BJUI. Optimal management of metastatic renal cell carcinoma: an algorithm for treatment

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1 2009 The Authors; Journal compilation 2009 BJU International Mini-review Article MANAGEMENT ALGORITHMS FOR METASTATIC RCC BELLMUNT et al. BJUI BJU INTERNATIONAL Optimal management of metastatic renal cell carcinoma: an algorithm for treatment Joaquim Bellmunt, Per Flodgren*, Jan Roigas and Stéphane Oudard Medical Oncology Department, RTICC (RD06/0020/109) Programa de Recerca de Càncer, IMIM-Hospital del Mar, Barcelona, Spain, *Department of Oncology, Lund University Hospital, Lund, Sweden, Klinik für Urologie, Vivantes Klinikum Am Urban, Berlin, Germany, and Hôpital Européen Georges Pompidou, Paris, France Accepted for publication 29 January 2009 The treatment of metastatic renal cell carcinoma (mrcc) has been changed by the introduction of targeted agents. Consideration of individual patient factors, such as previous treatment and prognostic risk, e.g. according to the Memorial Sloan- Kettering Cancer Center (MSKCC) risk criteria), can assist in ensuring that patients receive appropriate targeted therapies. Available clinical evidence shows sunitinib to be the reference standard of care for the first-line treatment of mrcc in patients at favourable or intermediate prognostic risk according to MSKCC criteria. Combined treatment with bevacizumab plus interferon-α can also be considered for the first-line treatment of mrcc in this setting. For the first-line treatment of poor-risk patients, temsirolimus has shown benefit in a phase III study, while sunitinib can also be considered. For second-line treatment in cytokine-refractory patients, sorafenib is recommended based on phase III trial results; sunitinib has also shown activity after failure of cytokine therapy or targeted agents. As well as antitumour activity, the tolerability of targeted agents should be evaluated in the context of individual patients, considering factors such as comorbidities and age. As our understanding of the activity of targeted agents for mrcc increases, we should ensure that these agents are used appropriately to provide patients with optimal treatment benefits. KEYWORDS renal cell carcinoma, sunitinib, targeted therapy, treatment algorithm INTRODUCTION The outlook for patients with advanced RCC has improved due to the availability of targeted therapies, and with advances in the understanding of how to use these agents. Novel targeted agents that have shown clinical efficacy in the treatment of metastatic RCC (mrcc) include the oral, multitargeted receptor tyrosine kinase (RTK) inhibitors sunitinib malate and sorafenib tosylate, the mammalian target of rapamycin kinase inhibitor temsirolimus and the vascular endothelial growth factor (VEGF) ligandbinding monoclonal antibody bevacizumab, given in combination with interferon-α (IFN-α) [1 4]., approved multinationally for firstand second-line use in advanced and/or mrcc [5], is considered a reference standard of care for the first-line treatment of mrcc [1]. Sorafenib was approved in 2005 for the treatment of cytokine-refractory advanced RCC [6]. Temsirolimus has been approved in Europe for the first-line treatment of patients with advanced RCC with a poor prognosis, i.e. three or more of six prognostic risk factors; five risk factors determined by the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria plus the additional factor of the number of metastatic sites [7]. Combined therapy with bevacizumab plus IFN-α has also received approval in Europe for first-line use in advanced RCC. When treating mrcc it is important to consider prognostic factors that might affect treatment outcome. These factors, including the Eastern Cooperative Oncology Group performance score (ECOG PS), tumour histology, the presence of comorbidities and hypertension, allow patient stratification into risk groups and subsequent optimization of treatment [8]. Models used to categorize patients include that developed at the MSKCC (grouping patients into risk categories of favourable, intermediate and poor, based on risk factors predictive of survival) [9] and disease-specific nomograms (to enable individualized patient prognostication and predict treatment outcome, taking into account clinical and biological features) [10]. In the context of the increasing number of novel targeted agents licensed for RCC, in this review we discuss the available clinical evidence on these agents and consider factors affecting treatment decisions. An evidencebased treatment algorithm that can be used to achieve optimal clinical benefit with targeted agents in patients with mrcc is presented. CLINICAL PROFILE OF TARGETED THERAPIES FOR MRCC SUNITINIB In a pivotal phase III, randomized trial, sunitinib significantly improved progressionfree survival (PFS, assessed by independent central review); median (95% CI) of 11.0 ( ) months, vs 5.1 ( ) for IFN-α, giving a hazard ratio (HR) of ( ; ), as shown in Table 1 [1,3,4,10 16], as well as the objective response rate (ORR) of 39 (34 44)% vs 8 (6 12)%, respectively () in the first-line treatment of patients with mrcc [1,10]. -treated patients achieved a final median overall survival (OS) of 26.4 ( ) months compared with 21.8 ( ) months for IFN-α-treated patients (HR 0.821, ; P = 0.051, log-rank test) [15]. The median (95% CI) OS 10 JOURNAL COMPILATION 2009 BJU INTERNATIONAL 104, doi: /j x x

2 MANAGEMENT ALGORITHMS FOR METASTATIC RCC TABLE 1 Summary of efficacy data from phase III trials in mrcc with targeted agents Experimental arm Control arm N Stage of treatment Data review ORR, % [1,10,11] IFN-α 750 First-line IC Suntinib 39 IFN-α 8 Bev + IFN-α2a [4] IFN-α2a + placebo Bev + IFN-α [13] IFN-α + placebo Tem [2,14] IFN-α 626 First line, poor-risk (modified MSKCC) 649 First line IA Bev + IFN-α 31 IFN-α First line IA Bev + IFN-α 26 IFN-α 13 ICR Tem 8.6 IFN-α 4.8 Sorafenib [3,12] Placebo 903 Second line ICR Sorafenib 10 Placebo 2 PFS overall 11.0 IFN-α 5.1 Bev + IFN-α 10.2 IFN-α 5.4 Bev + IFN-α 8.5 IFN-α 5.2 Tem 5.5 IFN-α 3.1 Sorafenib 5.5 Placebo 2.8 Median, months PFS by MSKCC risk group (A = Favourable) : 14.9 IFN-α 8.4 (B = Intermediate) 10.7 IFN-α 3.8 (C = Poor) 3.9 IFN-α 1.2 (A = Favourable) Bev + IFN-α 12.9 IFN 7.6 (B = Intermediate) Bev + IFN-α 10.2 IFN-α 4.5 (C = Poor) Bev + IFN-α 2.2 IFN-α 2.1 (A = Favourable) Bev + IFN-α 11.1 IFN-α 5.7 (B = Intermediate) Bev + IFN-α 8.4 IFN-α 5.3 (C = Poor) Bev + IFN-α 3.3 IFN-α 2.6 / Tem 7.0 IFN-α 5.6 Tem 5.1 IFN-α 2.3 OS : 26.4 IFN-α 21.8 P = Censored 26.4 IFN-α 20.0 P = No treatments after study, 28.1 IFN-α 14.1 P = Bev + IFN nyr IFN-α 19.8 nyr Overall Tem 10.9 IFN-α 7.1 P = Intermediate Tem 13.0 IFN-α 17.7 Poor Tems 10.2 IFN-α 6.0 Not reported Sorafenib 17.8 Placebo 14.3 (censored for crossover) P = Study included a third combined treatment arm (temsirolimus + IFN α); ICR, independent central review; IA, investigator-assessed; Bev, bevacizumab; Tem, temsirolimus; nyr, not yet reached. after censoring for patient crossing was 26.4 ( ) months for sunitinib and 20.0 ( ) months for IFN-α (HR 0.808, ; P = 0.036, log-rank test) [15]. The median OS in patients who had no treatments after the study was 28.1 (19.5 not available) months in sunitinib arm, vs 14.1 ( ) months in the IFN-α arm [15]. Baseline features predictive of a longer median PFS in the sunitinib group were corrected calcium of 10 mg/dl (P = 0.008), an ECOG PS of 0 vs 1 (P = 0.007) and 1 year from diagnosis to treatment () [11]. These results formed the basis for the development of a nomogram based on the pretreatment JOURNAL COMPILATION 2009 BJU INTERNATIONAL 11

3 BELLMUNT ET AL. baseline features to predict the PFS over 12 months for individual patients [10]. In two independent phase II studies, sunitinib showed robust clinical activity in the secondline setting [16,17]. Updated results from one of these studies indicated an ORR of 33 (24 43)% (independent central review), a median PFS of 8.8 ( ) months and a median OS of 23.9 ( ) months [18]. Analysis of pooled data from the two phase II studies indicated that the ORR might correlate with the PFS; patients with a higher ORR had a longer PFS than patients with a lower ORR [17,19]. has also shown efficacy in a broad range of patients in an ongoing expandedaccess study, including both treatment-naïve patients and those with cytokine-refractory or -intolerant mrcc (4185 patients). The median PFS for the total population was 10.8 ( ) months [20]. In one patient with brain metastases enrolled in the expanded-access study, sunitinib treatment for 12 weeks led to complete regression of the brain metastases, and the patient remained free of brain lesions after 21 months of sunitinib treatment, suggesting that sunitinib crosses the blood brain barrier. Also there were partial responses in lung and nephrectomy-area lesions [21]. The safety and tolerability profile of sunitinib has been found to be consistent across mrcc studies to date; most adverse events (AEs) were grade 1 or 2 in severity and manageable with standard medical intervention and/or modification of sunitinib dosing in 12.5 mg increments, according to individual patient needs [5,22]. AEs commonly include fatigue, gastrointestinal events such as diarrhoea, nausea and vomiting, and hand foot syndrome, hypertension and hypothyroidism [1,16,17,22 24]. In addition, the AE profile of sunitinib is largely similar to that of other targeted therapies [25]. SORAFENIB Sorafenib has been investigated in a randomized, placebo-controlled phase III trial in patients with cytokine-refractory mrcc [3]. At the initial analysis at crossover, sorafenibtreated patients had a significantly longer median PFS than placebo-treated patients (5.5 vs 2.8 months, respectively; ; Table 1). While the OS after 6 months of crossover failed to reach pre-specified significance levels, censoring for crossover indicated a significant difference between the arms (sorafenib 17.8 vs placebo 14.3 months; HR 0.78, 95% CI , P = 0.029) [12]. There were no significant differences in median PFS between patients initially randomized to sorafenib (400 mg twice daily) or IFN-α (9 MIU three times per week) in a two-part, phase II, first-line study (5.7 months, 95% CI ; vs 5.6 months, 95% CI , respectively; P = 0.504) [26]. After progression, 54% of IFN-α-treated patients who switched to sorafenib treatment had stable disease and the median PFS was 5.3 ( ) months. Increasing the sorafenib dose to 600 mg twice daily in patients with progression resulted in a median PFS of 3.6 ( ) months [26]. In addition, an ongoing large, expandedaccess study in patients with advanced RCC showed a median PFS of 35.1 ( ) weeks for sorafenib in treatment-naïve patients [27]. Of the 50 patients with brain metastases enrolled in the expanded-access study, there were confirmed partial responses (PRs) in two (4%) and 34 (68%) achieved stable disease [28]. As with sunitinib, these results suggest that sorafenib can cross the blood brain barrier. Sorafenib tolerability has also been consistent across studies in RCC conducted to date. The AE profile is similar to other targeted therapies in this setting (class-type effect), with most events being grade 1 or 2 in severity. In the expanded-access study, grade 3 or 4 AEs included hand foot syndrome, rash/desquamation and fatigue [27]. TEMSIROLIMUS In a pivotal phase III trial (Advanced RCC, ARCC), patients were stratified into the poorprognosis risk group if they had three of six poor risk features (five predefined MSKCC criteria: lactate dehydrogenase, LDH >1.5 times the upper limit of normal; haemoglobin < lower limit of normal; corrected serum calcium >10 mg/dl; time from diagnosis to first treatment of <1 year; Karnofsky PS 60 70; plus multiple organ sites of metastases), and treated with either temsirolimus alone, IFN-α alone or a combination of both [2]. The median (95% CI) OS was significantly longer in temsirolimus-treated patients than with IFN-α or the combined treatment, at 10.9 ( ), 7.3 ( ) and 8.4 ( ) months, respectively (P = for temsirolimus vs IFN-α; Table 1) [2]. The median PFS was also significantly longer in patients treated with temsirolimus alone than with IFN-α alone, at 5.5 vs 3.1 months, respectively (); the median PFS for temsirolimus plus IFN-α was 4.7 months [2]. Patients with advanced cytokine-refractory RCC were treated with temsirolimus in a separate phase II open-label study. The overall ORR was 7%, including one complete response (CR) and seven PRs; the median time to progression (TTP) was 5.8 months and median survival was 15.0 months [29]. Temsirolimus has been generally well tolerated in clinical studies in RCC to date [2]. In the phase III study, 67% of temsirolimustreated patients and 78% of IFN-α-treated patients had grade 3 or 4 AEs [2]. Compared with IFN-α, mild to moderate rash, peripheral oedema, stomatitis, hyperglycaemia, hypercholesterolaemia and hyperlipidaemia were more common with temsirolimus treatment [2]. BEVACIZUMAB PLUS IFN-α Bevacizumab has been evaluated in several trials in patients with mrcc, both alone and combined with other therapies. Combined therapy with bevacizumab plus IFN-α has been compared with IFN-α alone as first-line therapy for mrcc in two phase III, randomized studies, with investigatorassessed data only reported to date [4,13]. In the first study (of 649 patients), bevacizumab plus IFN-α2a was better than IFN-α2a alone for the median PFS (10.2 vs 5.4 months, respectively; HR 0.63; 95% CI , ) and ORR (31% vs 13%, respectively; ; Table 1) [4]. In the subset of patients (40% of the group total) with reduced-dose IFN-α2a (6 or 3 MIU instead of 9 MIU) plus bevacizumab, the median PFS was 12.4 ( ) months and the ORR was 32% [30]. However, the method for this subanalysis excluded patients with early progression of disease who received a full dose of IFN-α2a, which might affect the results reported [30]. In a second phase III study in 732 treatmentnaïve patients with mrcc, those receiving the combination of bevacizumab plus IFN-α had a median (95% CI) PFS of 8.5 ( ) months, vs 5.2 ( ) months for IFN-α 12 JOURNAL COMPILATION 2009 BJU INTERNATIONAL

4 MANAGEMENT ALGORITHMS FOR METASTATIC RCC TABLE 2 Prognostic factors and characteristics for patient stratification Prognostic factors and characteristics Relevance to choice of treatment MSKCC risk stratification Commonly used prognostic model for patient stratification in clinical studies [37 41] Serum haemoglobin levels Independent prognostic factors for survival Calcium levels Patients stratified into favourable, intermediate and poor risk groups Time from diagnosis to treatment Serum LDH levels Haemoglobin levels PS PS identified by several studies as independent prognostic factor for survival [39] Karnofsky ECOG Number of metastatic sites Independent prognostic factor for survival [42 44] Tumour histology Clear cell histology vs non-clear cell; former associated with a poorer prognosis than latter Several studies show that differences in response to therapies and clinical outcomes depend on histology [45] Baseline neutrophil/platelet counts Identified by a retrospective analysis of eight clinical trials as independent prognostic factors for treatment [35,36] Co-morbidities Independent prognostic factors for treatment Can affect choice of treatment and need stabilization before starting treatment [37,40] Age <65 vs >65 years Appears not to be important as a prognostic factor, but affects considerations of clinical benefit vs tolerability in the elderly [33] alone (estimated HR 0.71, 95% CI ; ) [13]. The ORR for bevacizumab plus IFN-α was 25.5 ( )% vs 13.1 ( )% in the IFN-α treatment arm () [13]. Single-agent bevacizumab studies include one in the second-line [31] and one in the first-line setting [32]. In the second-line study, there were no significant differences between the bevacizumab- and placebo-treated groups in median OS, although bevacizumab significantly prolonged the median TTP over placebo when administered at 10 mg/kg (4.8 vs 2.5 months; ) [31]. The ORR in the first-line study was 13% for bevacizumab alone compared with 14% for bevacizumab plus erlotinib [32]. As such, data available to date suggest that bevacizumab might not be appropriate for single-agent use in mrcc. The tolerability profile for bevacizumab plus IFN-α2a reflects the profiles for the two agents alone. In both phase III studies, the overall toxicity was greater in patients receiving bevacizumab plus IFN-α than with IFN-α alone [4,13]. In the second phase III study, grade 3 or 4 AEs occurred in 79% and 61% of patients treated with bevacizumab plus IFN-α and IFN-α alone, respectively, including a significantly higher incidence of grade 3 hypertension, anorexia, fatigue and proteinuria [13]. PATIENT STRATIFICATION The initial stratification of patients should be based on symptoms and disease progression status, to allow the selection of appropriate treatment. Systemic treatment is recommended for metastatic disease [33]. In some patients diagnosed with metastases (including those with multiple lesions) which might be resectable, surgery is potentially curative and should therefore be undertaken before using targeted agents [33]. The aim of treatment for symptomatic patients should be the reduction of symptom severity, with clinically significant tumour shrinkage [34]. To that end, symptomatic patients can be further divided on the basis of characteristics and prognostic factors or risk groups, to select optimal treatment. Prognostic factors identified by various studies are listed in Table 2 [33,35 45]. It is also important to consider safety and tolerability aspects based on individual patient profiles [35]. Treatment with sunitinib, sorafenib and other anti-angiogenic therapies has been associated with the incidence of hypertension. For example, in a study carried out by Azizi et al. [36], blood pressure was elevated in both normotensive and hypertensive patients treated with sunitinib. The presence of comorbidities, specifically unstable hypertension or a history of cardiovascular disorders, can also complicate the choice of treatment and might need to be attended to before starting therapy. TREATMENT ALGORITHM We present an overview of a treatment algorithm for mrcc, based predominantly on patient stratification according to previous treatment and prognostic risk groups (Fig. 1) [10,12 14,16,18,26,33,46]; other factors for consideration are discussed. The algorithm relies primarily on efficacy data due to the patient-specific nature of tolerability, although this is a key factor in treatment choice [25]. FIRST-LINE TREATMENT Therapy for patients with mrcc with no previous treatment can first be determined based on their allocation to favourable-, intermediate- or poor-risk groups according to MSKCC criteria [37]. JOURNAL COMPILATION 2009 BJU INTERNATIONAL 13

5 BELLMUNT ET AL. For favourable-risk patients, cytokine therapy, with IFN-α or interleukin-2 (IL-2), was the only effective therapy for mrcc for several decades. However, there were only modest increases in survival in limited subsets of patients with good risk profiles and clear-cell histology, and these treatments were associated with substantial toxicity [33]. Although treatment with high-dose IL-2 can result in long-lasting responses, this treatment is associated with acute toxicity and benefit is limited to a few patients with limited or no comorbidities and good PS [42,47 49]. Identifying patients with a potential to benefit might be possible through the use of molecular markers such as carbonic anhydrase IX, which could serve as a predictor of response to IL-2 treatment [50,51]. Based on clinical evidence, sunitinib should be considered the treatment of choice for patients stratified into the favourable-risk group. Analysis of MSKCC prognostic factors from the phase III, randomized study comparing sunitinib with IFN-α in the firstline setting indicated that sunitinib benefit extends across all risk groups (Table 1) [11]. Patients with no risk factors had a median PFS of 14.9 ( ) months for sunitinib, vs 8.4 ( ) months for IFN-α (Fig. 2) [11]. Bevacizumab plus IFN-α is an alternative first-line option for treating patients stratified into the favourable-risk group. Subgroup analysis of a phase III trial in previously untreated patients with mrcc indicated that in those with a favourable MSKCC score, the median PFS was 12.9 months for bevacizumab plus IFN-α2a compared with 7.6 months for IFN-α2a plus placebo (HR 0.6, P = 0.004; Fig. 3) [4,52]. In a second phase III study of similar design the median PFS in the favourable-risk group was 11.1 months in patients treated with bevacizumab plus IFNα2a, vs 5.7 months for those treated with IFN-α2a alone (P = 0.001; Table 1) [13]. Sorafenib has been examined in a phase II trial, and retrospectively in an expandedaccess study, for treating patients in the firstline setting. As described previously, sorafenib and IFN-α were not significantly different with respect to the median PFS in the phase II trial [26]. Sorafenib efficacy in previously untreated patients was examined retrospectively in the expanded-access study, where the median PFS was 35.1 ( ) weeks, with PRs in 4% and stable disease in 79% of 935 patients [27]. Sorafenib mrcc FIG. 2. Kaplan-Meier estimates of the median PFS during first-line treatment with sunitinib or IFN-α across favourable (A) and intermediate (B) MSKCC risk groups [11]. median A. Favourable risk PFS = 14.9 months 1.0 (95% Cl: ) IFN-α median 0.7 PFS = 8.4 months 0.6 (95% Cl: ) Excludes 17 patients in the IFN-α group for whom baseline data were missing. Outcome by investigator assessment. PFS probability B. Intermediate risk PFS probability MSKCC group 3 Favourable risk Intermediate risk Poor risk Excludes 17 patients in the IFN-α group for whom baseline data were missing. Outcome by investigator assessment. is not currently recommended for first-line use in mrcc by European guidelines [33], although it is recommended by the USA National Comprehensive Cancer Network guidelines, as well as other proposed treatment algorithms for the first-line treatment of selected patients [53,54]. INTERMEDIATE-RISK PATIENTS First-line Cytokines (IL-2) Sorafenib? Temsirolimus median PFS = 10.7 months (95% Cl: ) IFN-α median PFS = 3.8 months (95% Cl: ) For the first-line treatment of the intermediate-risk group, available data support the use of sunitinib. In a phase III Second-line Sorafenib mtor inhibitors? Sorafenib mtor inhibitors? Sorafenib mtor inhibitors? FIG. 3. Kaplan-Meier estimate of the median PFS during first-line treatment with bevacizumab plus IFN-α or placebo plus IFN-α across favourable (A) and intermediate (B) MSKCC risk groups [52]. PFS probability A. Favourable risk B. Intermediate risk PFS probability FIG. 1. Overview of the treatment algorithm for RCC [10,12 14,16,18,26,33,46]. median PFS = 12.9 months Placebo + IFN-α median PFS = 7.6 months median PFS = 10.2 months Placebo + IFN-α median PFS = 4.5 months Outcome by investigator assessment. randomized study comparing sunitinib with IFN-α in the first-line treatment of patients with mrcc, patients with one or two MSKCC risk factors had a median PFS of 10.7 ( ) months for sunitinib vs 3.8 ( ) months for IFN-α (Fig. 2) [11]. Bevacizumab plus IFN-α is a possible alternative to sunitinib in this group. In a phase III trial, patients with an intermediate MSKCC score had a median PFS of 10.2 vs 4.5 months, respectively, with bevacizumab plus IFN-α2a vs IFN-α2a alone (HR 0.55, ; Fig. 3) [4]. In a second phase III study, patients stratified into the intermediate MSKCC risk category had a median PFS of 8.4 months when treated with bevacizumab and IFN-α combined, compared with 14 JOURNAL COMPILATION 2009 BJU INTERNATIONAL

6 MANAGEMENT ALGORITHMS FOR METASTATIC RCC FIG. 4. Kaplan-Meier estimate of median OS in poorrisk patients receiving first-line treatment with temsirolimus, IFN-α or temsirolimus plus IFN-α [2]. Survival probability months for IFN-α alone (P = 0.002; Table 1) [13]. In a phase III trial (ARCC), temsirolimus was compared with IFN-α in patients with mrcc considered at poor-risk according to modified MSKCC criteria [2]. In the subgroup considered at intermediate risk according to MSKCC criteria, the median OS was shorter for temsirolimus (13.0 months) than for IFN-α (17.7 months), suggesting that temsirolimus might not be suitable for this risk group (Table 1) [14]. Corresponding values for median PFS were 7.0 months for temsirolimus and 5.6 months for IFN-α [14]. POOR-RISK PATIENTS Temsirolimus median OS = 10.9 months IFN-α median PFS = 7.3 months Temsirolimus + IFN-α median PFS: 8.4 months As discussed earlier, temsirolimus was found to prolong the median OS and PFS compared with IFN-α in the ARCC trial in patients considered at poor risk (modified MSKCC criteria; Fig. 4) [2]. Analysis of ARCC trial data also found that while temsirolimus extended the median OS and PFS in tumours with both clear and non-clear cell histology compared with IFN-α, the benefit was greater in tumours with non-clear cell histology [14]. Compared with IFN-α, temsirolimus also extended the OS and PFS in patients aged <65 years but not in patients aged 65 years [14]. Based on the results of the phase III and expanded-access studies, sunitinib might serve as an alternative treatment option for patients in the poor-risk group. In an analysis of the phase III study based on a limited population (48 patients), patients with three or more MSKCC risk factors had a median PFS of 3.9 ( ) months for sunitinib vs 1.2 ( ) months for IFN-α (Table 1) [11]. FIG. 5. Kaplan-Meier estimate of median PFS in patients receiving second-line treatment with sorafenib or placebo [3]. PFS (% patients) Poor-risk patients refractory to cytokines and treated with sunitinib in the large expandedaccess study had a median PFS of 4.8 ( ) months [23]. In both phase III studies with bevacizumab plus IFN-α, this combination did not appear to offer an advantage over IFN-α alone in the poor-risk group (Table 1) [4,13]. SECOND-LINE TREATMENT Sorafenib (n = 384) = 5.5 months Placebo (n = 385) = 2.8 months HR (sorafenib/placebo) = 0.44 (95% Cl: ) Time from randomization, months Results from a randomized, placebocontrolled phase III trial in patients with cytokine-refractory mrcc led to sorafenib being recommended for the second-line treatment of mrcc by the European Association of Urology guidelines (grade A recommendation) [33]. There was a significantly longer median PFS in sorafenibtreated patients (5.5 months) than in the placebo arm (2.8 months; ) at crossover in this phase III study (Fig. 5) [3]. Sorafenib was effective irrespective of MSKCC risk group. Of the 936 evaluable second-line patients in the sorafenib expanded-access study in the 2501 with mrcc, 3% had PRs and 81% had stable disease [55]. There are now data to support the use of sorafenib after other targeted agents. Treatment with sorafenib in patients refractory to sunitinib or bevacizumab reduced the tumour burden in nine of 27 evaluable patients [55]. In a separate study, one of 14 patients had a PR and some tumour shrinkage occurred in 10 other patients treated with sorafenib after failure of previous anti-angiogenic therapy [56]. Other targeted agents might also be considered for second-line treatment. approval was based on two phase II studies in patients with cytokine-refractory mrcc [16,17]. In addition, sunitinib has been examined in bevacizumab-resistant mrcc, where 23% of patients achieved a PR and the median PFS was 30.4 ( ) weeks [57]. In the expanded-access study in 3997 patients with cytokine-refractory or -intolerant mrcc, treatment with sunitinib resulted in a median PFS in patients with previous cytokine therapy of 9.6 months [23]. CONCLUSIONS AND FUTURE DIRECTIONS Based on available clinical data, the treatment algorithm for patients with mrcc indicates that sunitinib should be used as the treatment of choice in previously untreated patients stratified into the favourable- and intermediate-risk categories. In both these subsets, combined therapy with bevacizumab plus IFN-α is a suitable alternative, although the median PFS appears to be slightly shorter than with sunitinib [13]. In patients with a poor prognosis, temsirolimus should be considered for first-line treatment, with sunitinib as a viable alternative; results from the sunitinib expanded-access study indicate benefit in the poor-risk group. Additional factors such as tumour histology and patient age should be considered, along with tolerability. In our opinion, sorafenib might also be useful in the treatment of fragile patients where severe comorbidities are a concern, and other targeted agents might not be suitable. For second-line treatment, sorafenib can be used based on phase III results. The results from the sunitinib expanded-access study and other second-line studies indicate that sunitinib might also be effective in the second-line treatment of patients who have previously received targeted therapy. The algorithm outlined here is supported by the recommendations from the current European and USA guidelines summarized in Table 3 [33,53]. Other VEGF receptor-targeted agents that are currently under investigation will lead to alterations in the treatment algorithm for mrcc in the future. In a phase II study in 52 patients with RCC, axitinib gave an ORR (95% CI) of 44.2 ( )%, a median (range) TTP of 15.7 ( ) months and a median OS of 29.9 ( ) months. There was stable disease in 22 patients [58]. Antitumour activity has also been reported in a study JOURNAL COMPILATION 2009 BJU INTERNATIONAL 15

7 BELLMUNT ET AL. TABLE 3 Summary of the treatment algorithm and the European Association of Urology [33] and NCCN guidelines [53] Treatment setting Treatment algorithm EAU guidelines NCCN guidelines First-line Favourable risk Intermediate risk Poor risk Second-line Cytokines (IL-2; selected patients) Bevacizumab plus IFN-α Sorafenib (selected patients) Temsirolimus Sorafenib Agents in development (everolimus, axitinib) (Grade A) IL-2 and IFN-α (Grade B; selected patients with good risk profile and clear cell histology) (Grade A) Temsirolimus (Grade A)* Sorafenib (Grade A) *Poor risk category is three of six poor risk features (five predefined MSKCC criteria, see text). (Category 1) Temsirolimus (poor risk*; Category 1) Bevacizumab plus IFN High dose IL-2 (selected patients) Sorafenib (selected patients Sorafenib (Category 1 for cytokine-refractory mrcc; Category 2A after RTK inhibitor) (Category 1 for cytokine-refractory mrcc; Category 2A after RTK inhibitor) Temsirolimus (Category 2A for cytokinerefractory mrcc; Category 2B after RTK inhibitor) IFN (Category 2B) High dose IL-2 (Category 2B) Low dose IL-2 plus IFN (Category 2B) Bevacizumab (Category 2B) assessing axitinib activity in sorafenibrefractory patients [59]. Pazopanib has completed phase I evaluation [60] and is being investigated in a phase II randomized discontinuation trial [61] and a phase III study. Everolimus has shown antitumour activity in pre-treated patients with mrcc in phase II studies [46,62]. In a phase III trial in patients with mrcc who had progressed after treatment with RTK inhibitors, those treated with everolimus had a median PFS of 4.9 months (independent central review) compared with 1.87 months for placebo (HR 0.33, 95% CI ) [63]. Biomarkers might further identify patients with potential to benefit from targeted therapy and might be predictive of response, allowing individualized prognostication and treatment. The expression of several molecular markers is altered in RCC, and while it is beyond the scope of this article to review them, some could be useful in predicting treatment outcomes in mrcc. The treatment algorithm outlined here reviews the clinical data on the targeted agents currently being used to treat mrcc. The algorithm considers patient stratification based on risk category as well as previous therapy, elaborating further on the current guidelines. The treatment algorithm provides guidance on the optimal treatment strategy for patients with mrcc, to maximize clinical benefit and achieve meaningful results in the treatment and management of mrcc. ACKNOWLEDGEMENTS This manuscript was developed by the authors following an Advisory Group meeting, sponsored by Pfizer Inc. The authors received honorarium for participation in the meeting but not for the development of this paper. Medical writing support was provided by ACUMED (Tytherington, UK), with funding from Pfizer Inc. CONFLICT OF INTEREST Joaquim Bellmunt has had an advisory role with Pfizer, Wyeth, Bayer and Roche. Stéphane Oudard has had an advisory role with Pfizer, Wyeth and Bayer. Per Flodgren has had an advisory role with Pfizer and Bayer. Jan Roigas has had an advisory role with Pfizer. REFERENCES 1 Motzer RJ, Hutson TE, Tomczak P et al. versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370: Pfizer Inc. SUTENT, Summary of Product Characteristics, January Bayer Heathcare AG. Nexavar, Summary of Product Characteristics Wyeth Pharmaceuticals I. Torisel Summary of Product Characteristics Ravaud A. Key considerations in patient selection for the use of targeted therapy in metastatic renal cell carcinoma. Eur J Cancer Suppl 2007; 5: JOURNAL COMPILATION 2009 BJU INTERNATIONAL

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Oral presentation at the 33rd European Society for Medical Oncology Congress, Stockholm, Sweden, September 2008: 12 6 (Abstract 720) Correspondence: Joaquim Bellmunt, Solid Tumor Oncology (GU & GI), Medical Oncology Service, RTICC (RD06/0020/109) Programa de Recerca de Càncer, IMIM-Hospital del Mar, Paseo Maritimo 25-29, Barcelona 08003, Spain. jbellmunt@imas.imim.es Abbreviations: mrcc, metastatic RCC; RTK, receptor tyrosine kinase; VEGF, vascular endothelial growth factor; IFN, interferon; IL, interleukin; MSKCC, Memorial Sloan- Kettering Cancer Center; ECOG, Eastern Cooperative Oncology Group; PS, performance score; PFS, progression-free survival; OS, overall survival; PR, partial response; CR, complete response; HR, hazard ratio; ORR, objective response rate; AE, adverse event; ARCC, Advanced RCC (trial); LDH, lactate dehydrogenase; TTP, time to progression. 18 JOURNAL COMPILATION 2009 BJU INTERNATIONAL