Brenda Dickow

Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma

PURPOSE In April 2009, an expert group of 11 physicians and clinical nurses met to discuss the management of selected adverse events associated with the use of everolimus for the treatment of metastatic renal cell carcinoma (mRCC). Everolimus is an orally administered inhibitor of the mammalian target of rapamycin that recently received approval from the European Medicines Agency for the treatment of advanced RCC that has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy, and from the United States Food and Drug Administration for treatment of advanced RCC after failure of sorafenib or sunitinib. Before the approval of everolimus, no standard therapy existed for the treatment of mRCC after failure of VEGF-targeted therapy. RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) was the pivotal multicenter, phase III, randomised, double-blind, placebo-controlled trial of everolimus that led to approval for patients with disease progression on or after treatment with VEGF-targeted agents. Safety data from RECORD-1 were reviewed by these clinicians, all of whom had experience using everolimus in patients with mRCC. Adverse events discussed were non-infectious pneumonitis, infections, stomatitis and metabolic abnormalities. RESULTS The outcome of this discussion is summarised here. Guidance for management of these adverse events is provided. Both clinicians and patients should be aware of the potential side-effects of everolimus and understand that these side-effects are manageable with standard care to optimise patient benefit.

The Effect of Targeted Therapy on Overall Survival in Advanced Renal Cancer: A Study of the National Surveillance Epidemiology and End Results Registry Database

INTRODUCTION With the advent and availability of targeted therapy, the treatment of advanced/metastatic renal cell carcinoma (RCC) underwent a drastic change in 2005. The effect of this change on clinical outcome within the population has not been studied. The aim of this study was to evaluate the overall survival (OS), before, and after availability of targeted therapy, for advanced RCC cases in the population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry. MATERIALS AND METHODS All advanced (regional and distant stage) RCC cases diagnosed within the 2000 to 2008 time periods were included. Because SEER does not report the exact therapy, and because targeted therapy was initially approved in 2005, we evaluated and compared the OS outcomes of advanced RCC cases diagnosed between the years 2000 and 2003 (before targeted therapy era) with that of those diagnosed between 2005 and 2008 (targeted therapy era). RESULTS There was a significant improvement in OS for advanced RCC patients treated in the targeted therapy era (n = 12,330) compared with those treated in the era before targeted therapy (n =11,565) (median OS 20 months vs. 15 months, P = .0006). Multivariate analysis revealed that in the time period before targeted therapy, age older than 65 years, black race, and lack of nephrectomy were predictors of a shorter OS. CONCLUSION In univariate and multivariate analysis, targeted therapy demonstrated improvement in OS. Increasing access to targeted therapies is likely to improve outcomes in advanced RCC.

Safety and efficacy of molecularly targeted agents in patients with metastatic kidney cancer with renal dysfunction.

Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and the efficacy of these agents in patients with renal insufficiency (RI). This is clinically relevant, especially as about one-third of patients with mRCC have renal dysfunction. The primary objective was to assess the safety and efficacy of targeted agents in patients with mRCC with RI. Medical records of patients with mRCC at Wayne State University, started on sunitinib, temsirolimus, everolimus, or bevacizumab, were reviewed. Patients with a calculated creatinine clearance of less than or equal to 60 ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function. RI was observed in 33% of our patients with mRCC. The incidence of toxicities, responses, time to progression, and overall survival were not significantly different in patients with RI compared with patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with mammalian target of rapamycin inhibitors, than did patients with normal renal function. In conclusion, RI was commonly observed in our patients with mRCC. Molecularly targeted agents are well tolerated, and efficacy seems to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for patients receiving sunitinib and bevacizumab.

Phase II trial of bevacizumab and satraplatin in docetaxel-pretreated metastatic castrate-resistant prostate cancer.

BACKGROUND Satraplatin is an oral platinum compound that has demonstrated efficacy and tolerability in prostate cancer. Preclinical synergy between bevacizumab and platinum has been noted. METHODS Docetaxel-pretreated metastatic castrate-resistant prostate cancer patients with disease progression were eligible. Satraplatin 80 mg/m(2) orally on days 1 to 5, prednisone 5mg twice daily, and bevacizumab 10mg/kg on day 1, and 15 mg/kg on day 15 were administered in 35-day cycles. RESULTS Thirty one patients were enrolled. Grade 3 or 4 toxicities were pulmonary embolism in 2 patients and thrombocytopenia in 1 patient. 31% of the patients had a ≥ 30% decline in prostate-specific antigen. Median time to progression was 7.0 months (90% confidence interval [CI] 4.7-8.5mo) and median overall survival was 11.2 months (90% CI 9.1-16.4 mo). Polymorphism in the excision repair cross-complementation-1 (ERCC-1) gene was associated with time to progression (hazard ratio = 1.91). A circulating tumor cell count ≥ 5 was moderately prognostic of overall survival (hazard ratio = 1.49) as compared with CTC <5. CONCLUSIONS The combination was tolerable, and revealed promising efficacy in metastatic castrate-resistant prostate cancer. ERCC1 genotype maybe predictive of clinical benefit with platinum-based therapy in metastatic prostate cancer.

Phase II Trial of Capecitabine and Weekly Docetaxel for Metastatic Castrate Resistant Prostate Cancer

PURPOSE Synergy is observed with the combination of capecitabine and docetaxel due to docetaxel mediated up-regulation of thymidine phosphorylase. A phase II trial was performed with the combination for metastatic, castrate resistant prostate cancer. MATERIALS AND METHODS Eligible patients had metastatic, castrate resistant prostate cancer, no prior chemotherapy for metastatic disease and normal organ function. Docetaxel (36 mg/m(2) per week intravenously) on days 1, 8 and 15, and capecitabine (1,250 mg/m(2) per day in 2 divided doses) on days 5 to 18 were administered in 28-day cycles. The response was assessed every 2 cycles. Biomarker correlative studies were performed on blood dihydropyrimidine dehydrogenase, and the thymidine phosphorylase-to-dihydropyrimidine dehydrogenase and thymidine synthase-to-dihydropyrimidine dehydrogenase ratios in available prostate tumor tissue. RESULTS A total of 30 patients with a median age of 69 years were enrolled in the study. We noted bone pain in 21 patients (70%), Gleason score 8 or higher in 18 (60%), measurable disease progression in 9, bone scan progression in 18 and prostate specific antigen progression in 22. Grade 3 or 4 neutropenia was seen in 3 patients and grade 3 hand-foot syndrome was found in 2. No treatment related deaths occurred. A prostate specific antigen response of 50% or greater decrease was observed in 22 patients (73%), of whom 9 (30%) had 90% or greater decrease. A partial response was noted in 5 of 9 patients (56%) with measurable disease. Median time to progression was 6.7 months (90% CI 4.2-7.7) and median overall survival was 22.0 months (90% CI 18.4-25.3). CONCLUSIONS The combination was well tolerated and it demonstrated favorable response rates with durable remission and survival outcomes.

Additional file 1: Table S1. of Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy

Univariable logistic and Cox regression analyses for RR, PFS, and OS. Table S2. Univariable and multivariable logistic and Cox regression analyses of risk factors associated with RR, PFS, and OS. Note ‘Pretherapy NLR’ is grouped by its median of 3.2. Table S3. Univariable and multivariable logistic and Cox regression analyses of risk factors associated with RR, PFS, and OS. Note ‘Pretherapy NLR’ is considered as a continuous variable. Table S4. Univariable and multivariable Cox regression analyses of risk factors associated with PFS. Note that two variables ‘Duration of prior anti-VEGF Therapies’ and ‘Pretherapy NLR (with the cutoff value of 3)’ are combined. Table S5. Univariable and multivariable Cox regression analyses of risk factors associated with PFS. Note that two variables ‘Duration of prior anti-VEGF Therapies’ and ‘Pretherapy NLR (with the cutoff value of 3.2 [median])’ are combined. Figure S1. The boxplot of pretherapy NLR by the duration of prior anti-VEGF therapies. The p-value is calculated using the Kruskal. (DOCX 38 kb)

Multiplexed tissue protein assay to predict patient response to targeted therapy in advanced renal cell carcinoma.

382 Background: Although a number of prognostic biomarkers have been explored in advanced renal cancer, to date none have been useful in therapeutic outcome prediction. METHODS Following regulatory approval, formalin-fixed paraffin embedded pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The samples were analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Two panels of 9 protein biomarkers each were used to probe tissue sections for proteins along the mTOR and/or the VEGFR/PDGFR signaling pathways. Biomarker expression in regions of cancer were scored and levels correlated with the patients clinical outcome status. RESULTS Tissue samples of 30 pts treated with sunitinib were analyzed and scored in a blinded fashion using 4 biomarkers. If the sum of the scores assigned to VEGFA, VEGF2 and HIF2alpha was above 19, pt was predicted to be a responder. If initial score < 19 and the sum of VEGFR2 and VEGFB was 2 or more, the pt was predicted to have an objective response (OR)/stable disease (SD). If score < 2 the pt was predicted to have no benefit from sunitinib. 14 of 15 OR/SD pts and 11 of 15 with progressive disease (PD) were accurately predicted. 35 cases treated with mTOR inhibitor were analyzed. 6 biomarkers in the mTOR pathway were used to create a composite score. 11/14 OR/SD pts (sensitivity 79%) and 18/21 PD pts (specificity 86%) were accurately predicted using a score cutoff of 10. Median time to treatment failure (TTF) was 2 months in the PD pts, as compared to 11 months in the OR/SD group. A subgroup analysis of patients followed for 18 months or less showed linear correlation between the biomarkers and the TTF (Spearman correlation coefficient 0.43 with p value 0.04). Statistical modeling, results of ongoing validation testing, and score correlation with TTF will be presented. CONCLUSIONS These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information, to help guide therapy. FUNDING SOURCE Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by 20/20 gene systems.

Phase II trial of combination therapy with intravenous carboplatin (C) and oral everolimus (EVE) and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trial Consortium study.

156 Background: Platinum based therapies have demonstrated efficacy in DP mCRPC. EVE demonstrated preclinical efficacy in chemotherapy resistant prostate cancer models. Clinical synergy was noted between C and EVE, hence a phase II trial of the combination was conducted. METHODS Primary endpoint was time to progression (TTP). Progression was defined per RECIST criteria for measurable disease (MD), or skeletal event, or > 2 new areas of bone metastases. DP mCRPC patients with adequate renal and liver function, and performance status of 0 or 1 were eligible. Intravenous C at target AUC of 5 on day 1, and oral EVE 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), correlation of TTP and PSA response, with markers such as phopho mTOR, pAKT, p70S6 and circulating tumor cells (CTC). RESULTS 26 patients (pts) enrolled, including 8 African Americans, and accrual is complete. Median age was 69 years (range 54-86). Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) had bone pain. Gleason score was > 8 in 18 pts. 19 pts had measurable disease of which 15 had MD progression, 18 had bone scan progression, and 2 had PSA-only progression. 124 cycles have been administered; median 3 cycles (range 1 - 16). The predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. Of 26 pts who are response evaluable, 4 (15%) had a > 30% PSA decline and 1 had a >90% PSA decline. Of 19 pts with MD, 8 had stable disease and no objective responses were observed. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Correlative studies including pharmacokinetic and pharmacodynamic evaluations are ongoing, and will be reported. CONCLUSIONS The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluation may help identify a subset likely to benefit from mTOR inhibition strategy in mCRPC. CLINICAL TRIAL INFORMATION NCT01051570.