Role and relevance of quality indicators in the selection of first-line treatment of patients with metastatic renal cell carcinoma: a position paper of the MeetURO Group.

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

Cost analysis for different sequential treatment regimens for metastatic renal cell carcinoma in China.

PURPOSE: Targeted therapies, including sunitinib, sorafenib, axitinib, and everolimus, have recently become the mainstay for the treatment of metastatic renal cell carcinoma (mRCC). The objective of this study was to estimate the costs of sequential treatment regimens for mRCC and associated adverse events (AEs) from the Chinese payers' perspective. METHODS: Key inputs included in the calculation were patient population, dosing information, incidence rates and associated costs of Grade 3/4 AEs, treatment costs (including drug discount programs), and patients' progression-free survival (PFS) as a proxy for length of treatment. To calculate PFS, this study identified pivotal clinical trials and generated a reconstructed individual patient data set from the published Kaplan-Meier survival curves. The median PFS from the pooled estimates were used in the calculation. In the base-case scenario, sunitinib was used as first line and the other three therapies were used as second line. Sensitivity analyses were conducted where (1) sorafenib was used as first line, or (2) a third-line therapy was added to the base-case scenario. RESULTS: In the base case, the cost per patient per treatment month (PPPM) cost was the lowest for sunitinib + axitinib among all sequential regimens (¥14,898) and was the highest for sunitinib + sorafenib (¥20,103). If sorafenib is used as first line, everolimus had lower per patient per months (PPPM) cost than axitinib (¥17,046 vs ¥23,337), but also had shorter PFS (13.5 months vs 15 months). Second sensitivity analysis with an additional third-line therapy showed consistent results with the base-case scenario; axitinib as second line was the least costly. CONCLUSIONS: This study demonstrates that, for mRCC sequential treatment, sunitinib followed by axitinib generates the highest cost savings from the Chinese payers' perspective. Future studies are warranted to examine the cost-effectiveness of various mRCC treatment regimens in Chinese populations.

Proton Pump Inhibitors and Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma.

INTRODUCTION: Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and can affect the optimal absorption of concomitant oral medications, such as vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs). The purpose of this study was to investigate the effect of PPI use on survival in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. MATERIALS AND METHODS: We conducted a pooled analysis of mRCC patients treated in phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 2188 patients treated with sunitinib (n = 952), axitinib (n = 626) or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users showed similar overall survival compared with non-PPI users (hazard ratio [HR], 1.051; 95% confidence interval [CI], 0.769-1.438; P = .754; median, 24.1 vs. 21.3 months). Similarly, progression-free survival (HR, 1.016; 95% CI, 0.793-1.301; P = .902; median, 5.5 vs. 8.0 months) and objective response rates (23.3% vs. 27.4%; P = .344) were not different between PPI users and nonusers. These findings were consistent across International mRCC Database Consortium risk groups and according to line of therapy. Adverse events were similar between PPI users and nonusers. CONCLUSION: We showed that PPI use does not appear to negatively affect the efficacy and safety of select VEGF-TKIs in patients with mRCC. Documentation of concomitant medications and patient education on potential drug interactions are critical for optimizing the use of oral cancer-targeting therapy.

A Rapid Identification Method for Calamine Using Near-Infrared Spectroscopy Based on Multi-Reference Correlation Coefficient Method and Back Propagation Artificial Neural Network.

As a mineral, the traditional Chinese medicine calamine has a similar shape to many other minerals. Investigations of commercially available calamine samples have shown that there are many fake and inferior calamine goods sold on the market. The conventional identification method for calamine is complicated, therefore as a result of the large scale of calamine samples, a rapid identification method is needed. To establish a qualitative model using near-infrared (NIR) spectroscopy for rapid identification of various calamine samples, large quantities of calamine samples including crude products, counterfeits and processed products were collected and correctly identified using the physicochemical and powder X-ray diffraction method. The NIR spectroscopy method was used to analyze these samples by combining the multi-reference correlation coefficient (MRCC) method and the error back propagation artificial neural network algorithm (BP-ANN), so as to realize the qualitative identification of calamine samples. The accuracy rate of the model based on NIR and MRCC methods was 85%; in addition, the model, which took comprehensive multiple factors into consideration, can be used to identify crude calamine products, its counterfeits and processed products. Furthermore, by in-putting the correlation coefficients of multiple references as the spectral feature data of samples into BP-ANN, a BP-ANN model of qualitative identification was established, of which the accuracy rate was increased to 95%. The MRCC method can be used as a NIR-based method in the process of BP-ANN modeling.

Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy.

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.

Is there still a role for sorafenib in metastatic renal cell carcinoma? A systematic review and meta-analysis of the effectiveness of sorafenib over other targeted agents.

BACKGROUND: The treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib was the first TA to report a benefit in terms of PFS in this disease, and it has largely been used as a comparator in randomized trials. We tested its activity compared to other TAs by performing a systematic review and meta-analysis. METHODS: MEDLINE/PubMed, the Cochrane library, and the ASCO university websites were searched for randomized phase II or III trials that compared other TAs to sorafenib in mRCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The measured outcomes were progression free survival (PFS), overall survival (OS), and the overall response rate (ORR). Sub-analyses were performed for MSKCC prognostic groups and lines of therapy. RESULTS: A total of 3094 patients were evaluable for PFS. Other TAs significantly reduce the risk of progression compared to sorafenib (HR=0.78; 95% CI, 0.72-0.85; p<0.001). This difference remains significant in patients in a good prognostic group with respect to both first- (HR=0.61; 95%CI, 0.44-0.85; p=0.003) and second-line therapy (HR=0.58; 95% CI, 0.42-0.79; p<0.001). No significant differences were, however, found in patients with an intermediate prognosis in terms of both first- (HR=0.80; 95% CI, 0.60-1.00; p=0.05) and second-line treatment (HR=0.89; 95% CI, 0.73-1.07; p=0.21). In 2922 patients evaluable for OS, no significant difference was found between other TAs and sorafenib (HR=1.07; 95% CI, 0.97-1.18; p=0.18). A benefit was also not identified when the analysis was limited to patients treated with first or subsequent lines of therapy or in patients previously treated with sunitinib. Significant differences were found in terms of the ORR in the 2963 evaluable patients favoring other TAs (RR=1.48; 95% CI, 1.24-1.76; p<0.001). This difference remain significant when a sub-analysis was performed per line of therapy. CONCLUSIONS: Other TAs improve PFS but not OS when compared to sorafenib. The use of sorafenib in patients with an intermediate prognosis, especially in second-line therapy, does not have a detrimental effect on PFS and might be an option for certain patients.

Sorafenib: 10 years after the first pivotal trial.

Sorafenib is an oral multikinase inhibitor with anticancer activity against a wide spectrum of cancers. It is currently approved for the treatment of patients with hepatocellular carcinoma, advanced renal cell carcinoma or progressive, locally advanced or metastatic differentiated thyroid carcinoma. In this review, we present a number of studies that investigated the efficacy and safety of sorafenib in these settings. We also discuss the perspectives on the use of this molecule, including the role of sorafenib as comparator for the development of new drugs, the combination of sorafenib with additional therapies (such as transarterial chemoembolization for hepatocellular carcinoma) and the use of this treatment in several other advanced refractory solid tumors.

Efficacy of targeted therapy for metastatic renal cell carcinoma in the elderly patient population.

INTRODUCTION/BACKGROUND: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. PATIENTS AND METHODS: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. RESULTS: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those ≥ 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. CONCLUSION: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.

Tumor growth rate provides useful information to evaluate sorafenib and everolimus treatment in metastatic renal cell carcinoma patients: an integrated analysis of the TARGET and RECORD phase 3 trial data.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST) criteria may not be sufficient to evaluate the response of targeted therapies in metastatic renal cell carcinoma (mRCC). The tumor growth rate (TGR) incorporates the time between evaluations and may be adequate. OBJECTIVE: To determine how TGR is modified along the treatment sequence and is associated with outcome in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: Medical records from all patients prospectively treated at Gustave Roussy (IGR) in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) (sorafenib vs placebo, n=84) and the RECORD (everolimus vs placebo, n=43) phase 3 trials were analyzed. TGR was computed across clinically relevant periods: BEFORE treatment introduction (wash-out), UNDER (first cycle), at PROGRESSION (last cycle) and AFTER treatment discontinuation (washout). The association between TGR and outcome (overall survival [OS] and progression-free survival [PFS]) was computed in the entire TARGET cohort (n=903). INTERVENTION: Sorafenib, everolimus, or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: TGR, RECIST, OS, and PFS rates. RESULTS AND LIMITATIONS: Although nearly all the patients (IGR) were classified as stable disease (RECIST) after the first cycle, the great majority of the patients exhibited a decrease in TGR UNDER compared with BEFORE (sorafenib: p<0.00001; everolimus: p<0.00001). In sorafenib-treated but not in everolimus-treated patients (IGR), TGR at PROGRESSION (last cycle) was still lower than TGR BEFORE (washout) (p=0.012), while TGR AFTER progression (washout) was higher than TGR at PROGRESSION (last cycle) (p=0.0012). Higher TGR (first cycle) was associated with worse PFS (hazard ratio [HR]: 3.61; 95% confidence interval [CI], 2.45-5.34) and worse OS (HR: 4.69; 95% CI, 1.54-14.39), independently from the Motzer score and from the treatment arm in the entire TARGET cohort. CONCLUSIONS: Computing TGR in mRCC patients is simple and provides clinically useful information for mRCC patients: (1) TGR is independently associated with prognosis (PFS, OS), (2) TGR allows for a subtle and quantitative characterization of drug activity at the first evaluation, and (3) TGR reveals clear drug-specific profiles at progression.