bluuebunny/crossref_metadata_2025_split huggingface dataset:
Financial hardship among Medicare beneficiaries prescribed oral targeted therapies for advanced prostate cancer.
Authors: Caram Megan Veresh , Oerline Mary , Dusetzina Stacie , Modi Parth K. , Herrel Lindsey A. , Skolarus Ted A. , Hollenbeck Brent K. , Shahinian Vahakn B. 
Published: February 2020

68 Background: Abiraterone and enzalutamide are increasingly being used to treat advanced prostate cancer. Understanding barriers to adhering to treatment is of paramount importance in ensuring continued access to these important therapies. Patients with limited resources or insufficient access to mechanisms that lower their out-of-pocket cost are likely to suffer from significant financial toxicity and may engage in coping mechanisms such as rationing or abandoning their medication. Methods: To address the variability in measures of financial hardship, we performed a retrospective cohort study on a 20% sample of patients eligible for Medicare Part D who received their first fill of abiraterone or enzalutamide between July 2013 and June 2015. Patients were assigned to a provider based on their first prescription, and a hospital referral region (HRR) based on their ZIP code. The primary outcomes were to determine the proportion of days covered (PDC), overall prescription adherence, and average monthly out-of-pocket cost to patients prescribed abiraterone or enzalutamide, all within the first six months of treatment. Results: From mid-2013 to mid-2015, 4529 patients filled abiraterone or enzalutamide through Medicare Part D, within 305 HRRs. There was substantial variability in PDC, adherence, and out-of-pocket cost to patients among HRRs. The mean PDC was 84% with mean adherence of 73%, which included the 393 (8.7%) of patients who abandoned oral therapy after 1-2 fills. The median standard monthly out-of-pocket cost was $707, ranging between $0 and $3505. Among patients with low-income subsidies, median out-of-pocket cost by HRR ranged from $0 to $2815. We observed that PDC tracked closely with socioeconomic status – HRRs that included a higher proportion of patients eligible for Medicaid had lower PDCs and adherence, but lower standard out-of-pocket cost. Conclusions: This investigation demonstrated significant variation in PDC, adherence, and out-of-pocket cost among different HRRs for patients prescribed abiraterone and enzalutamide and that much of the variability in financial hardship measures among HRRs may be due to socioeconomic variables and regional variability.
Real-world data of cabozantinib in patients with VEGF-refractory metastatic renal cell carcinoma (mRCC): Results from the French Early Access Program (CABOREAL).
Authors: Gross-Goupil Marine , Flechon Aude , Chevreau Christine , Topart Delphine , Gravis Gwenaelle , Oudard Stephane , Tourani Jean-Marc , Geoffrois Lionnel , Meriaux Emeline , Thiery-Vuillemin Antoine , Barthelemy Philippe , Ladoire Sylvain , Laguerre Brigitte , Perrot Valérie , Billard Anais , Escudier Bernard , Albiges Laurence 
Published: February 2020

683 Background: Cabozantinib (Cabo) is approved in Europe for the treatment of mRCC in first line and after failure of tyrosine kinase inhibitors (TKI). We report the results from real-world use of Cabo in the French Early Access Program (EAP) (CABOREAL [NCT03744585]). Methods: Data were retrospectively collected from 26 centers. Patients (pts) were treated with Cabo during the Temporary Authorization for Use (ATU) period from Sep 12, 2016 to licensing in Feb 19, 2018. Pts were eligible after 2 prior VEGFR TKI unless clinical decision for 2nd line (L). The aim was to evaluate the use and activity of Cabo in real-life conditions. Overall survival (OS) was calculated from initiation of Cabo. Results: Overall, 410 pts were included. Median age was 63 years, 85% had clear-cell histology, 41% and 32% were intermediate/poor IMDC risk, respectively. Pts were mostly ECOG 1 (42%) or 2 (30%); 229 (56%) pts had bone metastasis (mets). Median follow-up was 14.4 months (m). Cabo was used as 2L, 3L and 4L or beyond for 101 (25%), 137 (33%) and 172 (41%) pts respectively; 204 pts (50%) were pretreated with nivolumab (Nivo). Activity results and dose reduction are summarized in the table. Starting dose was 60 mg (290 pts, 71%), 40 mg (109 pts, 27%) and 20 mg (8 pts, 2%). Treatment interruption occurred for 267 pts (65%), dose modification for 240 pts (59%) and schedule change for 64 pts (16%). Median daily dose was 40 mg/day. Treatment discontinuation occurred for 348 (85%) pts, with 86 (25%) due to adverse events. Notably, 184 (54%) pts received a subsequent systemic therapy. Conclusions: We report the largest real-world study of Cabo in mRCC to date. CABOREAL demonstrates that using dose modification, median Cabo duration was 7.6 m in a heavily pretreated population, with the longest treatment duration in patients with prior Nivo exposure. Clinical trial information: NCT03744585. [Table: see text]
Comparative cost-effectiveness analysis of avelumab plus axitinib versus pembrolizumab plus axitinib, ipilimumab plus nivolumab, and sunitnib for advanced renal cell carcinoma in the U.K. Perspective.
Authors: De Mello Ramon Andrade , Ayoub Emili , Castelo-Branco Pedro , De Almeida Zia Victor Andre , Savio Andre , Pozza Daniel Humberto , Tadokoro Hakaru , Teich Nelson 
Published: February 2020

689 Background: Avelulmab plus axitinib showed to improve clinical outcomes for patients with advanced renal cell carcinoma (aRCC) in the JAVELIN RENAL 101 trial. Several other immunocheckpints inihibitos (ICIs) options acquired a main role in the aRCC treatment, such as nivolumab plus ipilimumab and pembrolizumab plus axitinib. Our aim is to evaluate the cost effectiveness of avelumab/axitinib versus other FDA approved options for previously untreated patients with aRCC. Methods: A Markov model was used to estimate the costs and health outcomes of treatment of aRCC with sunitinib, or avelumab plus axitinib. Univariable and probabilistic sensitivity analyses were performed to determine the robustness of the model outcomes. The primary outputs of the model included the total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). Results: Avelumab plus axitinib provided and 4.77 additional QALY benefit. Total cost per patient was US$ 174,725 for avelumab/axitinib, US$ 178,725 for pembrolizumab/axitinib, US$ 169,390 for ipilimumab/nivolumab and US$ 97,846 for sunitnib. Avelumab/axitinib showed to be more cost-effective (ICER US$ 28,011/QALY) when compared to pembrolizumab/axitinib (ICER US$ 47,916/QALY) and ipilumumab/nivolumab (ICER US$ 95,392/QALY). Conclusions: Avelumab/axitinib is likely to be more cost-effective than ipilimumab/nivolumab, pembrolizumab/axitinib and sunitinib in the UK perspective. However further models, market discounts and stakeholders price negotiations could lead to variations of this scenario across the globe.
Phase II efficacy trial of pazopanib in nonclear cell metastatic renal cell cancer (mRCC): PINCR.
Authors: Costello Brian Addis , Ho Thai Huu , Perez Burbano Gabriela , Hillman David W. , Quevedo Fernando , Pitot Henry C. , Pagliaro Lance C. , Bryce Alan Haruo , Tan Winston , Joseph Richard Wayne , Leibovich Bradley C. , Castle Erik P. , Dronca Roxana Stefania , Kohli Manish 
Published: February 2020

696 Background: A number of treatments for metastatic renal cell carcinoma (RCC) have been FDA approved since December, 2005. Trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these treatments remains unclear in patients (pts) with metastatic non-clear cell RCC (mncRCC). Methods: This is a single arm Phase II study designed to determine the efficacy of pazopanib in mncRCC. Treatment was pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions were allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles were every 28 days. Main eligibility criteria included: (1) age ³ 18 years old; (2) histologic confirmation of ncRCC; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for mncRCC (5) measurable or non-measurable metastatic disease per RECIST criteria. The primary endpoint was overall survival rate at 12 months. Secondary endpoints were best tumor response rates after two cycles, PFS, OS and toxicity. Results: 38 pts were enrolled between May 16, 2013 and February 1, 2018. 35 pts were evaluable for primary endpoint. Median age 63 years old and 22/35 (62.9%) were male. Most common histology was papillary RCC, 14/35 (40%), and most common number of metastatic sites was 1. 29/35 (82.9%) had prior nephrectomy and 30/35 (85.7%) had no prior systemic therapy. Median number of cycles was 5. 12-month OS was 65.7% (90% CI, 50.5-78.9%). Best response in first 2 cycles: PR 11%, SD 60%, PD 9%, not evaluated 20%. Median PFS was 7.5 months (90% CI, 5.0-11.0); median OS 18.9 months (90% CI, 13.0-NE). Grade 3 / 4 AEs seen in 25 pts with hypertension, transaminitis and abdominal pain being most common (seen in >10%). Conclusions: There are limited data about the efficacy of available therapies for mncRCC. This study shows that pazopanib has similar efficacy compared to historical data in clinical trials using other TKIs in mncRCC. The safety profile of pazopanib in pts with mncRCC was found to be similar to that found in prior clinical trials studying pazopanib. Our findings warrant further investigation into the utility of pazopanib in metastatic ncRCC. Clinical trial information: NCT01767636.
Association of abiraterone and higher odds of cardiac complications compared to enzalutamide.
Authors: Cone Eugene Blanchard , Reese Stephen , Marchese Maya , Nabi Junaid , Kilbridge Kerry L. , Trinh Quoc-Dien 
Published: February 2020

70 Background: The standard of care for advanced prostate cancer is androgen deprivation therapy (ADT). The novel second generation agents abiraterone and enzalutamide were initially approved in castration resistant disease, but are now being used in the hormone sensitive setting. The FDA issued a 2010 warning about cardiovascular risks associated with ADT, but the risk of novel agents is less well understood, especially in comparison to each other. We sought to define the comparative cardiac risk profile of enzalutamide and abiraterone. Methods: We used VigiBase, the World Health Organization database of individual case safety reports, which collects data from more than 130 countries to identify drug associated adverse events (AE). Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac AEs related to abiraterone or enzalutamide therapy for prostate cancer. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: Vigibase contained 8203 AEs for abiraterone and 26024 for enzalutamide; 808 (9.9%) were cardiac-related for abiraterone, and 1000 for enzalutamide (3.8%). We found no disproportionality signal for cardiac events or any subtype for enzalutamide, but identified significantly higher odds of overall cardiac events (ROR 1.64, 95% CI 1.53—1.76), myocardial infarction (1.34, 1.17—1.58), arrythmia (2.09, 1.87—2.34), and heart failure (3.35, 2.92—3.85) for patients taking abiraterone. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of cardiac events for abiraterone but not for enzalutamide. Clinicians may need to consider these findings in the context of their patients’ comorbidities when prescribing ADT.
Impact of age in advanced renal cell carcinoma treated with immune checkpoint inhibitors.
Authors: Carretero-González Alberto , Lora David , Carril Ajuria Lucía , Martin Soberón Maria Cruz , Castellano Daniel , de Velasco Guillermo 
Published: February 2020

702 Background: Immune checkpoint inhibitors (ICIs) are beneficial in a subset of metastatic renal cell carcinoma (mRCC) patients. Elderly patients are usually under-represented in pivotal trials. Importantly, aging has been pointed as a potential detrimental factor for the benefit with ICIs as a consequence of the “immunosenescence” which could decrease the efficacy of these treatments. Methods: We assessed the potential role of aging according to Cochrane Collaboration's Guidelines. Search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care (SoC) in mRCC patients was performed. Trials must have included subgroup analysis evaluating the selected outcome (overall survival-OS-) in different subsets of patients according to age. Additionally, a retrospective series of mRCC patients treated with ICIs from our institution was also reviewed to assess the impact of age. Results: A total of 3415 patients (4 studies) were included in the meta-analysis (ICIs arm: 1709 patients; SoC arm: 1706 patients). Altogether, OS results favored ICIs. Older patients (aged more than 75 years-old) seem to present a less clear benefit with ICIs compared to SoC in comparison with younger patients (aged up to 75 years-old; p-value for difference between subgroups: 0.006) (Table). No differences between subgroups were found when considering 65 years-old as the borderline (p-value: 0.179). A similar trend was found in our series, with a numerically better median OS in patients younger than 65 years-old compared to those older than 65 years-old (31,6 vs. 23,6 months); the effect of age on outcomes was maintained along all International Metastatic RCC Database Consortium (IMDC) score subgroups. Conclusions: Elderly patients with mRCC, particularly older than 75 years-old, could benefit to a lesser extent compared to younger counterparts from receiving ICIs.[Table: see text]
Immune checkpoint inhibitors plus tyrosine kinase inhibitors combination in the first-line setting of metastatic clear cell renal cell carcinoma: A meta-analysis of randomized clinical trials.
Authors: Martin Soberón Maria Cruz , Carretero-González Alberto , de Velasco Guillermo , Carril Lucia , Castellano Daniel 
Published: February 2020

704 Background: ICIs + TKIs have shown to improve outcomes in treatment-naïve metastatic clear-cell renal cell carcinoma (ccRCC). We aimed to analize the efficacy of all combinations published including the subgroup analysis based on age, sex and IMDC prognostic factors score. Methods: We searched published RCTs in MEDLINE and EMBASE comparing ICIs + TKIs vs TKIs in 1L metastatic ccRCC. Outcomes selected to assess efficacy were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) in the intent-to-treat population. Hazard ratios (HR) for PFS and OS, and relative risk (RR) for ORR with 95% confidence intervals (CI) were used as efficacy measures. Subgroup-based meta-analysis was afterwards performed according to randomized-effect model. Results: We identified two eligible RCTs of ICIs + TKIs (avelumab [avelu] or pembrolizumab [pembro] + axitinib [axi]) versus TKIs (sunitinib). Combined sample size was 1,747 patients (avelu + axi arm 442 patients; pembro + axi arm 432 patients; sunitinib arm 873 patients). Globally, three outcomes favored the combination. Improved HRs for PFS (0.69), OS (0.64) and ORR (1.81) were found for combination (Table). Regarding subgroup analysis HRs for PFS were favorable for combination in male (0.665) and female (0.66). Benefit in combination arms was confirmed in terms of age < 65 years (0.68) and ≥ 65 years (0.66). Intermediate and poor IMDC subgroups showed statistically significant benefit for combination (HR 0.68 and 0.56), whereas PFS in favorable group (0.68) was not statistically significant. Conclusions: ICIs + TKIs combination therapy has consistently demonstrated to be superior in terms of OS, PFS and ORR in 1L ccRCC to TKIs alone. We hereby confirm statistically significant benefit per subgroups except for favorable IMDC subgroup.[Table: see text]
Improvements in first-line systemic mRCC therapy: Challenging insights from a cross trial comparison of overall survival and subsequent therapies in recent phase III trials.
Authors: Casper Jochen , Henderson Samantha , Casper Hannah , Kohne Claus-Henning 
Published: February 2020

705 Background: Using sunitinib (SUN) as the comparator, two out of three recent phase III clinical trials have shown an overall survival (OS) benefit in the alternative treatment arm (Checkmate 214 (C), Keynote 426 (K)). The Javelin 101(J) trial has yet to show a significant improvement. Methods: A cross-study comparison of OS for the sunitinib arms of C, K and J was carried out. Special focus was given to risk group stratification and subsequent therapies. Data from the SUN pivotal trial (SP) was also taken into account. Results: Across the C, K and SP trials, OS was similar at approximately 78%. Despite a lower percentage of favourable risk patients compared to K and SP, an OS of 82% was observed in J. At 18 months, OS survival curves split ranging from 65% ©, 72.1% (K) to 76% (J). OS in the SUN arm in J at 18 months was comparable to OS of Nivolumab/Ipilimumab in C (78%). The rate of subsequent therapies ranged from 34.3% (K), 39.2% (J) to 54% (C) in the SUN arms. At the time of the SP trial almost no subsequent therapy options existed. In the experimental arms, the rate of subsequent therapies was 51.8% ©, 20.5% (K) and 20.8% (J). The existing data give no clear evidence of a correlation between subsequent therapies and OS. However, an analysis of the subsequent therapies/patients discontinuing therapy ratio (ST/DIS) and type of subsequent therapy (PD1/L1 directed or therapy with proven OS benefit (pOS) in randomized trials) in the SUN arms may be more conclusive (see table). The rate of subsequent therapies (ST/DIS) as well as PD(L)1 or pOS therapies were highest in J, followed by K and C. Conclusions: Despite the difficulties of a cross trial comparison, this data should raise awareness of the influence of a more intense subsequent therapy. It points to the necessity to standardize subsequent therapies in 1st line trials if OS is a primary study aim. Given this analysis, it may be pertinent to ask if an optimal or near optimal subsequent therapy following SUN might be equal to a 1st line IO/IO therapy with regards to OS.[Table: see text]
Risk of fall and clinical fracture associated with androgen receptor inhibitors: A systematic review and meta-analysis.
Authors: Myint Zin , Momo Harry D. , Otto Danielle E. , Yan Donglin , DiPaola Robert S. , Wang Peng , Kolesar Jill 
Published: February 2020

71 Background: Patients treated with androgen receptor inhibitors (ARIs) report a higher incidence of falls; although a potential mechanism of action is unknown. This systematic review evaluates the relative risk (RR) of fall and fracture in prostate cancer (PCa) patients that receive ARIs. Methods: We conducted a comprehensive literature search using Cochrane, Scopus and MedlinePlus databases from inception through August 2019, and evaluated all published prospective phase II, III and IV randomized controlled trials that treated PCa patients with ARIs. Reported fall and fractures as adverse events (AEs) were extracted for analysis. Retrospective, phase I, non-randomized phase II, and studies with control arms that used one of the ARIs were excluded. A mixed effects model was used to estimate effects of ARI on the RR, with the included studies treated as random effects and study arms treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Results: Eleven studies met our inclusion criteria. The total population was 11,382; 6536 were in the ARI arm and 4846 in the control (CTL) arm. Study types were: 8 phase III; 2 phase II; 1 phase IV. Subjects in the ARI arm received enzalutamide, apalutamide or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations while in the CTL arm received placebo, bicalutamide or abiraterone. Treatment duration ranged from 5.4 to 20.5 mo for ARI vs. 5.4 to 18.3 mo for CTL. The reported incidence of fall was 481 (7.4%) in ARI and 201 (4.1%) for CTL. The incidence of fracture was 204 (3.1%) in ARI and 93 (1.9%) in control. The use of ARI was associated with an increased risk: all fall grades (RR 1.83; 95% CI 1.56-2.15; p <0.01); high grade fall (RR 1.69; 95% CI 1.09 – 2.62; p=0.019); all grade fracture (RR 1.56; 95% CI 1.23-1.97; p <0.01) and likely high grade fracture (RR 1.62; 95% CI 0.97 – 2.69; p=0.063). Conclusions: The use of ARI significantly increases falls and fractures in PCa patients as assessed by this meta-analysis study. Further studies would be warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.
mTOR pathway alterations in chromophobe renal cell carcinoma: Impact on metastasis development and overall survival.
Authors: Maroto Pablo , Anguera Georgia , Roldan Jose Maria , Caleiras E. , Santos M. , García-Donas Jesús , de Velasco Guillermo , Lanillos J. , Martínez AM , Calsina B. , Leton R. , Leandro-Garcia Lj , Monteagudo M. , Montero-Conde Cristina , Cascon Alberto , Robledo Mercedes , Rodríguez-Antona Cristina 
Published: February 2020

712 Background: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal cancer representing less than 5% of the kidney tumors. Molecular knowledge of this disease is limited, as well as prognostic factors for relapse if localized disease or response in the metastatic setting. Methods: From our database form different Spanish Hospitals, we identified a series of 89 chRCC with a localized stage and 3 patients stage IV at first diagnoses. We performed an in-depth characterization of mTOR pathway alterations, through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin and PTEN, and determined their impact on metastasis development and overall survival. Mutations in mitochondria and telomere maintenance genes were also assessed. TCGA kidney chromophobe project (KICH, n=64) was used for validation. Results: TP53, mTOR pathway ( MTOR, TSC2 or TSC1), telomere-related genes ( ATRX, TERT promoter or DAXX) and respiratory chain complex I, were mutated in 28%, 16%, 15% (26, 14, 12 of 87) and 15% (14 of 73) of primary tumors. PTEN and FLCN were mutated in four and three patients, respectively, two with bilateral tumors. IHC of phospho-S6 revealed positive staining in 37% of primary tumors (21 of 57), in association with MTOR, TSC2 and TSC1 mutations (P=0.009). Negative PTEN staining in 82% of cases (46 of 56) suggested PTEN loss as a chRCC characteristic, and was mutually exclusive with MTOR, TSC2 or TSC1 mutations (P=0.001). Weak or negative tuberin staining correlated with TSC2 mutations (P=0.02). Regarding metastasis development, TP53 mutations were enriched in malignant tumors (P=0.018), while telomere-related mutations showed a trend in the same direction. mTOR pathway mutations were associated with worse outcome. Overall survival in multivariable analysis adjusting for tumor stage gave a Hazard Ratio of 6.5 (P=0.009) This association was confirmed in TCGA-KICH (HR=11.9, P=0.05). Conclusions: Our study provides new genomic knowledge of chRCC and identifies novel markers of poor survival. Furthermore, we identified patients with mutations in mTOR pathway genes that showed high sensitivity to mTOR inhibitors.