Adjuvant Therapy in Renal Cell Carcinoma: Where Are We?

european urology supplements 6 (2007) 492 498 available at www.sciencedirect.com journal homepage: www.europeanurology.com Adjuvant Therapy in Renal Cell Carcinoma: Where Are We? Tim Eisen * University of Cambridge, Cambridge, UK Article info Keywords: Adjuvant therapy Renal cell carcinoma Sorafenib Sunitinib Abstract This review summarises available data and describes planned clinical trials designed to evaluate the potential of targeted agents as adjuvant therapy for renal cell carcinoma (RCC). Advanced RCC is refractory to standard cytotoxic chemotherapy, and clinical trials of adjuvant cytokine therapy in this therapeutic setting have not yet demonstrated clear evidence of clinical benefit. However, molecularly targeted therapies may offer a new approach for adjuvant therapy of this disease. Sorafenib (Nexavar 1 ; Bayer Healthcare, West Haven, CT, USA) and sunitinib (Sutent 1 ; Pfizer Inc, New York, NY, USA) are candidates for adjuvant therapy, because they are efficacious in the treatment of metastatic RCC and have side-effect profiles that can usually be well managed during long-term administration. The clinical benefit and tolerability of these agents as adjuvant therapies are being investigated in three ongoing phase 3 trials: ASSURE (adjuvant sorafenib or sunitinib in unfavourable renal cell carcinoma; Eastern Cooperative Oncology Group 2805), STAR (sunitinib trial in adjuvant renal cancer) and SORCE (a phase 3, randomised, double-blind, controlled study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse). The results of these studies will address important clinical and translational questions, the answers to which may help define future treatment strategies and guide treatments towards the most appropriate patients. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge, CB2 2RE, UK. Tel. +44 1223 404309; Fax: +44 1223 404208. E-mail address: tgqe2@cam.ac.uk. 1. Introduction In 2006, an estimated 38,890 new cases and 12,840 deaths due to cancer of the kidney and renal pelvis occurred in the United States [1]. Approximately 70% of patients with renal cell carcinoma (RCC) present with localised or locally advanced disease, which is potentially curable by nephrectomy alone [2,3]; however, recurrence rates are high (35 65%) for those patients with locally aggressive (intermediate high risk) tumours [4]. Therefore, there is a need for effective adjuvant therapy to reduce the number of patients who undergo an apparently curative procedure yet go on to develop metastatic disease. In addition, to maximise the potential benefit of adjuvant therapy for RCC, methods that allow 1569-9056/$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2007.01.017

european urology supplements 6 (2007) 492 498 493 Table 1 Past and ongoing clinical trials of adjuvant therapy in renal cell carcinoma Trial/author Treatment n Outcome Kjaer [7,8] Radiotherapy vs. observation 72 Overall survival: 50% vs. 62% (NS) Pizzocaro [9] MPA vs. observation 136 Relapse: 33% vs. 34% (NS) Adler [10] BCG + hormonotherapy vs. hormonotherapy alone 43 Progression-free survival: 82% vs. 48% (NS) Galligioni [11] BCG vs. observation 120 Disease-free survival: 63% vs. 72% (NS) Messing [5] Interferon vs. observation 283 Overall survival: 5.1 vs. 7.4 yr (NS) Clark [6] High-dose IL-2 vs. observation 69 Relapse: 76% vs. 65% (NS) Jocham [12] Autologous tumour vaccine vs. observation 553 * Progression-free survival: 77% vs. 68% ( p = 0.02) G250Ab vs. observation Ongoing HSPCC-96 vs. observation Ongoing Atzpodien vs. observation Ongoing ASSURE Sorafenib vs. sunitinib vs. placebo Ongoing STAR Sunitinib vs. placebo Ongoing SORCE Sorafenib vs. placebo Ongoing NS = not significant; MPA = medroxyprogesterone acetate; BCG = bacille Calmette Guérin; IL-2 = interleukin-2; Atzpodien = interferon plus IL-2 plus high-dose 5-fluorouracil. * 174 lost at randomisation. appropriate selection of suitable patients must also be identified. Advanced RCC is refractory to standard cytotoxic chemotherapy regimens. Evidence to date suggests that RCC is sensitive to immunologic manipulation; thus, cytokine-based therapy with interleukin-2 (IL-2) or interferon-a (IFN-a) has become the mainstay of care. However, both IL-2 therapy and IFN-a therapy demonstrate limited efficacy in advanced disease, and are associated with significant side-effect profiles, which raises questions about their suitability for use in the adjuvant setting. Indeed, a phase 3 trial comparing adjuvant IFN-a with observation did not demonstrate a significant difference in median overall survival (OS; 5.1 vs. 7.4 yr, p = 0.09)[5], whereas another trial comparing high-dose IL-2 with observation failed to show a difference in relapse rates after 2 yr (76 vs. 65%, p = 0.73) [6]. Trials of other adjuvant therapies for RCC have demonstrated little success (Table 1) [5 12]. For example, a comparison of radiotherapy versus observation showed no difference in OS after 26 mo (50% vs. 62%; [7,8]). A second study compared 1 yr of adjuvant medroxyprogesterone acetate versus no treatment in 136 patients following radical nephrectomy for nonmetastatic renal cancer. No difference in relapse rates between the two therapies was observed after 5 yr of follow-up (32.7% vs. 33.9%, respectively [9]). A number of trials of potential adjuvant therapies are currently ongoing or planned (Table 1), including cg250 (WX-G250; a chimeric monoclonal antibody); HSPPC-96 (vitespen; a tumour vaccine based on heatshock protein gp96); sorafenib (Nexavar 1 ; Bayer Healthcare, West Haven, CT, USA), and sunitinib (Sutent 1 ; Pfizer Inc., New York, NY, USA). The cg250 study is an international randomised trial that aims to recruit 612 patients with nonmetastasised clear cell RCC at high risk of relapse following nephrectomy and lymphadenectomy. Patients will receive weekly treatment with either cg250 or placebo over 24 wk. Phase 3 studies, including more than 600 patients, are also being undertaken at 145 sites worldwide to compare radical nephrectomy plus HSPPC-96 with nephrectomy alone. Future trials are likely to focus on increasing the efficacy of heat-shock protein vaccines by the concomitant use of conventional cytotoxic, cytostatic, and biologic agents. This paper reviews recent data and describes clinical trials currently in development to evaluate the potential of the targeted agents sorafenib and sunitinib as adjuvant therapy for RCC. 2. Patient selection for adjuvant therapy Radical nephrectomy is a potentially curative procedure for patients with localised RCC. However, despite this aggressive surgical therapy, up to 50% of patients who do not present with metastases at the time of surgery may subsequently develop a disease recurrence attributable to subclinical metastases [13]. This subgroup of patients may derive the greatest benefit from adjuvant therapy. Accordingly, risk models that accurately identify these patients are essential, allowing appropriate targeting of adjuvant therapy. Several models to predict the risk of tumour recurrence following nephrectomy have been developed. The Kattan risk model uses tumour histology, size, tumour node metastases (TNM) staging, and clinical presentation to predict the 5-yr probability of treatment failure among patients with RCC treated

494 european urology supplements 6 (2007) 492 498 with nephrectomy [14]. The University of California Los Angeles (UCLA) Integrated Staging System (UISS) model is based on Eastern Cooperative Oncology Group (ECOG) Performance Status, Fuhrman grade, and TNM staging [15]. Two other systems the Cindolo and Yaycioglu models utilise preoperative variables of clinical tumour size and presentation for provision of prognostic information [16,17]. In addition, a retrospective study found that patients in the pt3 4 TNM subgroups could be reclassified into three categories with significantly different prognoses following nephrectomy, suggesting that a modified TNM system could be used to predict cancer-specific survival [18]. The Leibovich risk model (the sign, stage, grade, and necrosis [SSIGN] system), recently developed at the Mayo clinic, aims to predict progression in patients with clinically localised, clear cell RCC who undergo radical nephrectomy [19,20]. The model uses primary tumour status, regional lymph-node status, tumour size, nuclear grade, and histologic tumour necrosis to stratify patients into low (total score: 0 2), intermediate (total score: 3 5), or high (total score: 6) risk of developing metastases. In a retrospective study of 1671 patients who underwent radical nephrectomy between 1970 and 2000, patients in the low-risk group had not reached a median metastasis-free survival after a median follow-up of 5.4 yr, whereas median metastasis-free survival was 2.2 yr in the intermediate-risk group and 0.8 yr in the high-risk group [20]. This model may ultimately facilitate the identification of which patients are most likely to benefit from adjuvant therapy. The results of prospective trials that corroborate this model will be of key importance. 3. Targeted agents as adjuvant therapies for RCC: rationale A candidate for adjuvant therapy for RCC must be effective and have a good safety profile, especially if it is to be administered for extended periods of time. Sorafenib and sunitinib are two multikinase inhibitors that fulfil these criteria [21]. In addition, as both sorafenib and sunitinib are administered as a simple oral dose, they may represent attractive options to patients who may otherwise receive inconvenient therapy that may be given intravenously or require inpatient treatment. 3.1. Sorafenib Sorafenib is a multikinase inhibitor that simultaneously targets upstream receptor tyrosine kinases (vascular endothelial growth factor receptor [VEGFR]- 2, VEGFR-3; platelet-derived growth factor receptor [PDGFR]-b; fms-like tyrosine kinase-3; c-kit) and downstream serine/threonine kinases (C-Raf, B-Raf) in both the tumour cell and tumour vasculature. The efficacy and safety of sorafenib in advanced RCC have been evaluated in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a randomised, double-blind, placebo-controlled study of sorafenib versus placebo in 903 patients with advanced RCC who had received one prior therapy. In a planned interim analysis, sorafenib significantly improved progression-free survival compared with placebo (as detailed in the article by Dr Escudier in this supplement). This finding led to a protocol modification allowing patients in the placebo group to cross over to sorafenib. A trend towards improved OS with sorafenib compared with placebo was observed both at the time of crossover and 6 mo post-crossover. In addition, the proportion of patients with tumour shrinkage was substantially greater following treatment with sorafenib (76%) versus placebo (25%). Sorafenib was well tolerated and most side effects were easily manageable. The most frequent adverse events associated with sorafenib included diarrhoea, rash/desquamation, fatigue, hand foot skin reaction and hypertension. The incidence of grade 3 4 fatigue was not increased in the sorafenib group compared with the placebo group. It is anticipated that the favourable adverse-event profile of sorafenib will be compatible with long-term administration and will enable patients to receive sorafenib for the duration of an adjuvant therapy protocol, typically 1 3 yr. 3.2. Sunitinib Sunitinib is also orally bioavailable and functions via inhibition of c-kit and the VEGF and PDGF receptors. Two sequentially conducted, single-arm, multicentre, phase 2 trials [22,23] investigated the use of sunitinib for the treatment of advanced RCC in patients who had failed initial cytokine therapy. Overall response rates were 40% and 44% for the two trials as reported following investigator assessment. Treatment-related adverse events (grades 3 4) in the first trial included neutropenia (13%), fatigue (11%), diarrhoea (3%), nausea (3%), stomatitis (2%), dermatitis (2%), and hypertension (2%) (as detailed in the article by Dr Bellmunt in this supplement). A phase 3 trial [24] investigating sunitinib as a first-line treatment in 750 patients with advanced RCC demonstrated that sunitinib improved progression-free survival (11 vs. 5 mo) and induced a greater overall response rate (37% vs. 9%) in comparison

european urology supplements 6 (2007) 492 498 495 with IFN-a. A nonsignificant trend towards improved overall survival was also observed in response to sunitinib compared with IFN-a. Frequently reported grade 3 4 adverse events in response to both treatments (sunitinib vs. IFN-a) included fatigue (7% vs. 11%) and nausea (3% vs. 1%). Grade 3 4 diarrhoea (5% vs. 0%), hypertension (8% vs. <1%), and hand foot syndrome (5% vs. 0%) were also reported but with greater frequency in patients receiving sunitinib compared with those receiving IFN-a. Grade 3 4 fatigue occurred with greater frequency in the IFN-a group compared with the sunitinib group. 4. Adjuvant therapy for RCC: planned trials Three large phase 3 trials are currently in development to evaluate the long-term safety and efficacy of multikinase inhibitors as adjuvant therapy for RCC: ASSURE (adjuvant sorafenib or sunitinib in unfavorable renal cell carcinoma), STAR (sunitinib trial in adjuvant renal cancer), and SORCE (a phase 3, randomised, double-blind controlled study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse). 4.1. The ASSURE trial ASSURE (ECOG 2805) is a randomised, double-blind, multicentre, phase 3 trial of adjuvant sorafenib versus adjuvant sunitinib versus placebo in patients with resected RCC [25]. The accrual target is 1332 patients and recruitment is currently open. Patients will be randomised in a 1:1:1 ratio to 1 yr of treatment with placebo, sorafenib, or sunitinib (Fig. 1). Follow-up will continue for 9 yr. Eligibility criteria include histologically or cytologically confirmed RCC (including clear cell and non-clear cell histologies); intermediate high-risk (pt1b, G3 4; pt2; pt3a, G1 2 with no adrenal involvement) or very high-risk (pt3a, G3 4 or G1 2 with adrenal involvement; ptb; ptc; pt4; any pt, any G, N+) disease; no prior adjuvant or neoadjuvant therapy; full surgical resection (radical or partial nephrectomy) by either open or laparoscopic technique; and no evidence of residual or metastatic RCC within 4 wk of randomisation. The primary objective of ECOG 2805 is to compare the disease-free survival of patients treated with adjuvant sunitinib versus sorafenib versus placebo. Other endpoints include a comparison of OS rate in each of the study arms and evaluation of the toxicity profile associated with prolonged administration of sunitinib or sorafenib. In addition, translational endpoints include assessment of angiogenic markers in tissue, blood and urine, frequency of oncogene or tumour suppressor gene mutations, and tumour and genetic polymorphisms as predictors of disease-free survival and therapeutic benefit. It should be noted that this study is not powered to show a difference between sorafenib and sunitinib. Fig. 1 The ASSURE clinical trial will evaluate sorafenib and sunitinib as adjuvant therapy. (ASSURE = adjuvant sorafenib or sunitinib in unfavourable renal cell carcinoma; TNM = tumour node metastases; ECOG PS = Eastern Cooperative Oncology Group Performance Status; p.o. = orally; q.d. = once daily; b.i.d. = twice daily.)

496 european urology supplements 6 (2007) 492 498 Fig. 2 The SORCE clinical trial will evaluate sorafenib as adjuvant therapy. 4.2. The STAR trial The STAR trial is a randomised, double-blind, phase 3 study of adjuvant sunitinib versus placebo in patients with high-risk RCC according to UISS criteria [26]. Its purpose is to compare disease-free time and safety of sunitinib with placebo in patients with high-risk kidney cancer postsurgery. The primary endpoint is disease-free survival. Secondary outcomes include relapse-free survival, OS, patientreported outcomes and safety. 4.3. The SORCE trial SORCE is a phase 3, randomised, double-blind study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse according to the Leibovich model [27] (Fig. 2). A projected total of 1656 patients will receive either placebo for 3 yr (arm A), sorafenib 400 mg twice daily for 1 yr then placebo for 2 yr (arm B), or sorafenib 400 mg twice daily for 3 yr (arm C) (randomised in a 2:3:3 ratio). Sorafenib will be offered to any patients who progress within 3 yr of start of treatment in arms A and B; this design is expected to be attractive to patients because it will minimise the number of patients who will receive only placebo. Follow-up assessments will be undertaken at 3 wk, 6 wk, and 3 mo, then every 3 mo until the patient has completed the third year of the study, then every 6 mo until the end of the fifth year of the study, then annually thereafter. Patient recruitment is expected to take 5 yr, with a further 3 yr of follow-up. Eligibility criteria for the SORCE trial include primary RCC of clear cell or non-clear cell histology, a Leibovich prognostic score of 3 8 (high or intermediate risk of metastatic RCC or death), nephrectomy between 4 wk and 3 mo prior to treatment start date, no prior anticancer treatment other than nephrectomy, and no evidence of residual disease after resection of RCC. Patients must be older than 18 yr with a Performance Status of 0 1 and without comorbidity expected to reduce life expectancy below 10 yr from the time of entering the trial. The primary endpoint of the SORCE study will be disease-free survival. The study is powered to detect an improvement in disease-free survival from 63.5% to 71% (hazard ratio = 0.75). This requires 608 disease-free survival events in 1656 patients (414 patients in arm A and 621 in each of arms B and C), using a log-rank test with 90% power and 5% twosided significance level. Secondary endpoints include RCC-specific survival time, OS, toxicity, biologic characteristics of resected primary RCC, genetic epidemiology, health economics, and corroboration of the Leibovich prognostic score. Tumour and blood samples will be collected for translational research to determine biologic parameters that may predict benefit from sorafenib. A key hypothesis that will be tested is that those patients who benefit most from adjuvant sorafenib are those whose tumours display deregulated VEGF/PDGF signalling. 5. Conclusions and future perspectives In light of the high recurrence rates after nephrectomy in patients with locally aggressive RCC, an effective, well-tolerated adjuvant therapy is needed to reduce the incidence of tumour recurrence and to increase survival rates. Adjuvant trials of new targeted agents, including sorafenib and sunitinib, have been designed to address several important

european urology supplements 6 (2007) 492 498 497 clinical and translational questions. Results of these trials are eagerly awaited as they will determine the role of new targeted therapies in the adjuvant setting and may help urologists to direct therapies towards the most suitable patients. Conflicts of interest Tim Eisen has received honoraria and research support from Bayer and Pfizer, and is a member of advisory boards for both companies. Acknowledgements The author kindly acknowledges the contribution of Kate Unsworth (GeoMed) for professional medical writing support and Karen Middleton (GeoMed) for editorial assistance, with funding for professional writing services from Bayer Healthcare Pharmaceuticals. References [1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106 30. [2] Golimbu M, Joshi P, Sperber A, et al. Renal cell carcinoma: survival and prognostic factors. Urology 1986; 27:291 301. [3] Lam JS, Shvarts O, Leppert JT, et al. 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498 european urology supplements 6 (2007) 492 498 interferon-alfa (IFN-a) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mrcc). J Clin Oncol 2006;24(Suppl):2s (abstract no. LBA3). [25] ClinicalTrials.gov. Sunitinib or sorafenib in treating patients with kidney cancer that was removed by surgery. Available at http://www.clinicaltrials.gov/ct/show/nct 00326898?order = 1. Accessed 26 October 2006. [26] ClinicalTrials.gov. A clinical trial comparing efficacy and safety of sunitinib and placebo in high risk renal cell cancer. Available at http://www.clinicaltrials.gov/ct/ show/nct00375674?order = 4. Accessed 27 November 2006. [27] Clinical Trials Unit. RE05/SORCE: a phase III randomised controlled study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse. Available at URL: http://www.ctu.mrc.ac.uk/studies/re05.asp. Accessed 27 November 2006.