Metastatic Clear Cell Renal Cancer Research Articles

197 The effect of anti-VEGF tyrosine kinase inhibitors on biomarkers and tumour heterogeneity in metastatic clear cell renal cancer

197 The effect of anti-VEGF tyrosine kinase inhibitors on biomarkers and tumour heterogeneity in metastatic clear cell renal cancer

A phase Ib study exploring the combination of everolimus and dovitinib in VEGF-refractory clear cell renal cancer.

531 Background: Everolimus (mTOR inhibitor) and dovitinib (VEGF and FGF-2 inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. In this study we establish the tolerability and an early activity signal of this combination. Methods: Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalated doses of daily oral everolimus (5-10 mg PO OD) and dovitinib (200-500mg 5/7 days PO) Dose-limiting toxicities (DLTs) were assessed determine the MTD. An expansion cohort (n=15) was treated to obtain additional efficacy and safety information. Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg PO OD and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (CTC grade 1-4) of patients respectively. Frequent biochemical abnormalities occurred such as hypertrygliceridaemia in 67%. Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% CI 2.2-11 months). Conclusions: Dovitinib and everolimus had modest activity, but did not meet all of the the planned efficacy endpoints. Fatigue was the dose limiting toxicity. Clinical trial information: NCT01714765.

The effect of sunitinib on biomarkers and tumor heterogeneity in metastatic clear cell renal cancer.

408 Background: The purpose of this work was to investigate the effect of sunitinib on tumour biomarkers and assess intratumoural heterogeneity in metastatic clear cell renal cancer (mRCC). Primary tumours and metastatic sites were examined. Methods: Multiple fresh frozen tissue samples (median=4) were taken from sunitinib naive (n=23) and sunitinib treated (18 weeks at sunitinib 50mg) patients (n=27) with mRCC. Tissue was taken from the primary renal tumours. Multiple analysis of DNA (aCGH), mRNA (Illumina Beadarray) and protein lysates (reverse phase protein array) were performed on each tumour sample. Analysis of metastatic tissue occurred where possible (n=4). A cohort of matched untreated and sunitinib/pazopanib treated paraffin embedded mRCC samples from 3 clinical trials was used for validation with automated quantitative analysis. Results: Treated and untreated patient had similar patient characteristics. Significant intratumoural heterogeneity in DNA, RNA and protein occurred. Sunitinib was associated with increased intratumoural heterogeneity in protein expression (p<0.05), but not DNA or RNA. Despite this heterogeneity, significant changes to protein expression with sunitinib occurred. Four proteins changed significantly in terms of both expression and variance with sunitinib (BCL2, MLH1, CAIX and mTOR; p<0.05 for each). Elevation of CAIX expression in sunitinib treated patients was confirmed in the validation cohort (p=0.01). Low levels of CAIX correlated with poor outcome in treated samples (HR=0.26, 95% CI: 0.11-0.61, p=0.001). A positive correlation between protein expression in the primary tumour and metastatic sites occurred. Individual metastasis within patients exhibited a variable radiological response to therapy, which was equally marked in the genetically more homogeneous primary tumours. Conclusions: Intratumoural heterogeneity occurs on many levels in mRCC. Sunitinib is associated with increase in protein heterogeneity. Despite this, upregulation of CAIX is a potential prognostic biomarker.

A prospective evaluation of VEGF-targeted treatment cessation in metastatic clear cell renal cancer

BackgroundVascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach. Materials and methodsThis study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed. ResultsSixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29–13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break. ConclusionsProgression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.

Systemic Treatment Options for Untreated Patients With Metastatic Clear Cell Renal Cancer

The introduction of therapy targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapomycin (mTOR) has significantly improved the outcome of patients with metastatic renal cancer. In this article a comprehensive overview of treatment choices for previously untreated patients with metastatic disease is given. Both established and emerging therapeutic options are discussed, as are prognostic factors predicting outcome.

Effect of cholesterol and triglyceride increases on time to progression in renal clear cell cancer patients treated with everolimus.

e15528 Background: An increased level of cholesterolemia (C) and triglyceridemia (T) secondary to an impairment of lipidic metabolism is a well known side effect of all mTOR inhibitors including everolimus. In the phase III pivotal study of everolimus in mRCC patients, an increase of C and T was reported in 77 and 73 % of patients, respectively. Increase of C and T may represent a surrogate parameter related to mTOR pathway inhibition. On these basis, we assessed the value of C and T increase as a factor predicting the efficacy of everolimus in metastatic clear cell renal cancer. Methods: We retrospectively evaluated 46 patients ( 36 male: 10 female; mean age 61.4 years +/- 11.5) with metastatic clear cell renal cancer who received a second/third line with everolimus after at least one tyrosine-kinase inhibitor (TKI). From routinely performed blood test, we retrieved the value of total C and T the day before the first everolimus admnistration and during the entire duration of treatment. We also considered for each patient variations of glycemia, blood pressure and BMI before and after beginning of treatment, as parameters of metabolic syndrome. Time to progression (TTP) and survival were evaluated. Results: Among all the potential predictive factors considered, only the increase of cholesterol and triglyceride (&gt; 20% compared to the baseline) within 2 months from the start of everolimus correlated with efficacy. Median TTP of the 19 patients with total early C upraising was statistically significant higher than in 27 patients without upraising (14.1 months vs 5.5 months, P= 0.009). Conversely, only a positive trend favoring patients with C upraising was recorded in median survival (24.9 months vs 16.0 months, P= 0.163 ). Both median TTP and median survival were found to be statistically significant higher in the 25 patients experiencing T upraising than in the 21 patients who did not (respectively, 13.0 months vs 4.9 months, P= 0.007 and 26.4 months vs 13.4 months, P= 0.018). Conclusions: Early C and T modifications predict everolimus efficacy in renal clear cell cancer.

Pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer: A clinical and biomarker study.

4508 Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mRCC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting. Methods: A single arm phase II study (2009-016675-29) evaluated 12-14 weeks of pazopanib prior to planned nephrectomy in 102 untreated patients with mRCC. Patients had MSKCC intermediate (n=80) and poor risk disease (n=22). The Primary endpoint of the trial was to achieve at least a 75% clinical benefit rate (absence of disease progression) with pazopanib at the time of surgery. Sequential tissue was used for biomarker analysis (exploratory endpoint). Tissue from a previous sunitinib trials with a similar design was included for comparative purposes. Results: Overall 81% of patients obtained clinical benefit prior to surgery. The partial response rate of the primary tumor was 14% by RECIST v1.1. The median reduction in the size of the primary tumor was 14% (range 33% to - 41%). No patients became inoperable due to local progression of disease. A nephrectomy was performed in 66% of patients. The two commonest reasons for not having surgery were patient choice (9%) and progression of disease (16%). There were 2 (3%) post operative surgical death. Delayed wound healing occurred in 5%. Progression during the treatment free interval for surgery was 26%. Median PFS has not been reached. Results from biomarker analysis of sequential tissue revealed therapy resulted in a significant decrease in CD31 (-49%), PDL-1 (-31%) and pS6K (-26%), while FGF-2 (+147%), MET (+34%) and Ki-67 expression increased with therapy. Increased ki-67 and CD31 correlated with a poor outcome. Conclusions: Nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients. Biomarker analysis shows dynamic changes some of which are prognostically significant. Clinical trial information: NCT01512186.

Expression of HIF1a and HIF2a in bone metastatic clear cell renal cell cancer and use as prognostic markers.

e15523 Background: Bone metastasis is a frequent complication of ccRCC and predictors of this type of progression are scanty. The aim of this study was to analyse HIF and HIF regulated gene expressions in bone metastatic ccRCC. Methods: A pre-target therapy era cohort of 125 ccRCC patients with &lt;100 month follow-up period have been collected with paraffin embedded primary tumors. 65 patients developed bone metastasis where 45 metastases were available for analysis. RNA was isolated from FFPE tissues and gene expression of HIF1A, HIF2A as well as HIF-regulated genes GLUT1, LDH5, GAPDH, CAIX, VEGF, VEGFR2 and EPOR were measured by RT-PCR using B2M as control. Protein product of these genes was measured on TMA arrays using standardized immunohistochemistry and an image analysis program (Mirax Viewer, 3DHistech). Results: Expression of HIF1A and HIF2A was significantly increased in bone metastatic primary ccRCC tumor tissues both at mRNA and protein levels. Significant upregulation of 3 out of 7 HIF-regulated genes (VEGFR2, EPOR and LDH5) in the primary tumor tissues of bone metastatic ccRCC was proved at mRNA levels and confirmed at protein level for VEGFR2 as well. In bone metastatic tissues a significant overexpression of HIF2A and VEGF mRNA was also detected compared to the primary site. Prognostic power of the protein expression in primary tumor was found for HIF1A (p= .001), HIF2A (p = .041), and VEGFR2 (p = .001) (confirmed at mRNA levels as well) for overall survival at time of surgical removal of primary renal tumor using Kaplan-Meier method and log-rank statistics. To further test the power of HIF1A and HIF2A as prognostic factors we have performed multivariate analysis considering available clinicopathological variables (gender, Fuhrman grade, stage) and found that HIF2A protein level outperformed all other factors in the model. Conclusions: These data indicate that HIF genes are overexpressed in bone metastatic ccRCC among which HIF2A expression at mRNA and protein levels can be used as a strong independent prognostic marker.

Sequencing Systemic Therapies in Advanced RCC: Is There a Best Strategy?

There is a strong rationale for sequencing targeted therapy in metastatic clear cell renal cancer. However the timing of the switch and the best agent to switch to remains unclear. Randomized data currently are supportive of the sequence of axitinib, followed by everolimus in those patients in which first-line vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy fails. Everolimus is also justified in the second-line setting, and the overall survival data for sorafenib in VEGF TKI resistant disease is impressive. A degree of cross-resistance appears to exist between all these current agents and has resulted in a drive toward the development of new therapies with novel modes of action.

Dynamic molecular changes with VEGF targeted therapy in metastatic clear cell renal cancer.

437 Background: The purpose of this study was to investigate for specific molecular changes associated with VEGF targeted in metastatic clear cell renal cancer (mRCC). This was achieved by taking tissue before and after VEGF TKI therapy. Methods: The study combined the data from 3 similar phase II prospective studies, investigating the role of VEGF therapy (pazopanib or sunitinib) prior to planned nephrectomy in untreated mRCC. A structured treatment break occurred during the planned nephrectomy (4 weeks). Paired tumour samples before and after 12-16 weeks of pazopanib or sunitinib were collected from these studies. Histopathology assessment (Furman grade, Ki-67, vascular density [CD31]), growth factor expression [FGF-2, c-MET, S-6-protein kinase] and immune parameters (CD3, 4, 8, PDL-1, FOXP3) before and after therapy were compared. Sequential functional imaging [FDG-PET] was performed to address the relationship between the primary tumour and metastatic sites. Results: Overall 62 patients had sequential tissue taken from these 3 prospective trials. Adequate quantities of sequential tissue were available from 48 patients. Pathological examination of the matched pairs before and after VEGF TKI showed a significant increase in tumour grade, Ki-67, lymphocyte infiltrate, and necrosis (p&gt;0.05), there was also a significant decrease in CD31 (p&lt;0.05). Significant changes to FGF-2, c-MET and FOXP3 expression was seen in the treated samples (p&lt;0.05). FDG-PET results from 23 patients showed a significant correlation in the response seen in the primary renal tumour and metastatic sites with sunitinib (r=0.46 p&lt;0.001). During the structured treatment break for nephrectomy (4 weeks) 37% of patients had disease progression (RECIST v1.1) underlining the aggressive nature of the disease after VEGF TKI therapy. This was associated with an increased risk of death on multivariate analysis (HR: 3.17; 95% CI, 1.46-6.86, p&lt;0.03). Conclusions: These results suggest VEGF targeted therapy is associated with a more aggressive tumor phenotype. Changes to immune parameters and up regulation of growth factors potentially implicated in resistance to VEGF targeted therapy occurred.

The Use of Reverse Phase Protein Arrays (RPPA) to Explore Protein Expression Variation within Individual Renal Cell Cancers

Currently there is no curative treatment for metastatic clear cell renal cell cancer, the commonest variant of the disease. A key factor in this treatment resistance is thought to be the molecular complexity of the disease. Targeted therapy such as the tyrosine kinase inhibitor (TKI)-sunitinib have been utilized, but only 40% of patients will respond, with the overwhelming majority of these patients relapsing within 1 year. As such the question of intrinsic and acquired resistance in renal cell cancer patients is highly relevant. In order to study resistance to TKIs, with the ultimate goal of developing effective, personalized treatments, sequential tissue after a specific period of targeted therapy is required, an approach which had proved successful in chronic myeloid leukaemia. However the application of such a strategy in renal cell carcinoma is complicated by the high level of both inter- and intratumoral heterogeneity, which is a feature of renal cell carcinoma as well as other solid tumors. Intertumoral heterogeneity due to transcriptomic and genetic differences is well established even in patients with similar presentation, stage and grade of tumor. In addition it is clear that there is great morphological (intratumoral) heterogeneity in RCC, which is likely to represent even greater molecular heterogeneity. Detailed mapping and categorization of RCC tumors by combined morphological analysis and Fuhrman grading allows the selection of representative areas for proteomic analysis. Protein based analysis of RCC is attractive due to its widespread availability in pathology laboratories; however, its application can be problematic due to the limited availability of specific antibodies. Due to the dot blot nature of the Reverse Phase Protein Arrays (RPPA), antibody specificity must be pre-validated; as such strict quality control of antibodies used is of paramount importance. Despite this limitation the dot blot format does allow assay miniaturization, allowing for the printing of hundreds of samples onto a single nitrocellulose slide. Printed slides can then be analyzed in a similar fashion to Western analysis with the use of target specific primary antibodies and fluorescently labelled secondary antibodies, allowing for multiplexing. Differential protein expression across all the samples on a slide can then be analyzed simultaneously by comparing the relative level of fluorescence in a more cost-effective and high-throughput manner.

Sequencing Systemic Therapies in Advanced RCC: Is There a Best Strategy?

There is a strong rationale for sequencing targeted therapy in metastatic clear cell renal cancer. However the timing of the switch and the best agent to switch to remains unclear. Randomized data currently are supportive of the sequence of axitinib, followed by everolimus in those patients in which first-line vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy fails. Everolimus is also justified in the second-line setting, and the overall survival data for sorafenib in VEGF TKI resistant disease is impressive. A degree of cross-resistance appears to exist between all these current agents and has resulted in a drive toward the development of new therapies with novel modes of action.

822P - A Phase I Dose Escalation Study Investigating Dovitinib and Everolmus in Combination in Metastatic Clear Cell Renal Cancer Patients who have Previously Failed VEGF Targeted Therapy

ABSTRACT Introduction Both dovitinib and everolimus are agents used, or under investigation in patients with renal cancer refractory to VEGF targeted therapy. It is potentially attractive to use these agents in combination in patients with VEGF TKI refractory disease. Together they target mTOR, VEGF and FGF-2. The purpose of this study is to establish a dose for this combination to take forward in randomised trials. Method This phase I study (EUDRACT 2010-021250-19) followed a classic dose escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer, who had previously failed VEGF tyrosine kinase inhibitors were included. Patients received fixed doses of drug in each escalating cohort (maximum n = 6) until dose limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during the first 6 weeks of therapy. If 2 episodes of grade 3 or more toxicity occurred in a specific cohort the DLT cohort had been reached. The study has appropriate ethical approval. Assement of response and progression free survival was by RECIST v1.1 Results Patients were entered into 2 cohorts before DLT occurred (cohort 0: dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg [n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of therapy. In cohort 0 the following toxicity was identified: Lethargy grade 2 3/6 and 3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3 toxicity after the first 6 weeks of therapy included pulmonary fibrosis 1/6, lipid abnormalities 2/6. Overall 1 patient (11%) had a partial response to therapy. Of the 5 patients who did not stop therapy during the first 6 weeks due to toxicity, 3 continued for 6 months or more without progression. Conclusion The maximum tolerable dose for this combination was dovitinib 200mg and everolimus 5mg. This dose is being taken forward in an expansion cohort which will explore efficacy. Disclosure T.B. Powles: Novarits Has supplied an educational grant for this project. Advisroy role for Novratis. S. Chowdhury: Advisory role. All other authors have declared no conflicts of interest.

808P - Selecting Patients for High-Dose Interleukin-2 on the Basis of Tumour Histology

ABSTRACT Background High-Dose Interleukin-2 (HD IL2) remains an option for treatment of metastatic renal cancer. In carefully selected patients, it can produce high rates of response with many durable remissions (Shablak A et al., J Immunotherapy 2011, 34(1):107–122). There remain uncertainties about the optimal way to select patients for treatment and here we update our approach to selecting patients for HD IL2 and include the analysis of carbonic anhydrase IX(CAIX) expression which has been previously suggested to correlate with response. Methods We present the outcomes of 103 patients with “favourable histology” (less than 10% papillary features and at least one of: >50% alveolar/solid (A/S) or >50% clear cell features) treated with first-line immunotherapy (including 19 who have failed prior targeted therapy) with HD-IL2. We examine the response rate in relation to histology and CAIX expression. Results Overall the response rate was 59/103 (57%) and the CR rate is 23/103 (22% - with 4 patients in PR and continuing treatment at the time of writing). Examination of the different features in relation to response suggested that the most important features were ≥ 50% A/S pattern as only 1/5 patients who had 50% A/S pattern and >80% CAIX staining the response rate was 22/37 (59%) and the CR rate was 9/37(24% with 4 patients in PR and continuing treatment at the time of writing). Conclusions These results extend and confirm our previously reported series (of 57 patients) and the overall response rate remains around 50% and that, combined with many durable complete remissions, results in an overall median survival 55 months (for all 103 patients) with an apparent plateau of 40% long term survivors. HD-IL2 remains an attractive option for carefully selected patients with metastatic clear cell renal cancer. The most tangible benefit of HD-IL2 is the ability to achieve durable complete remissions and our series suggests the optimal histological type in which to achieve this is patients whose tumour has Disclosure All authors have declared no conflicts of interest.

An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer

BackgroundBoth sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib. MethodsTwo sequential prospective single arm phase II studies investigated either 12weeks of sunitinib (n=43) or pazopanib (n=34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800mg once daily (OD)) and sunitinib (50mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12weeks of therapy. ResultsThere was no significant difference in the overall number of toxic events (grade 1–4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p>0.05). Increased grade 2–4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11–2.56] p<0.03). Sunitinib was associated with an increased grade 2–4 mucositis (16% versus 0% p=0.02) and fatigue (42% versus 15% p=0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p=0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p<0.05). There was no difference in the occurrence of asymptomatic toxicity. ConclusionThis indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient’s choice. Further comparative data from randomised trials are awaited.

The safety and efficacy of pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer.

427 Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting. Methods: A single arm phase II study (PANTHER 2009-016675-29) evaluated 12–14 weeks of pazopanib prior to planned nephrectomy in untreated patients with metastatic clear cell renal cancer. Patients had MSKCC intermediate and poor risk disease. Pazopanibwas stopped for a minimum of 16 days during nephrectomy. FDG-PET and DCEMRI were performed on a subgroup of patients. The study follows a Simon 2 stage design and we present the results of the initial stage(n=34). Results: Overall 30 (88%) of patients obtained clinical benefit (by RECIST) prior to surgery. The partial response rate of the primary tumor was 21% by RECIST. No patients became inoperable due to local progression of disease. A nephrectomy was performed in 25 (74%) of patients. The reasons for not having surgery were patient choice (n=5) and progression of disease (n=4). Delayed wound healing, a post operative bleed and a post operative death occurred in 1patient each (4%). The median blood loss, hospital stay and surgical time were 350mls, 7 days and 180mins respectively. FDG-PET and DCE MRI responses were reported. Conclusions: This interim analysis suggest nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients.

Clinical prognostic factors associated with outcome in patients with metastatic clear-cell renal cell cancer treated with everolimus.

443 Background: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This study expanded the original everolimus study of 41 patients with metastatic clear cell renal cell cancer to 66 patients to examine outcome and clinical prognostic factors associated with outcome Methods: Patients had confirmed predominantly clear cell RCC. Everolimus was given at a dose of 10 mg daily orally without interruption (28-day cycle), with dose modifications for toxicity (graded according to National Cancer Institute Common Toxicity Criteria, version 3.0). Patients were evaluated every 2 cycles (8 weeks) using Response Evaluation Criteria in Solid Tumors (RECIST). Results: Of 66 evaluable and treated patients, 73% were male, and 45% were &gt;60. Forty-five percent had right kidney involvement, 49% left kidney involvement, and 6% had dual kidney involvement. Eighty-six percent had prior systemic therapy, and 76% of patients had at least two metastatic sites including lung (72%), liver (26%), bone (48%), lymph nodes (50%), adrenal (21%), and other (39%). Twenty-four (36%) of patients had a progression-free survival (PFS) of ≥12 months, and 40 patients (61%) had an overall survival (OS) ≥12 months. Factors most likely to have an influence on OS benefit was high LDH, alkaline phosphatase, and calcium; low hemoglobin; and prior treatment with tyrokinase inhibitors. Conclusions: Everolimus was found to have clinical benefit in patients with clear cell RCC. Clinical prognostic factors may help determine patients most likely to receive benefit from everolimus. Information regarding curves and correlation between prognostic factors and OS and PFS will be presented.

Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer

To test the hypothesis that sequential (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant. Forty-four untreated mRCC patients were enrolled into this prospective phase II study. (18)F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUV(max)) at 4 and 16 weeks with overall survival (OS). Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUV(max) = 6.8, range: <2.5-18.4). In multivariate analysis, a high SUV(max) and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36-8.45) and 3.67 (95% CI: 1.43-9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40-1.99) or OS (HR for responders = 0.80; 95% CI: 0.34-1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43-19.02) and HR = 12.13 (95% CI: 3.72-46.45), respectively]. Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant.

The Outcome of Patients Treated with Sunitinib Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer

BackgroundThe role of cytoreductive nephrectomy in metastatic clear cell renal cell carcinoma (ccRCC) is controversial. ObjectiveTo determine the outcome of patients with metastatic ccRCC who receive sunitinib prior to planned nephrectomy. Design, setting, and participantsThe study combined the data from two prospective phase 2 studies that assessed upfront sunitinib (12–16 wk) prior to nephrectomy in previously untreated patients with metastatic renal cell carcinoma (RCC). Sunitinib was discontinued during the perioperative period (median: 29 d). InterventionSunitinib 50mg in six weekly cycles (4 wk on, 2 wk off). MeasurementsProgression-free (PFS) and overall survival (OS) using the Kaplan-Meier method. Results and limitationsTwenty-one patients (32%) had Memorial Sloan-Kettering Cancer Centre (MSKCC) poor-risk disease; 45 (68%) had intermediate-risk disease. Nephrectomy was not performed in 19 (29%), most commonly due to disease progression (n=12). The PFS for the cohort was 6.3 mo (95% confidence interval [CI], 5.1–8.5). Seventeen (36%) patients progressed during the treatment break, 13 (76%) of whom stabilised upon reinitiating of sunitinib. The OS for the cohort was 15.2 mo (95% CI, 10.3–NA). The OS for the intermediate MSKCC risk group was significantly longer than that for the poor-risk group (26.0 mo [95% CI, 13.6–NA] and 9.0 mo [95% CI, 5.8–20.5], respectively; p<0.01). In multivariate analysis, progression of disease prior to planned nephrectomy (hazard ratio [HR]: 5.34; 95% CI, 3.17–13.27), high Fuhrman grade (HR 3.27; 95% CI, 1.38–7.72), and MSKCC poor risk at diagnosis (HR 4.75; 95% CI, 2.05–11.02) were associated with short survival (p<0.01). However, in the absence of randomised studies it is not possible to determine if this approach is beneficial. ConclusionsUpfront sunitinib prior to planned nephrectomy in intermediate-risk disease is associated with a median survival of >2 yr despite frequent progression during treatment break. Progression in metastatic sites prior to planned surgery and MSKCC poor-risk disease was associated with a poor outcome.

The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer

BackgroundThe safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. MethodsTwo prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC. ResultsOverall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%-35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien–Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90–4200) ml and 189 (70–420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6–15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy. ConclusionsNephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.