Ronit Simantov

Change in Neutrophil-to-lymphocyte Ratio in Response to Targeted Therapy for Metastatic Renal Cell Carcinoma as a Prognosticator and Biomarker of Efficacy

BACKGROUNDnNeutrophil-to-lymphocyte ratio (NLR), if elevated, is associated with worse outcomes in several malignancies.nnnOBJECTIVEnInvestigation of NLR at baseline and during therapy for metastatic renal cell carcinoma.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective analysis of 1199 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC cohort) and 4350 patients from 12 prospective randomized trials (validation cohort).nnnINTERVENTIONnTargeted therapies for metastatic renal cell carcinoma.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnNLR was examined at baseline and 6 (± 2) wk later. A landmark analysis at 8 wk was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate using Cox or logistic regression models, adjusted for variables in IMDC score and NLR values at baseline.nnnRESULTS AND LIMITATIONSnHigher NLR at baseline was associated with shorter OS and PFS (Hazard Ratios [HR] per 1 unit increase in log-transformed NLR = 1.69 [95% confidence interval {CI} = 1.46-1.95] and 1.30 [95% CI = 1.15-1.48], respectively). Compared with no change (decrease < 25% to increase < 25%, reference), increase NLR at Week 6 by 25-50% and > 75% was associated with poor OS (HR=1.55 [95% CI=1.10-2.18] and 2.31 [95% CI=1.64-3.25], respectively), poor PFS (HR=1.46 [95% CI=1.04-2.03], 1.76 [95% CI=1.23-2.52], respectively), and reduced objective response rate (odds ratios = 0.77 [95% CI=0.37-1.63] and 0.24 [95% CI=0.08-0.72], respectively). By contrast, a decrease of 25-50% was associated with improved outcomes. Findings were confirmed in the validation cohort. The study is limited by its retrospective design.nnnCONCLUSIONSnCompared with no change, early decline of NLR is associated with favorable outcomes, whereas an increase is associated with worse outcomes.nnnPATIENT SUMMARYnWe found that the proportion of immune cells in the blood is of prognostic value, namely that a decrease of the proportion of neutrophils-to-lymphocytes is associated with more favorable outcomes while an increase had the opposite effect.

Angiotensin System Inhibitors and Survival Outcomes in Patients with Metastatic Renal Cell Carcinoma

Purpose: The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. Experimental Design: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan–Meier method. Results: A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus. Conclusions: In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice. Clin Cancer Res; 21(11); 2471–9. ©2015 AACR.

Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma.

BACKGROUNDnResponse remains an important endpoint in clinical cancer trials. However, the prognostic utility of best tumor response in metastatic renal cell carcinoma (mRCC) remains vague.nnnOBJECTIVEnTo define the prognostic relevance of the depth of remission in mRCC.nnnDESIGN, SETTING, AND PARTICIPANTSnPooled data from the Pfizer database for 2749 patients from phase 2 and 3 clinical trials in mRCC were analyzed. Tumor shrinkage was categorized according to the best percentage change in the sum of the largest diameter of target lesions. Outcome was computed using Kaplan-Meier curves and correlation was assessed via Cox regression, including a 6-mo landmark.nnnINTERVENTIONnSunitinib, sorafenib, axitinib, temsirolimus, or temsirolimus and interferon-α.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnCategorized tumor shrinkage, overall survival (OS), progression free survival (PFS).nnnRESULTS AND LIMITATIONSnMajor tumor shrinkage of 60% or more occurred in approximately 10% of patients and was associated with median OS of 54.5 mo. OS expectations steadily decreased with depth of remission (26.4, 16.6, 10.4, and 7.3 mo). The association was maintained when stratified by type of therapy, line of therapy, and performance status. Cox proportional regression analyses for the 6-mo landmark confirmed the prognostic relevance of major tumor shrinkage (hazard ratio 0.29, 95% confidence interval 0.22-0.39; p<0.001). The major limitation of our study is the variability of imaging intervals among studies.nnnCONCLUSIONSnThis is the first and largest analysis of best tumor response in mRCC. We demonstrate that depth of remission is an independent prognostic factor in mRCC.nnnPATIENT SUMMARYnIt remains unknown whether tumor shrinkage during therapy is needed to achieve clinical activity in metastatic renal cell carcinoma. Our analysis shows that the magnitude of tumor shrinkage correlates with better survival in patients. This observation may be used as a clinical research tool in future trials.nnnTRIAL REGISTRATIONnNCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00083889, NCT00065468, NCT00678392.

Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma

BACKGROUNDnBone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.nnnOBJECTIVEnThe purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.nnnDESIGN, SETTING, AND PARTICIPANTSnWe conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnStatistical analyses were performed using Cox regression and the Kaplan-Meier method.nnnRESULTS AND LIMITATIONSnWe identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively.nnnCONCLUSIONSnWe confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity.nnnPATIENT SUMMARYnIn this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.

Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations.

PURPOSEnObesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC.nnnMETHODSnThe impact of BMI (high BMI: ≥ 25 kg/m2 v low BMI: < 25 kg/m2) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors.nnnRESULTSnIn the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015).nnnCONCLUSIONnHigh BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.

Estimation of tumour regression and growth rates during treatment in patients with advanced prostate cancer: a retrospective analysis

BACKGROUNDnWe applied mathematical models to clinical trial data available at Project Data Sphere LLC (Cary, NC, USA), a non-profit universal access data-sharing warehouse. Our aim was to assess the rates of cancer growth and regression using the comparator groups of eight randomised clinical trials that enrolled patients with metastatic castration-resistant prostate cancer.nnnMETHODSnIn this retrospective analysis, we used data from eight randomised clinical trials with metastatic castration-resistant prostate cancer to estimate the growth (g) and regression (d) rates of disease burden over time. Rates were obtained by applying mathematical models to prostate-specific antigen levels as the representation of tumour quantity. Rates were compared between study interventions (prednisone, mitoxantrone, and docetaxel) and off-treatment data when on-study treatment had been discontinued to understand disease behaviour during treatment and after discontinuation. Growth (g) was examined for association with a traditional endpoint (overall survival) and for its potential use as an endpoint to reduce sample size in clinical trials.nnnFINDINGSnEstimates for g, d, or both were obtained in 2353 (88%) of 2678 patients with data available for analysis; g differentiated docetaxel (a US Food and Drug Administration-approved therapy) from prednisone and mitoxantrone and was predictive of overall survival in a landmark analysis at 8 months. A simulated sample size analysis, in which g was used as the endpoint, compared docetaxel data with mitoxantrone data and showed that small sample sizes were sufficient to achieve 80% power (16, 47, and 25 patients, respectively, in the three docetaxel comparator groups). Similar results were found when the mitoxantrone data were compared with the prednisone data (41, 39, and 41 patients in the three mitoxantrone comparator groups). Finally, after discontinuation of docetaxel therapy, median tumour growth (g) increased by nearly five times.nnnINTERPRETATIONnThe application of mathematical models to existing clinical data allowed estimation of rates of growth and regression that provided new insights in metastatic castration-resistant prostate cancer. The availability of clinical data through initiatives such as Project Data Sphere, when combined with innovative modelling techniques, could greatly enhance our understanding of how cancer responds to treatment, and accelerate the productivity of clinical development programmes.nnnFUNDINGnNone.

Early Tumour Shrinkage: A Tool for the Detection of Early Clinical Activity in Metastatic Renal Cell Carcinoma

BACKGROUNDnThe predictive role of objective remission remains undefined for targeted agents in metastatic renal cell carcinoma (mRCC); however, early tumour shrinkage (eTS) was shown to be predictive and/or prognostic for overall survival (OS) and progression-free survival (PFS) in mRCC in several small studies.nnnOBJECTIVEnTo evaluate the degree of eTS following systemic therapy that may predict survival in mRCC.nnnDESIGN, SETTING, AND PARTICIPANTSnData from 4334 patients with mRCC in phase 2 and 3 clinical trials between 2003 and 2013 were pooled for analyses. Early tumour shrinkage was assessed based on percentage change in sum of the longest diameters of target lesions at first postbaseline scan. Patients were categorised by a more or equal versus less optimal threshold of eTS, assessed using receiver operating characteristic (ROC) analysis. OS and PFS in patients with eTS were summarised using the Kaplan-Meier method.nnnINTERVENTIONnAxitinib, bevacizumab, interferon α, sorafenib, sunitinib, or temsirolimus.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnWe measured optimal thresholds of eTS and eTS as a predictor of OS or PFS.nnnRESULTS AND LIMITATIONSnOptimal threshold of eTS for the prediction of OS and PFS was determined to be approximately 10%. In Cox proportional hazards models, compared with patients without eTS, those with eTS had significantly longer OS (hazard ratio [HR]: 0.615; p<0.0001; median: 28.5 vs 16.0 mo) and PFS (HR: 0.628; p<0.0001; median: 10.5 vs 5.3 mo). The major limitation was the retrospective nature of our analysis, including different lines and types of therapy, although subset analyses detected a similar predictive pattern for eTS across all lines and types of therapy.nnnCONCLUSIONSnEarly tumour shrinkage ≥10% at first postbaseline assessment could serve as a putative early end point in patients with mRCC. A prospective evaluation of eTS in clinical trials is warranted.nnnPATIENT SUMMARYnEarly tumour shrinkage may be used to identify patients with metastatic renal cell carcinoma who would benefit from treatment with antitumour agents.nnnTRIAL REGISTRATIONnThe clinical trials are registered on ClinicalTrials.gov (NCT00267748, NCT00338884, NCT00835978, NCT00065468, NCT00083889, NCT00631371, NCT00920816, NCT00077974, NCT00137423, NCT00054886, NCT00678392, and NCT00474786).

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BACKGROUNDnA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.nnnPATIENTS AND METHODSnWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan-Meier method.nnnRESULTSnWe identified 4736 patients treated with sunitinib (n=1059), sorafenib (n=772), axitinib (n=896), temsirolimus (n=457), temsirolimus+interferon (IFN)-α (n=208), bevacizumab+temsirolimus (n=393), bevacizumab+IFN-α (n=391) or IFN-α (n=560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659-0.972, p=0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584-0.961, p=0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445-0.972, p=0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703-2.275, p=0.410). Adverse events were similar between users and non-users.nnnCONCLUSIONSnWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.

Comprehensive Analysis of Survival Outcomes in Non–Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials

Micro‐Abstract Non–clear cell RCC comprises a heterogeneous group of patients underrepresented in clinical trials. Overall, the median overall survival is shorter in non–clear cell versus clear cell RCC patients. Subsets of non–clear cell RCC patients might have outcomes similar to those of clear cell RCC patients. Prospective studies exploring current and novel agents in this patient population are warranted. Background: Clinical data from patients with non–clear cell renal cell carcinoma (nccRCC) receiving targeted therapy are limited, and many clinical trials have excluded these patients from study entry. We sought to investigate the outcomes of patients with nccRCC treated in clinical trials in the modern era compared with the outcomes of patients with clear cell RCC (ccRCC). Patients and Methods: We conducted a retrospective study of patients with metastatic RCC who had received targeted therapy in Pfizer‐sponsored phase II and III clinical trials from 2003 to 2013. Associations between the histologic type and treatment outcome (overall survival [OS] and progression‐free survival [PFS]) were assessed using the log‐rank test on univariate analysis or the Wald χ2 test from Cox regression on multivariable analysis, adjusted for baseline characteristics, including age, sex, Eastern Cooperative Oncology Group performance status, body mass index, International Metastatic RCC Database Consortium risk factors, previous nephrectomy, previous therapy, metastatic sites, angiotensin system inhibitor use, and statin use. Results: We identified 4527 patients with metastatic RCC: 4235 with ccRCC and 337 with nccRCC. Overall, the median OS was shorter for those with nccRCC than for those with ccRCC (15.7 vs. 20.2 months; hazard ratio [HR], 1.41; 95% confidence interval 1.22‐1.63; P < .001). When stratified by the International Metastatic RCC Database Consortium risk group, the median OS was inferior for the intermediate‐ and poor‐risk patients with nccRCC than for those with ccRCC. However, no differences were found in the favorable risk group for nccRCC versus ccRCC. The patients with nccRCC who had received vascular endothelial growth factor‐targeted therapy had shorter PFS compared with that of ccRCC patients (median, 6.1 vs. 8.5 months; HR, 1.49; P < .001) but similar PFS when treated with mammalian target of rapamycin inhibitors (median, 4.3 vs. 4.4 months; HR, 0.92; P = .63). Conclusion: Our findings have confirmed that patients with nccRCC are underrepresented in clinical trials and highlight the need for further prospective studies exploring current and novel agents for this patient population.

Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.

Micro‐Abstract Using data from 6 prospective clinical trials of sunitinib for metastatic renal cell carcinoma, we characterized the heterogeneity of patients identified as having an intermediate prognosis using the Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium risk models. In this group, the number of risk factors and Eastern Cooperative Oncology Group performance status might predict the outcome with sunitinib therapy. Background: The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models categorize patients with 1 or 2 risk factors as intermediate prognosis (INTMP). This category encompasses 15 and 19 permutations of the MSKCC and IMDC risk factors, respectively. The purpose of the present retrospective analysis of data from INTMP patients in 6 clinical trials was to determine whether this heterogeneity influences the response to sunitinib. Patients and Methods: Patients with INTMP metastatic renal cell carcinoma (mRCC) were identified using the MSKCC and IMDC classifications. The statistical data were analyzed using Cox regression analysis, Kaplan‐Meier methods, and Pearson χ2 tests. Results: The patient characteristics and risk factors were similar in the MSKCC (n = 548) and IMDC (n = 517) groups. Overall, 59% had 1 risk factor and 41% had 2 risk factors. The most common was low hemoglobin alone or with an interval of < 1 year since diagnosis. In both groups, patients with 1 risk factor had longer overall survival (OS) and progression‐free survival (PFS) than did those with 2 risk factors (P < .001 for both outcomes). Patients in the IMDC group with 1 risk factor had a greater objective response rate (ORR; P = .023). In both groups, OS was longer for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 than for those with ECOG PS 1 or 2 (P < .001). An ECOG PS of 0 was also associated with superior PFS and ORR in the MSKCC group (P < .05). Conclusion: INTMP comprises a heterogeneous group of mRCC patients in whom the number of risk factors and ECOG PS might predict the outcome with sunitinib.