criteria, a response rate of 40% was reported with a duration of response of 8.7 months. To confirm these findings a second larger phase II study was performed including 106 patients with clear cell metastatic RCC [34]. 34% achieved partial response and the median progression-free survival was 8.3 months. In the majority of patients, treatment with sunitinib was associated with fatigue and/or hypertension. Patients also frequently experienced grade 1 and 2 nausea, diarrhea and mucositis. Moreover, hypothyroidism is common in patients treated with sunitinib [35]. Then, a randomized phase III trial started, comparing the efficacy and safety of sunitinib to IFN- in first line treatment of patients with advanced RCC [36]. Patients were randomized to 6-week cycles of sunitinib (50 mg daily for 4 weeks, followed by 2 weeks off) or IFN- (9 million units three times per week). Results showed a significant improvement in progression-free survival (PFS) and a better response rate for sunitinib. On 750 patients, the response rate in the sunitinib arm was 31% versus 6% for INF-. PFS was 11 months in the sunitinib arm versus 5 months for IFN-. Overall survival was prolonged with sunitinib although the evaluation did not reach statistical significance. It should be noted that crossover to the sunitinib arm was allowed, which may mask any ultimate survival benefit. Based on this large phase III study, sunitinib is the standard first line treatment of metastatic RCC. On January 26, 2006 the FDA approved sunitinib for the treatment of advanced RCC. Sunitinib is available in 12.5, 25 and 50 mg capsules. The recommended dose is 50 mg/day PO for 4 weeks followed by 2 weeks of rest. This cycle is to be repeated until tumor progression or the occurrence of intolerable side effects. Recently, a continuous dosing schedule of 37.5 mg of sunitinib daily was evaluated in 107 renal cell cancer patients refractory to a cytokine-based regimen [37]. This regimen with continuous dosing showed a manageable safety profile. In the absence of a comparative trial, the intermittent schedule remains the standard. Studies to compare the alternative sunitinib dosing with the intermittent schedule are in progress. A meta-analysis of pharmacokinetic and efficacy data indicated that increased exposure to sunitinib is associated with clinical benefit, which suggests that drug exposure is relevant [38]. The role of sunitinib in the adjuvant setting will be evaluated in two large phase III studies (S-TRAC trial: Sunitinib Treatment of Renal Adjuvant Cancer; ASSURE trial: Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) in high-risk patients, compared with observation which remains the standard of care in this indication Sorafenib Sorafenib (Nexavar, Bayer Pharmaceuticals, West Haven) is an orally multi-targeted tyrosine kinase inhibitor that was originally developed as a Raf-1 inhibitor, an important mediator of the Ras/Raf/MEK pathway that lies downstream of receptor tyrosine kinases as VEGFR and PDGFR. Biochemical assays proved that it is also a potent inhibitor of VEGR2

5 60 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) and 3, PDGFR-, FLT3 and KIT [39]. Thus, it is the first oral multi-kinase inhibitor that targets upstream receptor tyrosine kinases as well as downstream tyrosine kinases in both tumoral cell and tumor vasculature. Although activating mutations in B-Raf have not been identified in RCC, constitutive activation has been observed in approximately 50% of tumors [40]. The activity of sorafenib in RCC was evaluated in two placebo-controlled trials in previously treated patients [41,42]. The first trial used a randomized discontinuation trial design, designed to determine whether continued treatment with sorafenib inhibited the tumor growth in patients displaying stable disease after a 12-week course of treatment [41].Of the 193 evaluable patients, 79 showed greater than 25% tumor shrinkage during the run-in-phase and continued open-label sorafenib, 65 patients had less than 25% change and were randomized to continue sorafenib or receive placebo. 51 patients discontinued the study. Primary endpoint was PFS measured 12 weeks after randomization. Median progression-free survival was significantly longer in the treated group compared to placebo. A larger trial evaluated 903 patients with advanced RCC who had failed prior standard treatment [42]. Patients were randomly assigned to sorafenib (400 mg bid) or placebo. Based upon results at the first planned interim analysis, the study was amended to allow those patients originally assigned to placebo to crossover and receive sorafenib, potentially obscuring differences in survival. The overall survival (OS) analysis before crossover showed an estimated 39% OS improvement for the sorafenib arm (HR = 0.72; p = 0.018). A final analysis of survival in this trial was presented at ASCO in June Patients treated with sorafenib had a median survival of 17.8 versus 15.2 months with placebo. While this difference was not statistically significant, it should be noted that crossover to sorafenib potentially confounded OS. A preplanned secondary analysis censoring placebo data showed a significant benefit for sorafenib versus placebo (17.8 months vs months, p = ), suggesting crossover has confounded OS. Interestingly, response rates in this phase III trial were much less than expected. It is postulated that clinically significant alterations in angiogenesis can occur without large changes in tumor size. The most common adverse events are hand foot skin reaction, diarrhea, hypertension and sensory neuropathic changes. Thyroid abnormalities were not common in patients treated with sorafenib and replacement therapy was rarely indicated [43]. The role of sorafenib compared with IFN- or other targeted agents in previously untreated patients is less clear. Early results from a randomized phase II trial of sorafenib versus IFN- in treatment naïve patients have been reported [38]. There was no increase in PFS in the group treated with sorafenib compared to IFN-. In this and another phase II trial the safety and anti-tumor activity of escalated doses of sorafenib was evaluated [44,45]. These trials conclude that escalated doses of sorafenib were well tolerated with promising anti-tumor activity. Nevertheless, the role of sorafenib dose-escalation in the management of patients with advanced RCC progressing on 400 mg twice daily, has to be determined in additional clinical trials. In conclusion, sorafenib has established efficacy in RCC and is well tolerated. Based on a phase III study, there is a role for the use of sorafenib in cytokine refractory patients. Additional studies are underway to define the efficacy of sorafenib as adjuvant therapy and in combination with other targeted agents or cytokines Bevacizumab Bevacizumab (Avastin, Genentech, South San Francisco) is a humanized monoclonal antibody that binds and neutralizes all the major isoforms of the VEGF protein. It has been shown to have activity in breast, colorectal and non-small cell lung cancer. The activity of bevacizumab in RCC has been investigated in a randomized double blind phase II trial [46]. A total of 116 patients were randomly assigned to two dose levels of the antibody (3 and 10 mg/kg) versus placebo. The study was stopped early when an interim analysis disclosed that high-dose bevacizumab was associated with a significant prolongation in TTP compared to placebo. There was no significant difference in median survival, but also in this study a crossover was allowed. In a phase III trial (AVOREN), 648 previously untreated patients were randomly assigned to IFN- plus either bevacizumab or placebo [47]. The association of bevacizumab to IFN- significantly increased PFS (10.2 months vs. 4.5 months; p = ) and response rates (30.6% vs. 12.4%) compared with IFN- alone. The data presented in this study on overall survival are not mature and will be reported when the prespecified number of deaths has occurred. Recently, these data have been confirmed by another prospective, randomized phase III trial of bevacizumab plus IFN- versus IFN- monotherapy. In this study 732 patients were enrolled. The median time to progression was 8.5 months in the combination arm compared with 5.2 months in patients receiving IFN- monotherapy (p < ) [48]. Bevacizumab plus IFN had a higher objective response rate versus IFN- (25.5% vs. 13.1%; p =< ). Overall toxicity was greater in the bevacizumab plus IFN group, including significantly more grade 3 hypertension (9% vs. 0%), anorexia (17% vs. 8%), fatigue (35% vs. 28%) and proteinuria (13% vs. 0%). Based on these trials, EMEA has recently approved bevacizumab in combination with IFN- for first line treatment of patients with advanced and/or metastatic renal cell cancer Axitinib (AG ) Axitinib (Pfizer, New York) is a novel small molecule inhibitor of VEGFR, PDGFR and KIT. A phase I study with axitinib showed a durable response in a patient with RCC [49]. Subsequently, a phase II trial has been conducted in 52 patients with cytokine refractory RCC [50]. Partial responses were seen in 40% of patients with 69% of patients remaining

6 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) on study with response or stable disease at a median follow-up of 1 year Pazopanib Pazopanib (GlaxoSmithKline, London) is an oral tyrosine kinase inhibitor of VEGFR-1,-2 and -3, PDGFR and KIT. Interim results from a phase II randomized discontinuation trial demonstrated that pazopanib has promising activity in untreated or cytokine/bevacizumab pretreated RCC accompanied by a favorable toxicity profile [51]. A placebo-controlled phase III trial is ongoing for untreated or cytokine-treated patients with RCC The mtor pathway The mammalian target of rapamycin (mtor) is a tyrosine kinase which forms part of the phosphoinositide 3-kinase (PI3K)/AKT pathway that is regulated by the PTEN tumor suppressor gene. This pathway has an important role in cancer cell survival and angiogenesis and is essential for VEGF mediated endothelial proliferation. mtor leads to stabilization of hypoxia-inducible factor-1 which activates on his turn so-called hypoxia-inducible genes including VEGF, EGFR and PDGFR. HIF activation also occurs as a result of VHL gene mutations. Another approach to target unregulated HIF signaling is to inhibit the AKT/mTOR pathway by using mtor inhibitors as rapamycin, everolimus (RAD001, Novartis) or temsirolimus (CCI-779, Wyeth). Inhibition of the mtor kinase activity results in cell cycle arrest. The agent that has undergone the most advanced study in RCC is temsirolimus, which is a rapamycin analog that functions as a competitive inhibitor of the mtor kinase. It has been evaluated in a phase II trial as a single agent in cytokine refractory RCC [52]. 111 patients with advanced RCC were randomly assigned to one of three different dose levels of temsirolimus (25, 75 or 250 mg IV). Despite the low objective response rate (7%), significant anti-tumor activity was suggested by the relatively long time to progression (5.8 months) and overall median survival (15 months). Surprisingly and contrary to what was observed with anti-angiogenic agents (main clinical benefit in good or intermediate risk factor groups), those with intermediate- and poor prognosis disease appeared to benefit the most. Neither the efficacy nor the toxicity appeared to correlate significantly with the dose. Based on these results, temsirolimus was evaluated in a phase III trial in which 626 previously untreated poor prognosis RCC patients were randomized to temsirolimus, the combination of temsirolimus plus IFN- or IFN- in monotherapy [53]. At least three of the following six predictors of short survival were required: a serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range, a hemoglobin level below the lower limit of the normal range; a corrected serum calcium level of more than 10 mg per deciliter, a time from initial diagnosis of renal-cell carcinoma to randomization of less than 1 year, a Karnofsky performance score of 60 or 70, or metastases in multiple organs. In comparison with the standard definition of poor prognosis as proposed by Motzer et al. [54], metastasis in multiple organs is an additional prognostic factor used in this study to better define the poor risk patients. Compared to single agent IFN-, temsirolimus improved overall survival among patients with metastatic RCC and a poor prognosis. Overall survival in the combination arm did not differ significantly from the IFN- group (HR 0.96, p = 0.70). The inferior results of the combination versus temsirolimus alone may have been due to the lower dose intensity of temsirolimus in the combination arm. In a subset analysis presented at ASCO in 2007, benefit was particularly noted in patients with non-clear cell histology [55]. Temsirolimus is clearly well tolerated which means it is an interesting drug for combination studies with other agents active in RCC. Further studies are needed to define the role of temsirolimus in first line therapy for patients with a more favorable prognosis combined with other TKI or as sequential therapy. Everolimus (RAD001), an oral mtor inhibitor, has shown activity in a phase II trial of patients with RCC [56]. Patients with no more than one prior therapy received everolimus 10 mg daily. Twelve patients (23%) exhibited a partial response and 14 (38%) had stable disease. Progression-free survival was 11.2 months. Another phase II trial evaluating everolimus in second line was recently presented at ASCO 2008 and shows encouraging anti-tumor activity in RCC patients which have had prior exposure to sorafenib or sunitinib (partial remissions were seen in 3 (16%) patients and stable disease for 3 months in 14 (74%) patients) [57]. These phase II data confirm the relevance of targeting the mtor pathway in RCC. 6. Conclusion The understanding of the molecular pathogenesis of RCC makes it possible to improve the efficacy of a treatment blocking multiple steps in the same pathway or multiple pathways. It is clear we are moving to a new era for patients with metastatic RCC. Multiple targeted agents blocking the VEGF pathway (sunitinib, sorafenib, bevacizumab) or the mtor pathway (temsirolimus) are now the standard treatment for most patients with advanced clear cell RCC. Thus, several new treatment options have been developed in a disease that is very chemotherapy resistant. Table 1 summarizes the phase III clinical trials with targeted agents in renal cell cancer. Multiple questions remain to be answered with all new treatment options including targeted molecular agents. For example their utility as sequential or combination therapy, the optimal duration of the therapy and the significance of stable disease in patients treated with angiogenesis inhibitors. Also the necessity and/or the timing of cytoreductive nephrectomy warrants further studies. Furthermore, the role of activity of these new agents in non-clear cell histology remains to be

7 62 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) Table 1 Summary of phase III clinical trials with targeted agents in renal cell cancer Study Line of treatment Risk group Arms of the study RR (%) PFS (months) Motzer et al. [32] 1st line ECOG 0-1 Sunitinib 31% PR, 48% SD 11 Interferon 6% PR, 49% SD 6 Escudier et al. [38] 2nd line ECOG 0-1 Sorafenib 2% PR, 78% SD 5.5 Placebo 0% PR, 55% SD 2.8 Escudier et al. [43] 1st line KI: 70% IFN- + placebo 13% OR, 50% SD 4.5 IFN- + bevacizumab 31% OR, 46% SD 10.2 Hudes et al. [48] 1st line KI: 60% Temsirolimus 8.6% OR 5.5 Poor risk IFN- 4.8% OR 3.1 Temsirolimus + IFN- 8.1% OR 4.7 RR: response rate; PFS: progression-free survival; PR: partial remission; SD: stable disease; OR: overall response; KI: Karnofsky index. established, since targeted therapy has generally been studied in clear cell RCC. Conflict of interest statement The authors have no conflict of interest. Reviewers Prof. Ronald M. Bukowski, Cleveland Clinic Foundation, Taussig Cancer Center/Experimental Therapeutics, Cleveland, OH 44195, United States. Dr. Joaquim Bellmunt, Passeig Marítimo 25-29, E Barcelona, Spain. References [1] Patel PH, Chaganti RS, Motzer RJ. Targeted therapy for metastastic renal cell carcinoma. Br J Cancer 2006;94: [2] Martel CL, Lara PN. Renal cell carcinoma: current status and future directions. Crit Rev Oncol Hematol 2003;45: [3] Patard JJ, Leray E, Rioux-Leclercq N, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23: [4] Board RE, Thistlethwaite FD, Hawkins RE. Anti-angiogenic therapy in the treatment of advanced renal cell cancer. Cancer Treat Rev 2007;33:1 8. [5] Javidan J, Stricker HJ, Tamboli P, et al. Prognostic significance of the 1997 TNM classification of renal cell carcinoma. J Urol 1999;162: [6] Vogelzang NJ, Priest ER, Borden L. Spontaneous regression of histologically proved pulmonary metastases from renal cell carcinoma: a case with 5-year follow-up. J Urol 1992;148: [7] Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokineactivated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316: [8] Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13: [9] Dilman RO, Church D, Oldham RK, et al. Inpatient continuous-infusion of interleukin-2 in 788 patients with cancer. The National Biotherapy Study Group Experience. Cancer 1993;71: [10] Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of highdose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21: [11] Schöffski P, Dumez H, Clement P, et al. Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol 2006;17: [12] Upton MP, Parker R, Yournans AY, et al. Histologic predictors of renal cell carcinoma response to interleukin-2 based therapy. J Immunother 2005;28: [13] Negrier S, Perol D, Ravaud A, et al. Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastastic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer 2007;110: [14] Vogelzang NJ, Lipton A, Figlin RA. Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: an outpatient multicenter trial. J Clin Oncol 1993;11: [15] Fossa SD, Martinelli G, Otto U, et al. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol 1992;3: [16] Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 2003;21: [17] Kugler A, Stuhler G, Walden P, et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med 2000;6: [18] Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004;363: [19] Jonash E, Wood C, Tamboli P, et al. Vaccination of metastatic renal cell carcinoma patiens with autologous tumour-derived vitespen vaccine: clinical findings. Br J Cancer 2008;98: [20] Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol 1969;101: [21] Montie JE, Stewart BH, Straffon RA, Banowsky LH, Hewitt CB, Montague DK. The role of adjunctive nephrectomy in patients with metastatic renal cell carcinoma. J Urol 1977;117: [22] Marcus SG, Choyke PL, Reiter R, et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. J Urol 1993;150: [23] Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345: [24] Mickisch GH, Garin A, Van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358: [25] Han KR, Pantuck AJ, Bui MH, et al. Number of metastatic sites rather than location dictates overall survival of patients with node-negative metastatic renal cell carcinoma. Urology 2003;61:314 9.

8 H. Prenen et al. / Critical Reviews in Oncology/Hematology 69 (2009) [26] Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004;22: [27] Maxwell PH. The HIF pathway in cancer. Semin Cell Dev Biol 2005;16: [28] Maynard MA, Ohh M. Molecular targets from VHL studies into the oxygen-sensing pathway. Curr Cancer Drug Targets 2005;5: [29] Togashi A, Katagiri T, Ashida S, et al. Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy. Cancer Res 2005;65: [30] Jones J, Otu H, Spentzos D, et al. Gene signatures of progression and metastasis in renal cell cancer. Clin Cancer Res 2005;11: [31] Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9: [32] Raymond E, Faivre S, Vera C. Final results of a phase I and pharmacokinetic study of SU11248, a novel multitarget tyrosine kinase inhibitor in patients with advanced cancers. Proc Am Soc Clin Oncol 2003;22:192. [33] Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295: [34] 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: [35] Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:81 3. [36] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356: [37] Srinivas S, Roigas J, Gilessen S, et al. Continuous daily administration of sunitinib in patients with cytokine-refractory metastatic renal cell carcinoma (mrcc). J Clin Oncol 2007;25:5040s. [38] Houk BE, Bello CL, Michaelson MD, et al. Exposure-response of sunitinib in metastatic renal cell carcinoma (mrcc): a population pharmacokinetic/pharmacodynamic (PKPD) approach. J Clin Oncol 2007;25:5027s. [39] Wilhelm SM, Carter C, Tang L, et al. BAY 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: [40] Turner KJ, Moore JW, Jones A, et al. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res 2002;62: [41] Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24: [42] Escudier B, Eisen T, Stadler WM. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356: [43] Tamaskar I, Bukowski R, Elson P, et al. Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 2008;19: [44] Szczylik C, Demkow T, Staehler M, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma. J Clin Oncol 2007;25:241s. [45] Amato RJ, Harris P, Dalton M, et al. A phase II trial of intra-patient doseescalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 2007;25:241s. [46] 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: [47] Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 2007;370: [48] Rini BI, Halabi S, Rosenberg JE, et al. CALGB 90206: A phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. ASCO GU Abstract No 350. [49] Rugo HS, Herbst RS, Liu G, et al. Clinical and dynamic imaging results of the first phase I study of AG , an oral anti-angiogenesis agent, in patients (pts) with advanced solid tumors. J Clin Oncol 2004;22:2503. [50] Rini B, Rixe O, Bukowski R, et al. AG , a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). J Clin Oncol 2005;23:4509. [51] Hutson TE, Davis ID, Machiels JP, et al. Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): interim results of a phase II randomized discontinuation trial (RDT). J Clin Oncol 2007;25:5031. [52] 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: [53] Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356: [54] Motzer RJ, Mazumdar, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17: [55] Dutcher JP, Szczylik C, Tannir R, et al. Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN) (Abstract). Proc Am Soc Clin Oncol J Clin Oncol 2007;25:243s. [56] Jac J, Giessinger S, Khan M, Willis J, Chiang S, Amato R. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC) (Abstract). Proc Am Soc Clin Oncol J Clin Oncol 2007;25:5107. [57] Jac J, Amato RJ, Giessinger S, Saxena S, Willis JP. A phase II study with a daily regimen of the oral mtor inhibitor RAD001 (everolimus) in patients with metastatic renal cell carcinoma which has progressed on tyrosine kinase inhibition therapy. Proc Am Soc Clin Oncol J Clin Oncol 2008 [Abstract 5113]. Biography Hans Prenen, M.D., Ph.D. was born in Belgium and studied medicine at the Catholic University of Leuven. He did a specialization in Internal Medicine and is currently in his last year of specialization in Medical Oncology at the department of general medical oncology at the University of Leuven. In 2006, he defended his thesis entitled signal transduction inhibitors for the treatment of gastrointestinal stromal tumors. During his training of medical oncology he worked 6 months at the Jules Bordet Institute in Brussels under the supervision of Prof. A. Awada. His special interest lies in the use of signal transduction inhibitors and anti-angiogenic agents in the treatment of cancer patients. He focuses on clinical and translational research projects. The aim of Dr. Prenen is to look for new and better molecular targeted therapies in solid tumors.