Oncology A Phase II Study of Presurgical Sunitinib in Patients with Metastatic Clear-cell Renal Carcinoma and the Primary Tumor In Situ

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1 Oncology A Phase II Study of Presurgical Sunitinib in Patients with Metastatic Clear-cell Renal Carcinoma and the Primary Tumor In Situ Axel Bex, Christian Blank, Wim Meinhardt, Harm van Tinteren, Simon Horenblas, and John Haanen OBJECTIVE METHODS RESULTS CONCLUSIONS To investigate response rate (RR) of the primary tumor after presurgical sunitinib before planned cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mrcc). Secondary endpoints were safety and if this strategy can be used to identify patients who progress rapidly and may not benefit from CN. Prospective study to detect a 25% response evaluation criteria in solid tumors RR (RECIST-RR) in the primary tumor (Simon two-stage design). CN was performed after 2 cycles of sunitinib 50 mg/d. Response in the primary tumor and metastatic sites, change of longest diameter of the primary tumor ( -LDT), progression-free survival (PFS), and adverse events were assessed. Twenty-two patients with primary mrcc were included. The trial did not enter the second stage because only 1 primary tumor responded partially in the first stage (4.5%). Median -LDT was 9.5% (range 2.2 to 36%). A 10% -LDT was significantly associated with a high probability to survive 2 years (P.01). At metastatic sites, 7 patients developed a partial response (31.8%), 7 stable disease (31.8%), and 8 progressive disease (36.4%). Subsequently 3 (13.6%) developed a complete response after CN and continued taking sunitinib. Median PFS is 7 months (range 0-41). Median follow-up is 23 months (range 2-41). Median overall survival has not been reached. Downsizing of primary tumors after 2 cycles of sunitinib is modest but associated with long-term survival. Patients with progression of metastases after pretreatment have short survival and are unlikely to benefit from CN. UROLOGY 78: , Elsevier Inc. In metastatic renal cell carcinoma (mrcc) the tyrosine-kinase inhibitor sunitinib leads to progressionfree survival (PFS) of 11.5 months and an overall survival (OS) of 26 months, 1 which may reach 40 months with adequate sequential therapy. 2 This has renewed the controversy surrounding cytoreductive nephrectomy (CN) for patients with primary mrcc. Response in the primary tumor has been observed and additional CN may not change clinical outcome. However, because 91% of patients included in the pivotal phase III trial of sunitinib vs interferon had a nephrectomy, 3 it is unknown whether the observed outcome Financial Disclosure: Axel Bex has received honoraria for taking part in advisory board meetings for Pfizer, Bayer and GlaxoSmithKline. Christian Blank has received honoraria for taking part in advisory board meetings for Pfizer, Bayer and Glaxo- SmithKline. John Haanen has received honoraria for taking part in advisory board meetings for Pfizer. Funding Support: This trial was supported in part by a research grant from Pfizer. From the Department of Urology, Department of Medical Oncology, and Department of Biostatistics, Cancer Institute, Amsterdam, The Netherlands Reprint requests: Axel Bex, M.D., Ph.D., The Netherlands Cancer Institute, Division of Surgical Oncology, Department of Urology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. a.bex@nki.nl Submitted: March 29, 2011, accepted (with revisions): May 24, 2011 applies to mrcc patients with the primary tumor in situ. Retrospective data suggest that CN in the era of targeted therapy is beneficial in some patients, especially those with good performance and intermediate Memorial Sloan Kettering Cancer Center (MSKCC) risk. 4 Presurgical targeted therapy may help to further identify those who suffer from early progression and may not benefit from surgery. 5 Two large phase III trials (CARMENA, EORTC SURTIME) are now investigating the role and sequence of CN in patients receiving sunitinib. 6 Responses of the primary tumor to sunitinib using response evaluation criteria in solid tumors (RECIST) criteria have been reported in retrospective analyses. 7,8 However, it is unknown whether these responses correlate with survival and to what extent patients sharing prognostic factors and subtypes respond in their primary tumors after a predefined length of therapy. Complete response (CR) of metastatic sites is rare after sunitinib, but partial response (PR) has been observed in 31-40% in trials. 3,9 A similar PR rate in primary tumors may have implications for prognosis, treatment strategies, and surgical approaches. Here, we report results from a prospective study initiated in June The trial was designed to detect a Elsevier Inc /11/$36.00 All Rights Reserved doi: /j.urology

2 25% PR rate of the primary tumor after 2 courses of sunitinib. Secondary endpoints focused on safety of presurgical sunitinib and on evaluating this strategy to identify patients who progress rapidly and may not benefit from CN. MATERIAL AND METHODS Patients participated in a phase II trial of sunitinib followed by nephrectomy in patients with mrcc and the primary tumor in situ. The trial had institutional review board approval and was registered under EudraCT number ( eudract.ema.europa.eu/). Written informed consent was obtained from all patients after they were informed about the objectives of the study. The main objective was to investigate the response rate of the primary tumor after sunitinib pretreatment. The main end point was any objective response in the primary tumor according to RECIST 1.1. Secondary endpoints were safety and morbidity; change of longest diameter of the primary tumor ( -LDT) in % (with negative values indicating a decrease); overall RECIST response at metastatic sites; PFS and OS; duration of hospital stay; percentage of withdrawal from nephrectomy as a result of sunitinib-related toxicity; and progression of the primary tumor during pretreatment. Surgical complications were graded according to Clavien-Dindo. 10 Eligibility included histologically confirmed clear-cell mrcc with a resectable asymptomatic primary in situ and an intermediate MSKCC risk profile, metastatic disease defined as 3 or more nonresectable metastases in case of 1 metastatic site, using RE- CIST or 2 metastatic sites, age 18 years, life expectancy 3 months, World Health Organization (WHO) performance status 0 or 1, leukocytes /L, platelets /L, hemoglobin 6.0 mmol/l, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and creatinine within 1.5 times the upper limit of normal, and no prior cytokines, tyrosine-kinase inhibitors, monoclonal antibodies, or chemotherapy. Local radiotherapy for bone lesions was allowed. In women of child-bearing age, anticonception was required. Statistical Analysis and Sample Size Estimation The study was designed to detect a 25% objective response rate (RR) in the primary tumor according to RECIST with an alpha of 0.05 and a power of 80% using a two-stage minimax design developed by Simon. 11 First, 22 patients were treated and if only 1 primary tumor responded, the study was to be stopped. If at least 2 responded, 18 additional patients would have been included for a total of 40 patients. If the total responses of primary tumors for both stages combined would be 8, sunitinib would have a 25% RR. This design allows for early termination if sunitinib is associated with low RECIST response in the primary tumor (here defined as 10% RR rate or lower). OS estimates were calculated using the Kaplan-Meier technique. A log-rank test was applied to compare survival between groups. Survival was defined as time from tumor assessment after 2 cycles of sunitinib until death. Patients still alive were censored. Treatment Patients received sunitinib 50 mg/d for 2 cycles (4 weeks/2 weeks off). One week before completion of the second cycle, Table 1. Patient characteristics at inclusion Number of patients 22 Age 52 (range 37-78) Gender Male 17 Female 5 Number of metastatic sites Metastatic sites Lung 19 Bone 8 Lymph node 14 Liver 4 Other 6 Clear cell grade at biopsy tumor assessments were made. CN was planned at the end of the second cycle with the last administration of sunitinib the day before surgery. All patients underwent delayed CN, including those with progression unless performance deteriorated to WHO 2 or worse. After 3 weeks rest, postoperative tumor assessments were repeated and sunitinib continued as 4/2 regimen until progression. In case of progressive disease (PD), second-line investigators choice treatment was offered. RESULTS Patient characteristics are summarized in Table 1. The trial did not continue into the second stage because only 1 primary tumor responded partially (4.5%). The median -LDT was 9.5% (range 2.2 to 36%) (Fig. 1). None of the primary tumors progressed. One patient developed a caval vein thrombus that led to more extensive surgery. 12 At metastatic sites, 7 patients developed a PR (31.8%), of whom 3 (13.6%) further regressed to CR aftr CN and continued sunitinib after 1-6 months, lasting 6, 22, and 31 months. Seven patients developed SD (31.8%) and 8 PD (36.4%). Four (18.2%) of those with PD deteriorated to WHO 2 and did not undergo CN. Median PFS is 7 months (range 0-41). Median OS has not been reached. Median follow-up is 23 months (range 2-41). Those with PD at metastatic sites before planned surgery had a median OS of 7.5 months (range 2-21). During CN (n 18), mean blood loss was 635 ml (range ) with a surgical time of 180 minutes (range ). Superficial wound healing impairment Clavien grade I was observed in 4 (22.2%). Median time off sunitinib after surgery was 24.5 days (range 21-49). Ten patients died of disease with a median OS of 5.5 months (range 2-15 months). Table 2 summarizes their characteristics in comparison with the 12 patients alive. When 10% -LDT is used as cut-off, those with 10% change of primary tumor diameter have a 78.8% probability to survive 2 years vs 27.3% for those with 10% change UROLOGY 78 (4),

3 Figure 1. Waterfall plot of change in longest diameter of the primary tumor ( -LDT) in % after 2 courses of sunitinib. Table 2. Patient characteristics separated into survivors and nonsurvivors Patients DOD Patients Alive Number of patients Overall survival (patients DOD) and current follow-up (patients alive) in months Median Range , 12, LDT primary tumor (%) Median 5.2% 16.2% Range % 0 36% Best response metastatic sites (RECIST) before CN PR 1 6 (3 CR)* SD 2 5 PD 7 1 Number of metastatic sites Metastatic sites Lung 10 9 Bone 4 4 Lymph node 7 7 Liver 2 2 Other 3 3 Size primary tumor in cm Median Range Dose reduction to 37.5 mg Preoperative 2 1 Postoperative 5 6 Second line therapy Sorafenib 1 0 Everolimus 2 1 DOD dead of disease. * Three patients with PR developed CR later. (P.01) (Fig. 2). Toxicity of sunitinib according to Common Terminology Criteria for Adverse Events (CT- CAE) v4.0 was generally mild. The percentage of patients experiencing grades 1-2 toxicity postoperatively increased for nausea from 22.7% preoperatively to 31.8%, and for vomiting and diarrhea from %, respectively. Percentage of grades 1-2 toxicity decreased for stomatitis from 40.1% preoperatively to 22.7% in the postoperative period, for hand-foot syndrome from %, and for fatigue from %. Grade 3 thrombocytopenia occurred preoperatively in 1 patient (4.5%). Postoperative grade 3 stomatitis and fatigue were noticed in 9.1%. Only 4 patients continued with second-line therapy. COMMENT The RECIST PR rate of the primary tumor after 2 cycles of sunitinib is low and only a modest median -LDT was observed. It has been argued that the changes induced by targeted agents are too subtle to be discriminated by RECIST. Most patients treated with targeted therapy in trials experienced SD, whereas CR is exceptional. 3,13 Vascular changes may long precede the effect on tumor growth. 14 Treatment with sorafenib or temsirolimus especially has resulted in low response rates of approximately 10%, although OS is significantly improved. 13,15 This has been recognized and other imaging criteria are used to evaluate minor changes in density or reduction of the longest diameter. The choi criteria define a PR as a 10% decrease in 1-D tumor size or a 15% decrease in attenuation on contrast-enhanced CT. They have recently been applied to patients with mrcc treated with sunitinib. 16 Though choi criteria may help to define early who benefits from sunitinib, their use did not change the management of these patients. Modified choi criteria use both changes in size and attenuation instead of either one of these. 17 In a retrospective study combined reduction in both size and arterial phase density of RCC metastases treated with sunitinib and cediranib correlated best with PFS. Others have evaluated a refined module, including mass, attenuation, size and structure which proved more accurate in predicting PFS than RECIST, choi or modified choi in patients with mrcc treated with sorafenib or sunitinib. 18,19 There is currently no consensus which 834 UROLOGY 78 (4), 2011

4 Figure 2. Overall survival defined as time from evaluation of either a 10% decrease or increase in longest diameter of the primary tumor to death of any cause. Patients who are still alive are censored at the last date known to be alive. imaging modality and response evaluation correlates best with outcome, but a change of 10% in the sum of the longest diameter of target lesions (SLD) is part of most alternative response assessments. Recently, a retrospective study using a threshold of 10% decrease of SLD discriminated 256 responders from 78 non-responders with a PFS of 11.1 months vs 5.6 months respectively. 20 These patients had mostly metachronic disease and metastases were used as target lesions. We used the same threshold for the primary tumor and observed that a 10% -LDT following 2 cycles of sunitinib discriminated significantly between patients with a high and low probability to survive 2 years. Establishing clinical factors that correlate with outcome is important because biomarkers to identify patients with primary metastatic RCC who may benefit from CN are lacking. Although the MSKCC prognostic factors are robust and applicable in the era of targeted therapy, 21 patients with primary mrcc are mostly of intermediate risk and belong to the largest subgroup with a broad range in OS. This trial included exclusively patients with intermediate MSKCC risk. Further discrimination is warranted and progression at metastatic sites may help to select those who may not benefit from CN. 5 Median OS of patients who progressed under presurgical sunitinib was 7.5 months. Seventy percent of those who died of disease (median OS of 5.5 months) had progression at metastatic sites before planned surgery (Table 2). These findings suggest that RECIST progression at metastatic sites may be used to identify those with a short survival and no benefit from additional surgery. This observation has been made previously in the cytokine era. 22 However, reduction of primary tumor size and progression at metastatic sites as predictors of outcome need confirmation in a larger prospective patient population and multivariate analysis. The EORTC SURTIME trial investigating the sequence of CN and systemic therapy with sunitinib will shed more light on these potential selection criteria. 6 Independent from predicting outcome, reduction of primary tumor diameter is important for planning surgical approaches, such as laparoscopy or nephron-sparing surgery. It is unlikely, however, that the observed downsizing may change surgical strategies. Although presurgical sunitinib may be of benefit in individual patients with surgically complex tumors, only few achieve sufficient downsizing to allow resection. 23 This is in line with earlier reports. In a retrospective analysis, volume reduction was more prominent than RECIST response after sunitinib. 7 Another retrospective study reported on primary tumors treated with a variety of targeted agents for various lengths. Only few patients had a RECIST response in the primary tumor and the most prominent downsizing was observed after a median of 105 days of sunitinib. 8 These retrospective data are however biased by variations in treatments, length of therapies, subtypes, and prognostic factors. One retrospective study included a small prospective pilot study of 2 cycles of sunitinib 50 mg before nephron-sparing surgery. In 14 tumors, the mean reduction of the maximum tumor diameter was 21.1%. 24 Few prospective phase II trials investigating pretreatment with targeted therapy for patients with primary tumors in place have been published Common end points were safety and efficacy of pretreatment. A trial of UROLOGY 78 (4),

5 bevacizumab for primary mrcc evaluated as secondary endpoint if pretreatment could be used to identify patients who may not benefit from additional CN. 27 Two trials with either sunitinib and sorafenib included metastatic and nonmetastatic patients. Hellenthal et al treated 20 patients with preoperative sunitinib at 37.5 mg for 3 cycles. 26 Although 85% experienced a reduced tumor diameter (median 11.8%; range 27-11%) none of the patients had a local PR. It has been suggested that sunitinib at 37.5 mg may result in lower response rates while maintaining similar PFS and OS outcome, athough this has never been investigated in a randomized setting. 28 The sorafenib trial included 30 patients, 13 with mrcc. After a median of 33 days of sorafenib (range 8-59 days), median decrease in primary tumor diameter was 9.6%. 25 In both trials, therapy was withdrawn up to 2 days before surgery without any surgical complications. A potential limitation of this trial is that 2 courses of sunitinib were given instead of treatment until best response. However, we recently compared early data on safety and efficacy with a group that used 3 courses of sunitinib pretreatment and we found no statistically significant difference. 29 In addition, retrospective data suggest that the most prominent size reduction is observed within 60 days. 7,8 Minor surgical complications were relatively frequent and may be related to the short interval between sunitinib and surgery. However, CN is a major intervention and wound healing impairments are common. The randomized EORTC trial will reveal a difference in complication rate and grade. CONCLUSIONS RECIST response in the primary tumor after 2 cycles of sunitinib is low. Primary tumor downsizing is limited but associated with long-term survival. Patients with RECIST progression of metastases before planned surgery have a short survival and are unlikely to benefit from CN. 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