Active Smoking Is Associated With Worse Prognosis in Metastatic Renal Cell Carcinoma Patients Treated With Targeted Therapies

Background

Smoking increases the risk of developing renal cell carcinoma (RCC) but the effect of tobacco consumption on survival outcome of patients with metastatic RCC (mRCC) treated with targeted therapies has not been well characterized.

Economic Burden of Metastatic Clear-Cell Renal Cell Carcinoma for French Patients Treated With Targeted Therapies

Background

Targeted therapies have transformed the treatment of metastatic clear-cell renal cell carcinoma (mccRCC). Despite the importance of mccRCC, studies on its economic burden in daily practice are sparse. The purpose of this retrospective study was to evaluate cost of illness for 224 patients with mccRCC included in the cohort published by Thiery-Vuillemin et al (Factors influencing overall survival for patients with metastatic clear-cell renal cell-carcinoma in daily practice. Clin Genitourin Cancer 2018; 16:e297-305), and then to determine the explanatory factors of cost of illness.

肾细胞癌靶向治疗研究现状

肾细胞癌被认为是最难治的恶性肿瘤之一。由于对肾细胞癌分子发病机制研究的进一步深入,在晚期肾细胞的治疗中出现了一系列成功范例。在过去20年,非特异性免疫治疗被认为是晚期肾细胞癌治疗标准。近年,随着分子靶向药物的研发和临床使用,肿瘤的分子靶向治疗已成为肿瘤治疗的研究热点,同时由于对肾细胞癌进一步了解,肾细胞癌的治疗已开始转向抗-血管内皮生长因子及其相关通路研究,大量的临床研究试验,证明了分子靶向治疗在晚期肾细胞癌的疗效,其中Sorafenib(索拉非尼)和Sunitinib(舒尼替尼)分别于2005年和2006年经美国FDA批准用于晚期肾细胞癌。本文将围绕VEGF在肾细胞癌的重要性和Bevacizumab(贝伐单抗)、Sunitinib和So-rafenib治疗晚期肾细胞癌研究进展等问题进行简要阐述。     

Clinical Trial Design in Small Cell Lung Cancer: Surrogate End Points and Statistical Evolution

BackgroundSmall-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored.Material and MethodsThrough examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS).ResultsThere was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%.ConclusionThere is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time.     

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma

BackgroundTo determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study.MethodsThe relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan–Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test.ResultsIn the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P < 0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan–Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P < 0.0001).ConclusionsA positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.     

Exposure to Multiple Lines of Treatment and Survival of Patients With Metastatic Renal Cell Carcinoma: A Real-world Analysis

Background

The purpose of the present retrospective analysis was to describe the trends in exposure to multiple lines of treatment and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who started therapy in 2 different periods (period 1, 2004-2010; and period 2, 2011-2017).

Contemporary Cytoreductive Nephrectomy Provides Survival Benefit in Clear-cell Metastatic Renal Cell Carcinoma

IntroductionA recent randomized trial questioned the role of cytoreductive nephrectomy in clear-cell metastatic renal cell carcinoma (ccmRCC). We reassessed the effect of cytoreductive nephrectomy on survival in a contemporary population-based ccmRCC cohort.Patients and MethodsWithin the Surveillance, Epidemiology, and End Results database (2010-2015), we focused on patients with ccmRCC. The primary endpoint consisted of overall mortality. Univariable and multivariable Cox regression models were applied in the overall cohort and in patients who underwent targeted therapy. Sensitivity analyses included 1:1 propensity score matching, 3- and 6-month landmark analyses, incremental survival benefit analyses, and metastases number and location-based stratifications.ResultsOf 4062 patients with ccmRCC, 2241 (55.1%) received targeted therapy; cytoreductive nephrectomy was performed in 2226 (54.8%) patients and 1168 (52.1%) patients in the overall and targeted therapy cohorts, respectively. Cytoreductive nephrectomy was associated with lower overall mortality in the overall cohort (median survival, 30 vs. 9 months; hazard ratio [HR], 0.43; P < .001), as well as in the targeted therapy cohort (median survival, 28 vs. 12 months; HR, 0.49; P < .001). In sensitivity analyses, cytoreductive nephrectomy was associated with lower overall mortality after 1:1 propensity score-matching (HR, 0.49; P < .001), in 3- and 6-month landmark analyses (HR, 0.49; P < .001 and HR, 0.51; P < .001, respectively), in metastases number and location-based stratifications, except for exclusive liver metastases, as well as in all incremental benefit analyses.ConclusionCytoreductive nephrectomy is associated with better survival in patients with ccmRCC, including those exposed to targeted therapy, after adjustment for multiple potential confounders.     

Sarcomatoid Renal Cell Carcinoma: Clinical Outcome and Survival After Treatment With Sunitinib

BackgroundRenal tumors with sarcomatoid changes are aggressive malignancies with poor prognosis. Immunotherapy and chemotherapy have provided little benefit. The efficacy of treatments targeting the vascular endothelial growth factor pathway is unclear because of the lack of clinical trial data and the small number of published series.Patients and MethodsWe reviewed the clinical records of 23 consecutive patients with advanced sarcomatoid renal cell carcinoma who were treated with sunitinib in our center. Overall survival (OS), progression-free survival, and response rate were evaluated. We also studied the effect on clinical outcome of performance status, prognostic risk group, and proportion of sarcomatoid component.ResultsMedian OS was 15.7 months (95% confidence interval [CI], 5.0-21.2). Median progression-free survival was 5.7 months (95% CI, 3.2-12.6). Seven patients (30%) had an objective response, 5 patients (22%) had stable disease, and 11 (48%) had progressive disease. The median survival of the 13 (56.5%) patients with performance status of 0 to 1 was 20.9 months (95% CI, 9.7-63.3) whereas the medial survival of the 10 (43.5%) patients with performance status of 2 to 3 was 5.0 months (95% CI, 1.1-16.5). Objective responses were observed only among the 13 (56.5%) patients with performance status of 0 to 1. Heng prognostic risk group and percentage of sarcomatoid component did not influence outcome.ConclusionSunitinib shows efficacy in advanced renal tumors with sarcomatoid differentiation particularly in patients with good performance status. Appropriate patient selection and risk-directed treatment remains essential in this aggressive disease.     

Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study

Background

About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination.

Prevalence,Disease-free,and Overall Survival of Contemporary Patients With Renal Cell Carcinoma Eligible for Adjuvant Checkpoint Inhibitor Trials

IntroductionDesigning adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk renal cell cancer (RCC) despite use of validated risk scores. Our objective is to investigate how differences in eligibility criteria may impact on potential study results in RCC adjuvant trials.Patients and MethodsRECUR is a multicenter European database capturing patient and tumor characteristics, recurrence patterns, and survival of those curatively treated for non-metastatic RCC from 2006 to 2011 without any adjuvant therapy. We used RECUR to evaluate prevalence, disease-free survival (DFS), and overall survival (OS) according to eligibility criteria of immunotherapy-based adjuvant trials IMMotion 010 (NCT03024996), Checkmate 914 (NCT03138512), Keynote-564 (NCT03142334), RAMPART (NCT03288532), and PROSPER (NCT03055013).ResultsOf 3024 relevant patients in RECUR, 408 (13.5%), 725 (24%), 609 (20.1%), 1363 (45.1%), and 1071 (35.4%) met eligibility criteria for IMMotion-010, CheckMate-914, Keynote-564, RAMPART, and PROSPER, respectively. The median and 5-year DFS Kaplan-Meier estimates in RECUR corresponding to each trial eligibility criteria were: not reached and 69.6% for RAMPART; not reached and 64.5% for PROSPER; 109.3 months (95% confidence interval [CI], 83.9-134.6 months) and 57% for CheckMate-914; 75.8 months (95% CI, 52.7-98.8 months) and 54.3% for Keynote-564; and 43.6 months (95% CI, 30.8-56.4 months) and 45% for IMMotion-010. Our analysis may be limited by the retrospective design.ConclusionsRECUR provides estimated DFS and OS benchmarks for placebo arms of adjuvant checkpoint inhibitor studies and hence likely time to trial reporting. Well-documented contemporary registries rather than past risk models should be used to design future adjuvant trials.     

First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape

Treatment paradigm for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the recent decades. From cytokines, interleukin-2 and interferon-α to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process.     

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials

Background

We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months.

Prognosis in Renal Cell Carcinoma: Analysis of Clinical Course following Nephrectomy

The clinical courses and survivals of 159 patients who underwentnephrectomy for renal cell carcinoma are reviewed. A longerdiseae-free period after nephrectomy was correlated with significantlybetter survival. Among patients in whom metastases in the lungsor bones were detected after nephrectomy, those with betweenone and five pulmonary or solitary bone metastases, wihtoutdefinite increases in their number and size in the six monthsfollowing their first appearance, survived significantly longerthan patients with a similar number of metastases but whichdid increase in number and size in the following six months,or patients with six or more pulmonary or multiple bone metastases.Even when metastases detected after nephrectomy were confinedto the lungs or bones throughout the observation period, thepatients did not necessarily show significantly better survivalsthan patients with metastases detected in multiple sites.     

The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma

Introduction

Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC.

Materials and Methods

This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry–liquid chromatography method.

Results

We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups.

Conclusion

In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC.

Implications for Practice

Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.